Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:25][CH2:24]4)[CH:21]=[N:20][C:19]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:33])(=[O:8])=[O:7])([CH3:5])[CH3:4]>C(Cl)(Cl)Cl>[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:24][CH2:25]4)[C:21]([Br:1])=[N:20][C:19]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:33])(=[O:8])=[O:7])([CH3:5])[CH3:4]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)ncn3C3CC3)cc21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4F)nc(Br)n3C3CC3)cc21
Reaction time: 18 h
Yield: 78.1 %

Procedure:
Add bromine (0.34 mL, 6.545 mmol) dropwise over 5 minutes to a solution of 1-isopropylsulfonyl-2-amino-6-(1-(cyclopropyl)-4-(2-fluorophenyl)-imidazol-5-yl)-benzimidazole (2.61 g, 5.95 mmol) in chloroform (0.7 L) and stir for 18 hours. Wash with water, saturated sodium bicarbonate, dry with magnesium sulfate, filter and remove solvents under reduced pressure. Purify the residue on silica gel eluting with ethyl acetate/dichloromethane mixtures to provide the title compound (2.41 g). MS(ES+): m/z=518.0 (M+H)+
Reaction SMILES: COC(=O)[C@@H](C1C=CC=[CH:8][C:7]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)O.C(C(C(C([O-])=O)O)O)([O-])=[O:27].[Na+].[K+]>C1(C)C=CC=CC=1>[C:19]1([C@@H:7]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:8][OH:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: COC(=O)[C@H](O)C1C=CC=CC1(OC1CCCCO1)c1ccccc1
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OC[C@H](OC1CCCCO1)c1ccccc1
Reaction time: 1 h

Procedure:
Into toluene (15 ml) was added (R)-2-phenyl-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)mandelic acid methyl ester (7.0 g) obtained in 2) above, and thereto was dropwise added a 70% sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution (8.73 g) with ice cooling. The resulting mixture was stirred at the same temperature for 1 hour, the reaction mixture was added into a 30% aqueous (+)−potassium sodium tartrate solution (31.3 g), then stirred for 1 hour, and the organic layer was separated. The organic layer obtained was washed with water and further with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was distilled off to obtain a colorless oily compound mentioned above (6.10 g, 97.9%).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl[C:11]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)[C:14]([Cl:31])=[CH:13][N:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[Cl:31][C:14]1[C:15]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)=[N:16][C:11]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=2)=[N:12][CH:13]=1
Reactant: CC(C)n1cc(N)cn1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of 1-isopropylpyrazol-4-amine (0.083 g, 0.66 mmol), 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.110 g, 0.327 mmol) and TsOH.H2O (0.013 g, 0.066 mmol) in 1,4-dioxane (2.0 mL) was heated in the microwave to 100° C. for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (0-100% EtOAc in petroleum benzine 40-60° C. then 0-10% MeOH in EtOAc) to give the title compound 30 (0.094 g, 68%). LCMS-D: rt 3.355 min; m/z 425.3 [M+H]+.
Reaction SMILES: Cl[Si:2](Cl)([CH2:5][CH3:6])[CH2:3][CH3:4].[CH:8]([F:11])([F:10])[F:9].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>>[CH2:3]([Si:2]([CH2:5][CH3:6])([C:8]([F:11])([F:10])[F:9])[C:8]([F:11])([F:10])[F:9])[CH3:4]
Reactant: FC(F)F
Reactant: CC[Si](Cl)(Cl)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CC[Si](CC)(C(F)(F)F)C(F)(F)F
Yield: 44 %

Procedure:
A similar procedure to the one reported in EXAMPLE 2 was followed except dichlorodiethylsilane (5.12 g, 32.5 mmol, 1 eq) was used as the substrate along with 2eq each of CF3H and KHMDS to obtain pure diethyl bis(trifluoromethyl)silane 3.2 g, 44% yield. 1H NMR (400 MHz): δ 1.08 (m, CH2), 1.16 (m, CH3); 13C NMR (100.5 MHz): δ-1.10 (s, CH2), 5.55 (s, CH3), 128.6 (qq, 1JC—F=319 Hz, 3.35 Hz, CF3); 19F NMR (376.3 MHz): δ-60.2 (s); 29Si NMR (79.5 MHz): δ-2.43 (sept, 2JSi—F=39.4 Hz, 1 Si).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.O1CCCC1>[O:9]=[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][N:3]1[NH:2][C:18](=[O:19])[O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN1CCCNC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(NN1CCCNC1=O)OCc1ccccc1

