Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:32])=[C:5]([C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(Cl)(Cl)Cl>C(#N)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:32])=[C:5]([C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:4][C:5]#[C:6][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:28][CH2:27]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCNCC2)C1c1cccc([N+](=O)[O-])c1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC#Cc3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1

Procedure:
10.2 Grams of methyl 2-piperazinylethyl 2,6-dimethyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 4.5 g of 3-phenylpropargyl bromide in 100 ml of acetonitrile were stirred at 30° C. for 5 hours under heating condition. After the reaction was finished, chloroform was added to the reaction mixture, and the mixture was washed with a saturated sodium hydrogen carbonate aqueous solution and water in this order, and dried with anhydrous sodium sulfate. The dried chloroform extract was concentrated by removing the solvent by evaporation, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane-methanol:dichloromethane =1:100). The product thus purified was then converted into a hydrochloride by adding hydrochloric acid-dioxane, and recrystallized from ethyl acetate-methanol-water to yield 1.2 g of methyl 2-[4-(3-phenyl-2-propynyl)-1-piperazinyl]ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate in the form of light yellow needle-like crystals. Melting point: 217°-220° C.
Reaction SMILES: N[C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].C(C=O)=O.O1C[CH2:24][CH2:23][CH2:22]1>O>[N:12]1[C:11]2[C:2](=[C:3]([C:13]([O:15][CH3:16])=[O:14])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(N)c(N)c1C(=O)OC
Reactant: C1CCOC1
Agent: O=CC=O
Solvent: O
Product: COC(=O)c1ccc2ncccc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
A mixture of dimethyl 3,4-diaminophthalate (11.2 g, 0.05 mol) in tetrahydrofuran is treated with glyoxal (2.9 g, 0.05 mol) in water at reflux temperature, stirred for 4 hours at reflux temperature and overnight at room temperature, and concentrated in vacuo. The resultant residue is partitioned between water and methylene chloride. The organic phase is dried (MgSO4) and concentrated in vacuo to give a brown solid residue. Recrystallization from methanol gives the title product as a pink powder (9.67 g, 78.6%) mp 124°-125° C., identified by H1NMR, C13NMR, and IR spectral analyses.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[OH:12][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=1)[CH:2]=[O:1]
Reactant: CC(C)c1cc(O)cc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)c1cc(O)cc(C=O)c1
Reaction time: 4.5 h

Procedure:
To a stirring solution of 3-(hydroxymethyl)-5-isopropylphenol in 10 mL of CH2Cl2 was added 1.23 g (5.69 mmol) of PCC. The mixture was stirred for 4.5 h, Et2O was added, and the mixture was stored in a refrigerator. The solvent was concentrated, and the crude product was purified by flash silica gel chromatography (15% EtOAc/hexanes) to provide 218 mg of 3-hydroxy-5-isopropylbenzaldehyde as a pale yellow solid.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:22]([CH2:24][NH:25][C:26](=[O:33])[C@@H:27]([OH:32])[CH2:28][CH:29]([CH3:31])[CH3:30])#[N:23].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl.CCOC(C)=O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([CH:5]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[O:32][C@@H:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:26]([NH:25][CH2:24][C:22]#[N:23])=[O:33])=[CH:13][CH:14]=1
Reactant: N=C(OC(c1ccc(Br)cc1)C1CCCCC1)C(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@H](OC(c1ccc(Br)cc1)C1CCCCC1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (4-bromophenyl)(cyclohexyl)methyl 2,2,2-trichloroethanimidoate of step 2 (4.18 mmol, 1.73 g) in CH2Cl2 (15 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide from Step 1, Example 67 (4.18 mmol, 0.71 g) and then PPTS (0.42 mmol, 0.105 g). The mixture was stirred at r.t. for 72 h. A red solution resulted. The mixture was diluted with EtOAc and washed with NaHCO3. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography gave the less polar diastereomer and the more polar isomer.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:8]([O:18][CH2:19][CH2:20][OH:21])=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:6]=1)C>C1COCC1.C(O)C.[OH-].[K+]>[Cl:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:10]=[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:8]=2[O:18][CH2:19][CH2:20][OH:21])[C:4]([OH:29])=[O:3])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reaction time: 20 h
Yield: 90.9 %

