Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[O:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:34]=[N+:35]([O-:53])[CH:36]=[C:37]([Cl:52])[C:38]=1[CH2:39][C@@H:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([O:50][CH3:51])[CH:43]=1)O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:52][C:37]1[CH:36]=[N+:35]([O-:53])[CH:34]=[C:33]([Cl:32])[C:38]=1[CH2:39][C@H:40]([O:21][C:20]([C:18]1[N:19]=[C:15]([CH2:14][O:13][C:12]2[CH:23]=[CH:24][CH:25]=[C:10]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=2)[O:16][CH:17]=1)=[O:22])[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([O:50][CH3:51])[CH:43]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(OCc2nc(C(=O)O)co2)c1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2coc(COc3cccc([C@@H](NC(=O)OC(C)(C)C)c4ccccc4)c3)n2)cc1OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 36.4 %

Procedure:
To a stirred suspension of 2-[[3-[(S)-(tert-butoxycarbonylamino)-phenyl-methyl]phenoxy]methyl]oxazole-4-carboxylic acid (350 mg, 0.825 mmol) in DMF (12.3 mL) was added (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (284 mg, 0.825 mmol), DMAP (50.4 mg, 0.412 mmol) and EDC hydrochloride (316.2 mg, 1.65 mmol). The reaction was stirred at room temperature for 23 h. The majority of the DMF was removed in vacuo and the residue was partitioned between ethyl acetate (30 mL) and saturated aqueous NaHCO3 solution (30 mL). The aqueous phase was extracted twice with ethyl acetate (20 mL) and the combined organic phases were washed with brine, dried on MgSO4, filtered then concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-50% EtOAc in dichloromethane, to give the title compound (225.6 mg, 36%) as a colourless solid.
Reaction SMILES: [OH-].[NH4+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([S@:13]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)=[O:14])[NH:10][C:9]=2[CH:26]=1>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([S:13]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)=[O:14])[NH:10][C:9]=2[CH:26]=1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 0.17 h

Procedure:
To a 50 mL beaker was added about 1 g of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]suffinyl]-1H-benzimidazole to 30 mL of dimethylformanide (DMF) containing 1 mL of ammonium hydroxide. Additional (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole was added to the resulting solution until a suspension of the material was formed. The solution was stirred for approximately 10 minutes, and then filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) or Nylon filter. The resulting saturated solution was placed in a shallow petri dish, covered and stored under ambient conditions (approximately 25° C.) and a humidity range of 0 to 50 percent until crystals formed (between 1-4 days). The identity of the title compound is confirmed by single crystal x-ray diffraction and/or Raman spectroscopy. The resulting material was shown to contain between about 96 and 98 percent (w/w) of the 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole and between about 2 and 4 percent (w/w) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:13][C:14]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:15]=1[C:16]([NH:18][C:19]1[S:20][C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[C:22](C2C=CC=CN=2)[N:23]=1)=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:22]2[N:23]=[C:19]([NH:18][C:16](=[O:17])[C:15]3[C:14]([F:13])=[CH:43][CH:42]=[CH:41][C:40]=3[F:44])[S:20][C:21]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Nc1nc(-c2ccccn2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Reactant: COc1ccc([Mg]Br)cc1OC
Product: COc1ccc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)cc1OC

Procedure:
Compound 109 was prepared from 22a and 3,4-dimethoxyphenylmagnesium bromide as described for the preparation of Compound 107.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]([CH:12]([C:17]1[S:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][N:21]=1)[CH2:13][CH2:14][CH2:15]I)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:4][CH:12]([C:17]1[S:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][N:21]=1)[CH2:13][CH2:14][CH2:15][N:2]([CH3:3])[CH3:1]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCI)c1ncc(S(N)(=O)=O)s1
Reactant: CNC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)CCCC(O)c1ncc(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Dimethylamine was bubbled through a solution of 2-(1-t-butyldimethylsiloxy-4-iodobutyl)-5-thiazole sulfonamide (0.78 mmol, 0.37 g ) in THF (8 mL) at 0° C. After 30 minutes the solvent was removed and the residue taken up in THF and TBAF (1.17 mmol) added. The reaction was stirred at rt for 2 hours. The reaction was concentrated and the residue subjected to flash chromatography (5% MeOH/NH3 /CHCl3) to afford 0.16 g (72%) of 2-(1-hydroxy-4-(N,N-dimethylamino)butyl)-5-thiazole sulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH:9]12[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:10]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 22 h
Yield: 86.6 %

