Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Si:16]([O:23][CH2:24][C:25]1([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[O:30][C:29]2[CH:31]=[CH:32][C:33]([N+:35]([O-:37])=[O:36])=[CH:34][C:28]=2[NH:27][C:26]1=O)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[N-:48]=[N+:49]=[N-:50].[Na+]>CC#N>[Si:41]([O:40][CH2:39][C:25]1([CH2:24][O:23][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:30][C:29]2[CH:31]=[CH:32][C:33]([N+:35]([O-:37])=[O:36])=[CH:34][C:28]=2[N:27]2[N:48]=[N:49][N:50]=[C:26]12)([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:43])[CH3:42]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2-n2nnnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
Trifluoromethanesulfonic anhydride (650 μL, 3.9 mmol) was added dropwise over 5 min to a stirred solution of 2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.62 g, 1.3 mmol) and NaN3 (0.50 g, 7.7 mmol) in MeCN (15 mL) at −10° C. (ice/MeOH bath) under nitrogen. The mixture was allowed to warm to room temperature slowly, then stirred at room temperature overnight. The mixture was then re-cooled to −10° C. and quenched by the addition of cold EtOAc (30 mL) followed by cold saturated NaHCO3 (30 mL) [note: saturated NaHCO3 solution was added over ca. 5 min]. Further EtOAc (50 mL) and H2O (30 mL) was added and the aqueous and organic layers were partitioned. The organic layer was dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded on to silica gel and then purified by column chromatography on silica gel using hexane/DCM as eluent (1:0 to 0:1) to give the product (320 mg, 49% yield).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([CH3:29])=[CH:31][CH:32]=3)[O:16]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC[C@@H]2CC[C@H](n3cnc4c(NCC5CC5)ncnc43)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.295 g, 1.0 mmoles), 4-dimethylaminopyridine (20 mg, 0.2 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. p-Methylbenzoyl chloride (1.08 mL, 7.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was suspended in ethyl acetate and undissolved salts were removed by filtration. The filtrate was concentrated and applied to preparative silica gel plates (20×20×0.2 cm). The plates were developed in a mixture of chloroform:acetone (95:5). The product was scraped from the preparative plate and eluted from the silica gel with ethanol. The product was further purified by flash chromatography on a silica gel column (2.5×40 cm) with a mixture of chloroform:methanol (98:2). Lyophilization afforded 0.330 g of 6-(cyclopropylmethylamino)-9-[(2R,5S)-5-[(p-methylbenzoyloxy)-methyl]-tetrahydro-2-furyl]-9H-purine as an oil (78% yield).
Reaction SMILES: O.O.[C:3]([OH:8])(=O)[C:4](O)=[O:5].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1.C(O)C.Cl>O>[OH:5][C:4]1[C:3]([OH:8])=[N:16][C:11]2[C:12](=[CH:13][CH:14]=[C:9]([CH3:17])[CH:10]=2)[N:15]=1
Reactant: O=C(O)C(=O)O
Reactant: Cc1ccc(N)c(N)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2nc(O)c(O)nc2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of oxalic acid dihydrate (20 g), 3,4-toluenediamine (20 g), ethanol (60 ml), conc. hydrochloric acid (20 ml) and water (50 ml) was refluxed for 5 hours. After cooling to room temperature, the precipitate was removed by filtration, washed with water and dried to yield 27.1g of 2,3-dihydroxy-6-methylquinoxaline, mp> 300° C. Phosgene was bubbled through a mixture of 27.1 g of the 2,3-dihydroxy compound in 200 ml of p-xylene and 5 ml of DMF at 120° C. The solution was degassed with nitrogen, clarified and the solvent flash evaporated to yield 26.2 g of 2,3-dichloro-6-methylquinoxaline, mp 112°-115° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C.[C].[Pd]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1=CC(c2ccccc2)Oc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc(C2CCc3ccccc3O2)cc1

Procedure:
The flav-3-ene was catalytically hydrogenated in acetic acid (60 ml) using 10% palladium carbon catalyst (150 mg) at room temperature and a atmospheric pressure. 750 ml hydrogen was absorbed over 3 hr. The reaction mixture was filtered, diluted with water, extracted with toluene, and the evaporated extract chromatographed on neutral alumina, eluting with toluene. The product was recrystallised from ethanol yielding flavan (2.75 g) m.pt. 43°-44° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14]2)(=O)=O)=CC=1.[C-:24]#[N:25].[K+].O>CS(C)=O>[C:24]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14]1)#[N:25]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCC1CCc2ccccc2O1
Reaction time: 2 h