Procedure:
To a stirred solution of 3,5-bis(3-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (2.009 g, 4.658 mmol) in THF (30 ml) and ethanol (15 ml) was added IN KOH (9.32 ml). After 20 h, the reaction was concentrated in vac. The residue was diluted with water (40 ml) and acidified with 2N HCl (9.32 ml). After 2 h, the solids were collected, rinsed with water, dissolved in EtOAc, dried over Na2SO4, filtered, concentrated in vac, and the residue dried to give the desired product as a white solid (1.708 g, 91%); mp 184-192 (partial melt), solidifies, and melts 200-202° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.12 (q, J=4 Hz, 2H), 3.28 (t, J=4 Hz, 2H), 4.45 (t, J=4 Hz, 1H), 7.45-7.60 (m, 6H), 7.70 (s, 2H), 7.91 (s, 2H), 13.10 (s, 1H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[CH2:22])[C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1)[CH2:9][CH2:10][CH3:11]>CN(C)C=O>[CH2:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:19](=[O:21])[CH3:20])[CH2:4][CH2:22]2)=[CH:16][CH:17]=1)[CH2:9][CH2:10][CH3:11]
Reactant: C[S+](C)C
Reactant: C=C(C(C)=O)c1ccc(CCCC)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(C2(C(C)=O)CC2)cc1
Temperature: 0 °C
Yield: 61.9 %

Procedure:
507 mg of sodium hydride (55% in paraffin oil) is introduced into 20 ml of dimethylformamide under nitrogen at 0° C., and 1.38 g of trimethylsulfonium iodide is added. After 30 minutes at this temperature, 1.06 g of ketone 52 is added in drops to 4 ml of dimethylformamide. It is stirred for 1 more hour at 0° C., then quenched with sodium chloride solution, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 702 mg of title compound 53 is obtained as a colorless oil.
Reaction SMILES: [C:1](=[S:5])([NH2:4])[CH2:2][CH3:3].Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=O>C(O)C>[CH2:2]([C:1]1[S:5][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:3]
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: CCC(N)=S
Solvent: CCO
Product: CCc1nc(-c2ccc(O)cc2)cs1
Reaction time: 7 h
Yield: 40.2 %

Procedure:
A mixture of 3.6 parts of propanethioamide, 8.6 parts of 2-bromo-1-(4-hydroxyphenyl)ethanone and 79 parts of ethanol was stirred for 7 hours at reflux temperature. The reaction mixture was concentrated to 1/4 of its volume and 2,2'-oxybispropane was added to the residue. The precipitate was filtered off and taken up in water. After basifying with NH4OH, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 3.3 parts (40.2%) of 4-(2-ethyl-4-thiazolyl)-phenol (interm. 17).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:26][O:27][CH2:28][CH2:29]Br>C1COCC1>[CH3:26][O:27][CH2:28][CH2:29][NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1sc2nccnc2c1N
Reactant: COCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2nccnc2c1NCCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (1.0 g g, 4.48 mmol) prepared by the method of Schneller and Clough, J. Het. Chem., 12: 513 (1975), was treated with potassium bis(trimethylsilyl)amide (0.5M in toluene, 8.96 ml) in 15 ml THF at -70° C., and allowed to warm to room temperature. 2-Bromoethyl methyl ether (0.454 ml, 4.70 mmol) was added, and the reaction was stirred under N2 at 60° C. overnight. The mixture was cooled and evaporated, then purified by column chromatography on silica gel eluting with 1:9 ethyl acetate:hexanes to yield 0.640 g (51%) of the title compound as a yellow solid: 1H NMR (300 MHz, DMSO-d6) d 1.32 (t, 3H), 3.3 (s, 3H), 3.56 (t, 2H), 4.25 (q, 2H), 4.32 (t, 2H), 7.70 (br t, 1H), 8.76 (s, 1H), 8.77 (s, 1H); MS (DCI/NH3) m/e 282 (M+H)+.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.Cl.[NH2:16][C@@H:17]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:33]([O:37][C:38]([N:40]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:41]1[C:50]2[C:45](=[CH:46][C:47]([NH:51][CH:52]([C:56]3[CH:61]=[C:60]([CH3:62])[C:59]([CH2:63][CH2:64][OH:65])=[C:58]([CH3:66])[CH:57]=3)[C:53](O)=[O:54])=[CH:48][CH:49]=2)[CH:44]=[CH:43][N:42]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:70]([O:69][C:67]([N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:41]1[C:50]2[C:45](=[CH:46][C:47]([NH:51][CH:52]([C:56]3[CH:57]=[C:58]([CH3:66])[C:59]([CH2:63][CH2:64][OH:65])=[C:60]([CH3:62])[CH:61]=3)[C:53]([NH:16][C@@H:17]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:54])=[CH:48][CH:49]=2)[CH:44]=[CH:43][N:42]=1)=[O:68])([CH3:73])([CH3:72])[CH3:71]
Reactant: CCOC(=O)C[C@@H](N)c1cccc([N+](=O)[O-])c1
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc(C)c1CCO
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)C[C@@H](NC(=O)C(Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1)c1cc(C)c(CCO)c(C)c1)c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
EDC (187 mg, 0.97 mmol) and HOAt (132 mg, 0.97 mmol) were added to a solution of 39A (268 mg, 0.97 mmol) and 50C (500 mg, 0.89 mmol) in DMF (10 mL). Triethylamine (0.36 mL, 2.7 mmol) was added to the reaction mixture and it was stirred at 50° C. for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 20% MeOH in CH2Cl2) to yield 50D (580 mg, 83%) as a yellow solid. MS (ESI) m/z 786.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH:11]=[C:10]([C:13](=O)[CH2:14][C@H:15]2[N:18]([C:19](=P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[C:17](=[O:45])[C@@H:16]2[C@H:46]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH3:47])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH2:14][C@H:15]3[N:18]([C:17](=[O:45])[C@@H:16]3[C@H:46]([O:48][Si:49]([C:52]([CH3:53])([CH3:54])[CH3:55])([CH3:51])[CH3:50])[CH3:47])[C:19]=2[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)C1=CCN(C(=O)OCC=C)CC1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C(C2=CCN(C(=O)OCC=C)CC2)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Yield: 72.3 %