Procedure:
3-Aminotetrahydro-2(1H)-pyrimidinone, monohydrochloride (30 g, 0.198 mol) was dissolved in a mixture of 240 ml water and 200 ml tetrahydrofuran. The pH was adjusted to 8.5 and benzylchloroformate (33.8 g, 0.198 mmol) was added dropwise while keeping the pH between 8 and 9. After the pH remained constant, the mixture was stirred for an additional hour. The tetrahydrofuran was removed in vacuo and the resulting crystals were filtered off with suction, triturated with ether and dried in vacuo. Yield 35.6 g, melting point 161°-163° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C1COCC1>[CH3:14][S:15]([O:1][CH:2]1[CH2:3][N:4]([C:6](=[O:7])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccccc1)N1CC(O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A stirred solution of (3-hydroxyazetidin-1-yl)(phenyl)methanone (13.5 g, 76.2 mmol), methanesulfonyl chloride (12.6 g, 110 mmol) and triethylamine (12.3 g, 121 mmol) in THF (300 ml) was heated at 50° C. for 3 h. Then, the reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration. The filtrate was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 to 80:20, ethyl acetate/heptane) provided 1-benzoylazetidin-3-yl methanesulfonate (12.8 g, 66%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[O:47]=[C:48]([NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=1)[CH2:49][CH2:50][C:51](O)=[O:52]>C1COCC1>[O:52]=[C:51]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:50][CH2:49][C:48]([NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:63])([F:64])[F:65])[CH:57]=1)=[O:47]
Reactant: c1csc(C2NCCc3ccccc32)c1
Reactant: O=C(O)CCC(=O)NCc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)N1CCc2ccccc2C1c1cccs1)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
236 mg (1.1 mmol) of 1-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline, 380 mg (1.0 mmol) of HATU and 263 μl (1.9 mmol) of NEt3 were added in succession to a solution of 275 mg (1.0 mmol) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid (intermediate VVV01) in THF (8 ml) and the mixture was then stirred for 24 h at RT. Then it was diluted with EE (30 ml) and washed twice with a 4M aqueous NH4Cl solution and with a 1M aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated to small volume under vacuum. Column chromatography (EE) of the residue produced 410 mg (0.87 mmol, 87%) of 4-oxo-4-(1-thien-2-yl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric acid amide. MS: m/z 473.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O)C.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>Cl.O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[C:14]1[C:13]([CH:12]=[O:19])=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:2]
Reactant: O=Cc1ccccc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=Cc1ccccc1-c1c(O)cccc1O