Procedure:
A mixture of 8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (238 mg, 1.12 mmol), benzyl chloroformate (160 μL, 1.12 mmol) and triethylamine (280 μL, 2.0 mmol) in DCM (20 mL) was stirred at room temperature for 22 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (25 mL). The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (336 mg, 87%) as a clear oil. δH (DMSO-d6) 7.45-7.28 (5H, m), 5.17-5.03 (2H, m), 4.18-4.06 (2H, m), 3.79-3.69 (2H, m), 3.10-2.90 (2H, m), 1.85-1.72 (2H, m), 1.60-1.49 (2H, m), 1.41 (9H, s).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([OH:23])=[C:17]([CH2:24][CH3:25])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>>[CH2:1]([C:8]1[O:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH2:24][CH3:25])[C:18]([O:23][S:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=2)(=[O:31])=[O:30])=[C:19]([CH2:21][CH3:22])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1O
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Yield: 32.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diethyl-4-hydroxy-phenyl)-methanone (0.5 g, 1.38 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.65 g, 2.74 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with 10% EtOAc/hexane gave 0.251 g (32%) of the title compound as an off white solid, mp 143-147° C. 1H NMR (DMSO-d6) δ 1.01 (t, 6H), 1.84 (s, 3H), 2.20 (s, 3H), 2.51 (q, 4H, with DMSO peak), 3.81 (s, 2H), 7.01 (d, 2H), 7.16-7.20 (m, 1H), 7.23-7.27 (m, 2H), 7.45 (s, 2H), 7.49-7.53 (m, 2H), 8.06 (d, 1H). mass spectrum (−ESI), m/z 561 (M−H). Anal. Calcd. for C31H30O8S: C, 66.18; H, 5.37; N, 0.00. Found: C, 65.80; H, 5.50; N, 0.22.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:23]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:32]([OH:34])=O)[CH2:13][CH2:12]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:26][CH:27]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:32]([NH:11][C:17]2[CH:18]=[CH:19][C:20]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:30][CH2:29][O:28][CH2:25][CH2:24]3)=[CH:21][CH:16]=2)=[O:34])[CH2:13][CH2:12]1
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(2-methoxybenzyl)-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (340 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (267 mg) was added thereto at 0° C., the temperature was returned to room temperature, and the mixture was stirred for 1 hour under nitrogen atmosphere. The solvent and excess thionyl chloride were evaporated under reduced pressure, and the resulting residue was suspended in tetrahydrofuran (30 ml), which was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (197 mg) and triethylamine (906 mg) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred at room temperature for 1 hour under nitrogen atmosphere, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(2-methoxybenzyl)-N-[4-[[N-methyl N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (337 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(O)C.O>[Br:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Br)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccccc1Br)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (2.81 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(o-bromobenzyl)-4-phenyl-5-oxohexanoic acid (3.0 g., 0.006 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled, acidified with dilute hydrochloric acid (10 ml.), and the yellowish solid which precipitates is collected and air-dried to yield 3.5 g. Recrystallization from ethanol gives material with m.p. 210°-213.5°C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=2[N:11]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[C:5]2[N:11]=[C:2]([CH3:1])[S:3][C:4]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1nc2c[n+]([O-])ccc2s1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(Cl)nccc2s1