Procedure:
Allyl 2-[(3S,4R)-4-{2-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxoethyl}-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (2.0 g) was dissolved in degassed toluene (40 ml) and the solution was heated to reflux for 8 hours. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (50 g) eluting with a mixture of n-hexane and ethyl acetate (19:1-7:3 V/V) to give allyl (5R,6S)-3-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.94 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14]([CH2:18][CH2:19][CH3:20])=[N:13]1)[CH2:7]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14]([CH2:18][CH2:19][CH3:20])=[N:13]1)[CH2:7]2
Reactant: CCCC1=NC2(Cc3ccc([N+](=O)[O-])cc3C2)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: CCCC1=NC2(Cc3ccc(N)cc3C2)C(=O)N1

Procedure:
To a solution of (±)-5′-nitro-2-propyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one from Step A (20.0 mg, 0.073 mmol) in degassed MeOH (5 mL) was added 10% palladium on carbon (10 mg). The suspension was placed under a hydrogen balloon for 1 h, then filtered through a pad of Celite, concentrated, and dried under high vacuum to give the title compound. MS: m/z=244 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1)#[N:20].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: N#Cc1cccc(O)c1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cccc(C#N)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 68.8 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.16 g of 3-cyanophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.2 g of 4-(2-butynyloxy)-6-(3-cyanophenoxy)pyrimidine (the present compound (40)), m.p.: 121.2° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[C:4]([CH3:14])[N:3]=1.C(Cl)(Cl)Cl.[Br:19]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:19][C:11]1[S:10][C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:14])[N:3]=[C:2]([CH3:1])[N:7]=2)=[N:13][CH:12]=1
Reactant: Cc1cc(Nc2nccs2)nc(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncc(Br)s2)nc(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask were added 50 mg of (2,6-dimethyl-pyrimidin-4-yl)-thiazol-2-yl-amine (23-2), chloroform (3.0 mL) and 47 mg of N-bromosuccinimide. The reaction was allowed to stir at room temperature for 2 hours. The chloroform was diluted with ethyl acetate and washed with saturated sodium bisulfite solution. The ethyl acetate was dried (MgSO4) and the solvent removed under high vac to give the desired product. The title compound was used as is. 1H-NMR (400 MHz, DMSO-d6) 11.05 (1H, s), 7.53 (1H, s), 6.69 (1H, d), 6.69 (1H, s), 2.54 (3H, s), 2.35 (3H, s). MS(M+1)=285.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O.C([O-])(=O)C.[Na+].[N:17]#[C:18]Br>C(O)(=O)C>[OH2:6].[C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:17]
Reactant: N#CBr
Reactant: Nc1cccc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CNc1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 174.9 %

Procedure:
To a 3-aminobenzoic acid (Aldrich, 9.05 g, 66 mmol) in acetic acid:water (70 mL, 1:1) was added sodium acetate (8.12 g, 99 mmol) and the mixture was cooled in an ice-water bath. Cyanogen bromide (8.38 g, 79.2 mmol) was added in two batches in 10 min and the stirring was continued for 18 h at room temperature. The reaction mixture was poured into 350 g of an ice-water mixture with stirring. The precipitate was collected through filtration, washed with cold water (about 70 mL), dried in air, and crystallized from methanol-water. The white solid was separated through filtration, dried in air followed by drying in a pistol at toluene reflux in vacuo to give 10.40 g (95%) of the title compound, mp 238°-240° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[I:12].Cl>O>[I:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:13])=[O:4]
Reactant: COC(=O)c1ccncc1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccncc1I
Temperature: 60 °C
Yield: 94.4 %