Procedure:
A mixture of 15.8 g (47 mmol) of 2-p-toluenesulfonyloxyethyl-3,4-dihydro-2H-1-benzopyran and 3.4 g (52 mmol) of potassium cyanide in 320 ml of dimethyl sulfoxide is stirred for 2 hours. After addition of water, the product is extracted with chloroform containing a little methanol and then the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using cyclohexane containing 10% ethyl acetate, 7.8 g of compound are obtained in oil form.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[C:8]([CH3:16])=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=1[CH3:12])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.Cl.[CH:52]([N:55]1[CH2:60][CH2:59][CH:58]([NH2:61])[CH2:57][CH2:56]1)([CH3:54])[CH3:53]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][C:7]1[C:8]([CH3:16])=[C:9]([C:13](=[O:15])[NH:61][CH:58]2[CH2:59][CH2:60][N:55]([CH:52]([CH3:54])[CH3:53])[CH2:56][CH2:57]2)[NH:10][C:11]=1[CH3:12]
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)O)c1C
Reactant: CC(C)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1c(C)[nH]c(C(=O)NC2CCN(C(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.6 %

Procedure:
263 mg of (1.17 mmol) 4-(2-methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid were dissolved in DMF (10 mL). 488.4 mg (1.28 mmol) of HATU and DIEA (224 μl) were added and the resulting mixture was stirred for 45 minutes at RT. A solution of 276.3 mg (1.28 mmol) of 1-isopropyl-piperidine-4-ylamine-dihydrochloride and 448 μl of DIEA was added. The reaction mixture was stirred over night after which it was concentrated. The residue was diluted with DCM and washed with a saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4 and concentrated. Preparative HPLC(CH3CN/H2O gradient+0.05% formic acid) gave pure 3-[5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid methyl ester (166 mg) as a colorless amorphous material. MS (ESI+): m/e=351 [M+H]+.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:17]=1)([O-:5])=[O:4].I[CH3:19]>CN(C=O)C>[CH3:19][N:15]1[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:17][C:10]=2[CH2:11][CH2:12][CH2:13][C:14]1=[O:16]
Reactant: CI
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h
Yield: 33.4 %

Procedure:
202 mg of NaH (50%) are added to a solution of 771 mg of 7-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 20 ml of DMF. The reaction medium is stirred for 15 minutes and then 583 mg of iodomethane are added. The mixture is stirred for 4 hours at ambient temperature and then run into ice-cold water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a heptane/ethyl acetate (80/20 to 50/50) mixture. 275 mg of 1-methyl-7-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19]Cl)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:30][CH2:31]2)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)nc2ccccc2c1OCc1ccccc1
Reactant: CCCCCC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(=O)N1CCN(Cc2nc3ccccc3c(OCc3ccccc3)c2C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (200 mg), 1-hexanoylpiperazin (130 mg), potassium carbonate (111 mg), and DMF (6 mL) was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 4-(benzyloxy)-2-[(4-hexanoylpiperazin-1-yl)methyl]-3-methylquinoline (241 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13]([N:15]2[CH2:20][CH:19]=[CH:18][CH2:17][CH:16]2[C:21](O)=[O:22])=[O:14])=[C:4]([F:24])[CH:3]=1>C(O)C.Cl>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:21](=[O:22])[CH:16]3[CH2:17][CH:18]=[CH:19][CH2:20][N:15]3[C:13]2=[O:14])=[C:4]([F:24])[CH:3]=1
Reactant: CC(C)Oc1cc(NC(=O)N2CC=CCC2C(=O)O)c(F)cc1Cl
Agent: Cl
Solvent: CCO
Product: CC(C)Oc1cc(N2C(=O)C3CC=CCN3C2=O)c(F)cc1Cl

Procedure:
The solution of 1,43 g (0,004 moles) of 1[[(4-chloro-2-fluoro-5-isopropoxyphenyl)amino]carbonyl]-1,2,3,6-tetrahydro-2-pyridinecarboxylic acid in 20 ml of ethanol and 20 ml of 2N HCl is boiled under reflux for 4 hours. Rotevaporation of the reaction solution furnishes the title compound as a faintly yellow syrup, which is homogeneous by TLC (Rf=0,35 on silica gel with ethyl acetate-hexane 1:1) when visualized with a 1% KMnO4 solution.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[N:7]#[C:8][NH2:9].[ClH:10].O1CCOCC1>CCOCC>[ClH:10].[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:8](=[NH:7])[NH2:9])[CH:6]=1
Reactant: Cc1cn[nH]c1
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cnn(C(=N)N)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 4-Methyl-1H-pyrazole (4.9 g, 60 mmol) was added cyanamide (2.5 g, 60 mmol), HCl (5.6 mL, 62 mmol, 4 M in dioxane) and dioxane (60 mL). The reaction was heated to 110° C. and aged for 9 h. It was then aged at rt overnight. The mixture was diluted with Et2O and stirred for 10 min. The product was isolated by filtration and washed with Et2O to afford the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[CH:17][CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:20][C:21]1[C:29]2[C:28](Cl)=[N:27][CH:26]=[N:25][C:24]=2[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[Br:20][C:21]1[C:29]2[C:28]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[CH:17][CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])=[N:27][CH:26]=[N:25][C:24]=2[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=1
Reactant: C[C@H](N)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1c(Br)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 72 %