Procedure:
2-Methyl-thiazolo[4,5-c]pyridine 5-oxide (230 mg, 1.38 mmol) was refluxed 2 hrs in 4 ml of phosphoryl chloride. The reaction mixture was evaporated and extracted with ethyl acetate and saturated sodium bicarbonate-solution. The organic extracts were dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->0:100 gradient). The desired product was obtained as a light yellow solid (180 mg, 70%), MS: m/e=185.1 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[CH2:15])[C:10]([O:12]CC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C>[CH2:15]=[C:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: C=C(CCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=C(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
4-Phenyl-2-methylenebutyric acid, ethyl ester (10 g, 49 mmole) was dissolved in 100 mL of absolute ethanol. Potassium hydroxide (3.32 g, 85%, 50 mmole) was added to the solution and the solution stirred overnight at room temperature. After 18 h, all of the ester was hydrolyzed. The solvent was removed under reduced pressure and the syrup dissolved in water. Enough concentrated HCl was added to acidify the solution (pH<3) and the product was extracted with ether (3×50 mL). The solution was dried over MgSO4, filtered and the solvent removed under reduced pressure. Recovered 8.6 g of product (97% yield).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20](O)[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P(Cl)(Cl)([Cl:30])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([Cl:30])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Yield: 91 %

Procedure:
Then, 5 g (0.013 mole) of the obtained ethyl 2-(p-octyloxyphenyl)-4-hydroxypyrimidine-5-carboxylate was dissolved in 25 ml of phosphorus oxychloride, and the mixture was refluxed with heating for 3 hours. The excess phosphorus oxychloride was distilled under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: CHCl3) to give 4.9 g of ethyl 2-(p-octyloxyphenyl)-4-chloropyrimidine-5-carboxylate (yield: 91%).
Reaction SMILES: C([O:8][C:9](=[O:19])[CH2:10][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CO.[Rh]>[CH2:14]1[CH2:13][CH2:12][C:11]([CH2:17][NH2:18])([CH2:10][C:9]([OH:19])=[O:8])[CH2:16][CH2:15]1
Reactant: N#CC1(CC(=O)OCc2ccccc2)CCCCC1
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Yield: 27.7 %

Procedure:
1.0 g (3.8 mmol) of (1-cyanocyclohexyl)acetic acid benzyl ester was distilled in 20 ml of methanol, mixed with 0.2 g of Rh/C 5 percent and hydrogenated at 10 bars of hydrogen pressure. After 23 hours at room temperature the suspension was filtered, the filtrate was concentrated to 3 ml, mixed with 25 ml of ethanol, concentrated to 4 ml and put on the cooling shelf. The precipitated product was filtered, washed with ethanol and dried. 0.18 g of Gabapentin was obtained, corresponding to a yield of 27 percent (relative to the (1-cyanocyclohexyl)acetic acid benzyl ester used). Data for the produce was:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].Cl.C(N(CC)CC)C>C(#N)C>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[C:20]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:24][CH2:25]1)=[O:9]
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Reactant: COC(=O)c1ccccc1NC(=O)CCl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1

Procedure:
10.06 Grams of methyl o-(α-chloroacetylamino)benzoate, 15.2 g of N-(3,4-dimethoxybenzoyl)piperzine.monohydrochloride and 16 g of triethylamine were suspended in 55 ml of acetonitrile, and the mixture was reacted at 49°-50° C. for 4 hours. After completion of the reaction, the reaction mixture was ice-cooled, and the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 14.68 g of o-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C=O)C>[CH2:17]([N:10]1[CH2:11][C:12](=[O:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[C:9]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CNC(=O)N1c1cccc(I)c1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccc2)C(=O)N1c1cccc(I)c1

Procedure:
A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (1.7 g) in DMF (20 ml) was treated with sodium hydride (60% oil dispersion, 280 mg) and benzylchloride (1.93 ml) at 20° C. After 2 h the reaction mixture was treated with aqueous 2M HCl, extracted with EtOAc and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography on Biotage (40 g) eluting with petroleum ether-EtOAc (9:1 to 3:2) to give the title compound (1.38 g). LCMS RT=3.27 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.CO[CH:14]([N:17]([CH3:19])[CH3:18])OC>>[CH3:14][N:17]([CH3:19])/[CH:18]=[C:9]1/[C:10](=[O:11])[C:4]2[S:3][C:2]([N:1]=[CH:14][N:17]([CH3:19])[CH3:18])=[N:6][C:5]=2[CH2:7][CH2:8]/1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1nc2c(s1)C(=O)/C(=C/N(C)C)CC2
Temperature: 100 °C
Reaction time: 65 h