Procedure:
Water was added to 3.20 g of sodium hydroxide to make 30 ml of aqueous solution in total. To the solution, 5.83 g of 3-iodo-isonicotinic acid methyl ester (U.S. Pat. No. 6,277,871B1, O'Conner et al.) was added. The mixture solution was stirred while heating at 60° C. for three hours. The reaction mixture was cooled in ice, to which concentrated hydrochloric acid was added to adjust pH to 2-3. Precipitates were collected by filtration and dried under reduced pressure to give 5.21 g of 3-iodo-isonicotinic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:26])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:25])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:24])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:23])[C:20](O)=[O:21])=[O:5])[CH3:2].[CH3:27][NH:28][CH3:29]>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:26])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:25])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:24])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:23])[C:20]([N:28]([CH3:29])[CH3:27])=[O:21])=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C)C

Procedure:
Starting materials: 15-ethoxycarbonyl-2,6,10,14-tetramethyl-2,6,10,14-pentadecatetraenoic acid and aqueous dimethylamine solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])=[CH:5][CH:4]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][NH:11][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C(C)(C)CN)cc1
Product: COc1ccc(C(C)(C)CNCc2ccc(C(F)(F)F)cc2)cc1
Yield: 84.1 %

Procedure:
Reductive amination of 2-(4-methoxyphenyl)-2-methylpropan-1-amine (500 mg; 2.79 mmol) with 4-(trifluoromethyl)benzaldehyde (0.38 ml; 2.79 mmol) as per general procedure A afforded N-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethyl)benzyl]amine (792 mg; 84% yield).
Reaction SMILES: O1CC(=O)COC1.[CH2:8]([C:10]1([CH2:17]C)[O:15][CH2:14][C:13](=[O:16])[CH2:12][O:11]1)C.O1C2(CCCCC2)OCC(=O)C1>>[CH3:8][C:10]1([CH3:17])[O:15][CH2:14][C:13](=[O:16])[CH2:12][O:11]1
Reactant: CCC1(CC)OCC(=O)CO1
Agent: O=C1COC2(CCCCC2)OC1
Agent: O=C1COCOC1
Product: CC1(C)OCC(=O)CO1

Procedure:
IR (NEAT): significative bands at 3360, 1440, 1380 cm-1By working in a similar way but using 1,3-dioxan-5-one, 2,2-diethyl-1,3-dioxan-5-one and 1,5-dioxaspiro[5,5]undecan-3-one, in place of 2,2-dimethyl-1,3-dioxan-5-one, the following compounds were respectively obtained: 1.3-dioxan-5-one oxime, 2-diethyl-1.3-dioxan-5-one oxime and 1.5-dioxaspiro[5.51]undecan-3-one oxime.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2([C:38]([O:40]C(C)(C)C)=[O:39])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[C:20](=[O:45])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2([C:38]([OH:40])=[O:39])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[C:20](=[O:45])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(C(=O)OCc3ccccc3)CC2=O)(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(C(=O)OCc3ccccc3)CC2=O)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Trifluoroacetic acid (100 ml) was added to a solution of 4-benzyloxycarbonyl-1-[1,4-bis(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone (38.8 g) obtained in Reference Example 1 in toluene (100 ml), the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. Then, di-tert-butyl dicarbonate (17.6 ml) was added to a mixture of the residue, sodium carbonate (38.7 g), water (300 ml) and ethyl acetate (300 ml) at room temperature while stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was separated into layers, the aqueous layer was adjusted to pH 3 with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried with magnesium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:methanol=10/1) to obtain the title compound (29 g) as yellow powders.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[CH2:20][CH2:21][OH:22]>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:20][CH2:21][O:22][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Clc1cncc(OC2CCNCC2)n1
Reactant: COc1cccc(CCO)c1
Solvent: CN(C)C=O
Product: COc1cccc(CCOc2cncc(OC3CCNCC3)n2)c1
Reaction time: 16 h

Procedure:
A solution of the product obtained in Step 2 above (0.043 g, 0.20 mmol) in DMF (1.1 mL) was added to a mixture of 3-methoxyphenethyl alcohol (0.061 g, 0.40 mmol) and K-t-BuO (1.0 M in tert-butanol; 0.4 mL, 0.40 mmol) in DMF (0.8 mL). The reaction mixture was vortexed for 16 h at 50° C. under nitrogen, quenched with water (0.1 mL) and concentrated in vacuo. The residue was partitioned between water (2 mL) and 4 ethyl acetate (4 mL) and poured through a hydromatrix column, which was eluted with ethyl acetate/Et3N (95:5). Solvents were evaporated off and the residue was dissolved in methanol/water (50 mL) and loaded onto a conditioned weak cation exchange SPE column (1 g, Amberlyst CG-50 I). The column was washed with water (10 mL) and methanol (10 mL). The compound was eluted with aqueous 2.0 M NH3 in methanol (20 m) and concentrated in vacuo. The residue was analysed for identity and purity by LC-UV/MS. Yield: 8 mg (12%). HRMS m/z calcd for C18H23N3O3 (M)+ 329.1739, found 329.1743.