Procedure:
To a solution of 550 g. of resorcinol in 1 l. of ethanol were added 530 g. of benzaldehyde and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated under reflux for 90 minutes with stirring and, after completion of the reaction, the reaction mixture was poured into 5 l. of a cold water to give a pale brown powdery resin.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH:13]=1)[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[N+:17]([O-])([OH:19])=[O:18].C(OCC)(=O)C.O>S(=O)(=O)(O)O>[N+:14]([C:5]1[CH:4]=[C:3]([N+:17]([O-:19])=[O:18])[C:2]([F:1])=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])([O-:16])=[O:15]
Reactant: COC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 14.5 g (63 mmol) methyl 5-fluoro-2-nitrophenoxyacetate in 17 ml conc. sulfuric acid (H2SO4) at 8° C. was added slowly via an addition funnel a mixture of 5.0 ml (76 mmol) of 70% nitric acid and 5.0 ml of conc. H2SO4. After addition was complete, the reaction was stirred an additional 1 hour at 15° C. The reaction mixture was poured into 150 ml of 1:1 ethyl acetate/water and the resulting layers were separated. The aqueous phase was extracted with ethyl acetate (2×60 ml) and the combined organics were dried (Na2SO4) and concentrated in vacuo to give 17.2 g (98% yield) of the desired nitrated product as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[N:13]=[C:14]([CH3:17])[NH:15][CH:16]=2)[CH:7]=[CH:6][N:5]=1.[CH3:18]I.O>C1COCC1>[CH3:18][N:15]1[CH:16]=[C:12]([C:11]#[C:10][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[CH:9]=2)[N:13]=[C:14]1[CH3:17]
Reactant: CI
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#Cc2cn(C)c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (76 mg, 55%, 1.57 mmol) was suspended in 2 mL of dry THF. A solution of 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.76 mmol) in 8 mL of dry THF was added and the reaction mixture was stirred at room temperature for 30 min. A solution of methyliodide (142 mg, 1.00 mmol) in 1 mL of dry THF was added and stirring was continued overnight. The reaction mixture was poured into 70 mL of water and extracted three times with ethyl acetate (70 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient) and a mixture of two regioisomers was obtained. This mixture could be separated by HPLC (chiralpak AD, heptane/ethanol 4/1) and the desired compound was obtained as a white solid (40 mg, 25%), MS: m/e=212.2 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[CH2:10][C:11]([OH:13])=[O:12].O>C1(C)C=CC=CC=1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:10][C:11]([OH:13])=[O:12]
Reactant: OCC(F)(F)F
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)COCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
To a 3-neck 2-liter round-bottom flask equipped with a mechanical stirrer, reflux condenser and addition funnel was added sodium hydride (60% dispersion in mineral oil) (41.70 g, 1.043 moles) and 1000 ml of toluene under nitrogen. 2,2,2-Trifluoroethanol (52.02 g, 0.520 moles) was added dropwise and this mixture was stirred at room temperature for 0.5 hours. A solution of bromoacetic acid (72.45 g, 0.520 moles) in 100 ml of toluene was then added dropwise and the resulting mixture heated at reflux for 48 hours. After cooling the mixture to room temperature, water (250 ml) was added and the layers separated. The aqueous layer was washed with ether (3×75 ml) and then acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was extracted with ether (3×100 ml) and the combined extracts washed with saturated sodium chloride solution (1×75 ml), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Distillation of this oil gave 31.6 g of the product as a colorless oil, bp 110°-118° C./16 mm.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1>>[CH3:8][C:7]1[C:2]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)=[N:3][CH:4]=[N:5][C:6]=1[CH3:9]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1ncnc(Cl)c1C
Product: Cc1ncnc(Nc2ccc(C(F)(F)F)cc2)c1C
Yield: 15 %

Procedure:
To 4.3 g (0.03 mole) of 4-chloro-5,6-dimethylpyrimidine were added 4.8 g (0.03 mole) of p-aminobenzotrifluoride; the mixture was then heated at 100°-150° C. for about 3 minutes. The reaction mixture quickly became a solution and soon produced a precipitate which was separated and then made alkaline by the addition of 50 ml of a dilute aqueous solution of sodium hydroxide. The insolubles were collected by filtration, washed with water and then recrystallised from a 7:3 by volumemixture of ethanol and water, to give 1.2 g (yield 24%) of the desired Compound No. 38 in the form of a pale brown powder melting at 137°-139° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:10]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:10]1=[S:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cccc3ccc(O[Si](C)(C)C(C)(C)C)cc23)C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cccc3ccc(O[Si](C)(C)C(C)(C)C)cc23)C1=S
Temperature: 80 °C

Procedure:
A mixture of (R)-3-(tert-butoxycarbonylamino)-1-[7-(tert-butyl-dimethylsilyloxy)naphthalen-1-yl]-2-oxopyrrolidine, as described above in Step F, (113 mg, 0.247 mmol) and Lawesson's Reagent (50 mg, 0.124 mmol) in dry toluene (0.5 mL), under argon, was heated to 80° C. for 1 hour. The reaction mixture was allowed to cool, then poured directly onto a silica gel column and chromatographed, eluting with a gradient of hexane—5% to 25% EtOAc to yield the titled product as a clear oil.
Reaction SMILES: [C:1]([CH2:5][N:6]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].C[O-].[Na+].[O:31]1[CH2:44][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42]>CO>[C:1]([CH2:5][N:6]1[CH2:17][CH2:16][N:15]([CH2:44][CH:32]([OH:31])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:14][CH2:13][N:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2]
Reactant: O=C(O)CCCCCCCCC1CO1
Reactant: COC(=O)CN1CCNCCN(CC(=O)OC)CCN(CC(=O)OC)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CN1CCN(CC(=O)OC)CCN(CC(O)CCCCCCCCC(=O)O)CCN(CC(=O)OC)CC1