Procedure:
(S)-2-(1-Aminoethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (370 mg, 1.46 mmol) was treated with 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (793 mg, 2.19 mmol), cesium fluoride (120 mg, 0.79 mmol), N,N-diisopropylethylamine (2.3 ml, 13.20 mol) and tert-butanol (10 ml) as a solvent according to Preparation 13. The residue was purified using SP1® Purification System (0% to 35%, hexane-ethyl acetate) to give 0.61 g (72% yield) of the title compound. Purity 100%.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1>>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)[C:12]=2[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: CCCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: c1nc[nH]n1
Product: CCCCCC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 3, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxyquinoline was reacted with 1H-1,2,4-triazole to give 4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 151°-152° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([C:13]([F:16])([F:15])[F:14])CC[O:10]2)[CH:3]=1.F[C:18]1[CH:23]=CC(O)=C(C(O)C(F)(F)F)[CH:19]=1.C1(O)C=CC=CC=1.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>>[F:16][C:13]([F:14])([F:15])[C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:23][CH:18]=[CH2:19])=[O:10]
Reactant: Oc1ccc(F)cc1C(O)C(F)(F)F
Reactant: Oc1ccc(F)cc1C1(C(F)(F)F)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: Oc1ccccc1
Product: C=CCOc1ccc(F)cc1C(=O)C(F)(F)F

Procedure:
Synthesis of the requisite 4-fluoro-2-[2-(trifluoromethyl)oxetan-2-yl]phenol may be carried out from 4-fluoro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (see J. Zhang et al., Synth. Commun. 2011, 41, 3045-3052). Selective alkylation of the phenol, using allyl bromide and a base such as potassium carbonate, followed by a Swern oxidation of the benzylic alcohol, provides 2,2,2-trifluoro-1-[5-fluoro-2-(prop-2-en-1-yloxy)phenyl]ethanone. This material was reacted with trimethylsulfoxonium iodide and potassium tert-butoxide to afford 2-[5-fluoro-2-(prop-2-en-1-yloxy)phenyl]-2-(trifluoromethyl)oxetane; the allyl group was removed using tetrakis(triphenylphosphine)palladium(0) and morpholine.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].C([O-])([O-])=O.[K+].[K+]>>[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH:12][C:16](=[O:17])[CH2:15][Cl:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCl)NCC(=O)OCc1ccccc1