Procedure:
A suspension of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (3.5 g, 20.81 mmol) in dimethoxymethyldimethylamine (12 mL, 90 mmol) was heated at 100° C. with stirring for 65 h. The RM was then evaporated to dryness in vacuo and the residue was suspended in EtOAc. After 1 h at 4° C., the solid was filtered off, washed with EtOAc and then dried under high vacuum at 60° C. to give the pure title product as brown crystals. LC: tR 3.25 min (method D). MS: M+H=279. 1H-NMR in DMSO-d6: 8.40 (s, 1H); 7.23 (s, 1H); 3.15 (s, 3H); 3.05 (s, 6H); 2.97 (s, 3H); 2.91 (t, 2H); 2.67 (t, 2H).
Reaction SMILES: CCN(CC)CC.[CH2:8]1[CH:12]2[CH2:13][NH:14][CH2:15][CH:11]2[CH2:10][N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:23]([N:14]1[CH2:13][CH:12]2[CH2:8][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:11]2[CH2:15]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3)CC2C1
Temperature: 115 °C

Procedure:
Et3N (0.5 mL) was added into a solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.2 g) and benzoyl chloride (0.11 mL) in THF (10 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 5-benzoylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[CH:12]([C:31](=[O:32])[NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[C:11]([CH3:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2N=C(C)CC2=O)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2N=C(C)C(C(=O)Nc3ccc(F)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 4.1 g of 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one in 75 ml of benzene and 2.5 g of triethylamine is combined with 2.75 g of p-fluorophenylisocyanate while stirring at ambient temperature. After standing overnight, the mixture is evaporated, the residue taken up in 0.3 N hydrochloric acid, the resulting crystals collected, washed with water, dried, triturated with ethyl acetate and recrystallized from methanol to yield the 1-(p-methoxyphenyl)-3-methyl-4-(p-fluorophenylcarbamoyl)-2-pyrazolin-5-one of Formula II with R=OCH3, R'=H and R"=F, melting at 254°-256° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:43][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NC1CCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide (0.1 mmol) and cyclopentylamine (10 mmol) according to conditions described in general procedure C. Compound is produced (25 mg) as a light yellow solid; Mp: 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 1.23-1.38(m, 4H), 1.53-1.88(m, 4H), 3.22-3.25(m, 4H), 3.84-3.86(m, 4H), 4.08-4.15(m, 1H), 5.06(bs, 1H), 6.07(bs, 1H), 6.76(d, J=11.7 Hz, 1H), 7.07(d, J=8.4 Hz, 1H), 7.25-7.31(m, 2H), 7.48-7.58(m, 2H), 7.85-7.98(m, 3H), 8.14(s, 1H), 8.25(s, 1H); MS: 528 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Br:13])[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].C[Si](C)(C)[O:17][CH:18](O[Si](C)(C)C)[CH3:19].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(Cl)Cl>[CH2:18]1[O:17][C:9]2([C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:12]([Br:13])[CH:11]=3)[CH2:7][CH2:8]2)[O:14][CH2:19]1
Reactant: O=C1CCc2cc([N+](=O)[O-])c(Br)cc21
Reactant: CC(O[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2c(cc1Br)C1(CC2)OCCO1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a suspension of 5-nitro-6-bromo-1-indanone (11.0 g, 43 mmol) and bis(trimethylsilyloxy)ethane (22.0 mL, 90 mmol) in CH2Cl2 (90 mL) at room temperature was added trimethylsilyltrifluoromethanesulfonate (100 μL). The mixture was stirred for 2 h and the homogeneous solution was quenched with saturated aqueous NaHCO3 (100 mL). The CH2Cl2 layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel, eluting with ethyl acetate:hexanes (2:5), furnished 10.2 g (79%) of the title compound as a pale yellow solid.