Procedure:
To a methanol solution of 1,4,7-tris(carbomethoxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A methyl ester) is added 1.0 equivalent of freshly prepared anhydrous sodium methoxide and the solution is allowed to stir for several hours. To this solution is added one equivalent of 10,11-epoxyundecanoic acid and the solution is brought to reflux overnight. The solvent is removed in vacuo to give a crude hydroxyethylated product, 1,4,7-tris-(carbomethoxymethyl)-10-[2′-hydroxy-10′-carboxy(decyl)]-1,4,7,10-tetraazacyclododecane. Two to five equivalents of this product are dissolved in dimethylformamide (DMF) and corresponding equivalents of dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide are added with stirring overnight. To this solution is added one equivalent of generation 2 PAMAM and stirring is continued another 24 hours. The corresponding DO3A methyl ester conjugate is selectively hydrolyzed by treatment with aqueous sodium hydroxide in methanol. Treatment of the DO3A conjugate with excess Gadolinium(III) acetate (Gd(OAc)3) (buffered to pH=6) followed by incubation with excess diethylenetriaminepentaacetic acid (DTPA) and purification of the conjugate using preparative reverse phase HPLC gives a hydroxyethyl DO3A PAMAM starburst conjugate product which contains two to five equivalents of gadolinium which can not be removed by further challenges with excess DTPA.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13](=O)[C:14]([CH3:17])([CH3:16])[CH3:15])[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][C:22]=1[F:39])[CH2:2][CH2:3][CH3:4].Cl.[NH2:41][O:42][CH:43]([CH3:45])[CH3:44].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([CH2:12]/[C:13](=[N:41]\[O:42][CH:43]([CH3:45])[CH3:44])/[C:14]([CH3:15])([CH3:16])[CH3:17])[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][C:22]=1[F:39])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)ON
Reactant: CCCCc1nc(C)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(C/C(=N\OC(C)C)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
A mixture of 6-butyl-3-(3,3-dimethyl-2-oxobutyl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methylpyrimidin-4(3H)-one (0.15 g), 2-(aminooxy)propane hydrochloride (0.63 g) and pyridine (5 mL) was stirred at 100° C. for 16 hr. The mixture was allowed to cool to room temperature, and the reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.036 g, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1
Reactant: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
105.7 g (0.32 mol) of crude rac-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one, dissolved in 1 liter of acetone, are treated with 88.6 g (0.64 mol) of potassium carbonate and 39.9 ml (0.64 mol) of methyl iodide and the mixture is stirred at room temperature for 22 hours. The mixture is evaporated to dryness and the residue is taken up in methylene chloride. The organic phase is washed with water, dried and evaporated. Recrystallisation of the residue from methylene chloride/ethanol gives rac-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 170°-174° C.
Reaction SMILES: [C:1]([CH:3]1[CH:7]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[C:1]([CH:3]1[CH:7]([C:8]2[N:12]=[N:11][N:10]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[N:9]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1CCCC1c1nnn[nH]1
Reactant: CCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCn1nnc(C2CCCC2C#N)n1

Procedure:
The tetrazole (b) obtained above (11.0 g; 0.067 moles) was dissolved in acetonitrile (150 mL) containing one equivalent of triethylamine (6.8 g; 0.067 moles). The solution was heated to reflux followed by the addition of 1-bromo dodecane (16.8 g; 0.067 moles). Isolation of the 2-isomer was achieved employing the same conditions described for Example 11.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][CH2:12][C:13]1[N:14]=[CH:15][N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=1)([CH3:9])[CH3:8].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[CH3:9][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[CH:17]=1)([CH3:6])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(COCC[Si](C)(C)C)cn1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(CO[Si](C)(C)C(C)(C)C)cn1COCC[Si](C)(C)C
Temperature: -60 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
nBuLi (2.2 mL of a 1.9M solution in hexanes, 4.2 mmol) was added dropwise to a −78° C. solution of 4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (1.20 g, 3.5 mmol) in THF (10 mL). The reaction mixture was stirred at −60° C. for 2 h, cooled to −78° C. and ethyl chloroformate (0.70 mL, 7.3 mmol) was added dropwise. The solution was allowed to warm to RT, quenched by addition of sat'd NaHCO3 and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-50% EtOAc/hex) to afford the title compound (1.21 g, 83%) as a light brown oil and as a mixture of the expected two isomers. Major isomer: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.05 (s, 1H), 5.90 (s, 2H), 4.75 (s, 2H), 4.34-4.43 (m, 2H) 3.48-3.58 (m, 2H) 1.40 (t, J=7.15 Hz, 3H), 0.91-0.89 (m, 2H), 0.87 (s, 9H), 0.06 (s, 6H), −0.06 (s, 9H).