Procedure:
DOTA-G-tri-t-butyl ester 4, an intermediate compound in the synthesis of the conjugate 22, was synthesized starting with glycine benzylester hydrochloride (Aldrich), as described in Scheme 1. Chloroacetylchloride (Aldrich) was added to glycine benzylester hydrochloride in the presence of K2CO3 to produce N-(chloroacetyl)-glycine benzyl ester 1. The ester 1 was added to a suspension of DO3A-tri-t-butyl ester hydrochloride 2 (see U.S. Pat. No. 5,573,752) in K2CO3 to produce DOTA-G-tri-t-butyl-benzyl ester 3. Subsequent catalytic hydrogenation produced the DOTA-G-tri-t-butyl ester 4.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:7]=[N:6][CH:5]=[N:4]1.CCN(CC)CC.[C:22]([O:26][C:27](ONC(C1C=CC=CC=1)C#N)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[N:3]1([CH2:8][CH:9]2[NH:10][CH2:11][CH2:12][N:13]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:14]2)[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: c1ncn(CC2CNCCN2)n1
Reactant: CC(C)(C)OC(=O)ONC(C#N)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCNC(Cn2cncn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a suspension of 2-(1H-1,2,4-triazol-1-ylmethyl)piperazine dihydrochloride (104 mg, 0.39 mmol) and Et3N (157.7 mg, 1.56 mmol) in CH2Cl2 (3 ml) was added [{[(tert-butoxy-carbonyl)oxy]amino}(cyano)methyl]benzene (106.5 mg, 0.43 mmol). The mixture was stirred for 2 hours at room temperature. The solvent was evaporated in vacuo, and the residue was purified by column chromatography on silica gel (MeOH/CHCl3= 1/50- 1/10) to give tert-butyl 3-(1H-1,2,4-triazol-1-ylmethyl)-1-piperazinecarboxylate (50.9 mg, 48.9%): HPLC-MS (ESI): Calcd for C, H20N6O2 [M+H]+ 268, found: 268.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=[C:11]([N+:12]([O-])=O)[C:6]=2[N:5]=[CH:4]1)[CH3:2]>CO.O.[Pd]>[NH2:12][C:11]1[C:6]2[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[C:7]=2[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=1
Reactant: CCn1cnc2c([N+](=O)[O-])cc(C(=O)OC)cc21
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCn1cnc2c(N)cc(C(=O)OC)cc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of methyl 1-ethyl-4-nitro-1H-benzimidazole-6-carboxylate (D206) (700 mg, 2.81 mmol, 1 equiv) in MeOH (50 ml) and H2O (5 ml) was added 10% palladium on charcoal (50% wet, 400 mg, 28% w/w) and NH4COOH (1.77 g, 28.1 mmol, 10 equiv) and the resulting mixture was stirred at 70° C. for 30 min then cooled to room temperature. The catalyst was filtered off through a pad of celite and most of the MeOH was removed in vacuo. The residue was diluted with AcOEt and the organic layer was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give methyl 4-amino-1-ethyl-1H-benzimidazole-6-carboxylate (D207) (500 mg, 81%) as a white solid which was used in the next step without further purification. [M+H]+=220.2, RT=2.17 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+].CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH3:9])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cncc(Br)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of 3,5-dibromopyridine (134a, 20 g, 84.4 mmol) in DMF (200 mL) was stirred at RT under nitrogen atmosphere and then 21.3 mL of sodium methoxide (25% by wt. in methanol (92.8 mmol) was added slowly. The reaction mixture was stirred overnight at 70° C. under N2. The reaction was cooled to RT and quenched with water (200 mL) and extracted with Et2O (2×200 mL). The combined organic extracts was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude 3-bromo-5-methoxypyridine (134b 14.8 g, 93% theory) afforded a colorless oil after purification by flash chromatography on silica gel (EtOAc:hexane 1:10).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N:7]2.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:37])([CH3:36])[CH2:27][C:28]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH:29]=O)[CH:25]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:36])([CH3:37])[CH2:27][C:28]([C:31]([F:33])([F:34])[F:32])([OH:35])[CH:29]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:7]3)[CH:25]=1
Reactant: Nc1cccc2nc(CN3CCOCC3)ccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(CN3CCOCC3)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 180 mg (0.74 mmol) of 5-amino-2-(morpholin-4-ylmethyl)quinoline is reacted with 274 mg (0.89 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 0.8 ml of concentrated acetic acid and 20 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0-100%), 220 mg (56% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]1[CH:3]([C:4]([NH2:6])=[NH:5])[CH2:2]1.Cl.[CH2:8]([O:10][C:11](=[O:19])[C:12](=O)/[CH:13]=[CH:14]/OCC)[CH3:9].[O-]CC.[Na+]>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[CH:13]=[CH:14][N:6]=[C:4]([CH:3]2[CH2:2][CH2:1]2)[N:5]=1)=[O:19])[CH3:9]
Reactant: CCO/C=C/C(=O)C(=O)OCC
Reactant: N=C(N)C1CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccnc(C2CC2)n1
Yield: 45.9 %

Procedure:
Reference: Riley, T. A.; Hennen, W. J.; Dalley, N. K.; Wilson, B. E.; J. Heterocyclic Chem., 1987, 24, 955-964. Heat a mixture of cyclopropylcarbamidine hydrochloride (2.05 g, 17 mmol), (E)-4-ethoxy-2-oxo-but-3-enoic acid ethyl ester (4.39 g, 25.5 mmol), ethanol (12 mL), and sodium ethoxide (1.16 g, 17 mmol) in a microwave at 140° C. for 20 min. Concentrate the reaction mixture under reduced pressure and partition the residue between ethyl acetate and brine. Separate the organic layer and concentrate under reduced pressure. Purify the residue by silica gel chromatography (10-30% ethyl acetate/hexane) to give 2-cyclopropyl-pyrimidine-4-carboxylic acid ethyl ester (1.5 g, 46%) as light yellow oil. MS (m/z): 193.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](Cl)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
880 mg of 4-methoxyphenol was dissolved in 10 ml of N,N-dimethylformamide. 790 mg of potassium t-butoxide was added thereto. Then, 1.7 g of 4-benzyloxy-2-nitro-chlorobenzene was added thereto. The mixture was stirred for 1 hour at 110°-120° C. The reaction mixture was introduced into a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: toluene) to obtain 1.92 g of 5-benzyloxy-2-(4-methoxyphenoxy)nitrobenzene.