Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[N:31][CH:30]=2)=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:35]([C:33]4[CH:32]=[N:31][CH:30]=[C:29]([C:26]5[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=5)[N:34]=4)=[O:36])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1cncc(-c2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cncc(-c3ccc(F)cc3)n2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 90.2 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl4-carboxamide (75 mg, 0.27 mmol), 6-(4fluorophenyl)pyrazine-2-carboxylic acid (58.4 mg, 0.27 mmol), HATU (101.5 mg, 0.27 mmol), HOBT (36 mg, 0.27 mmol) and DIPEA (140 μl, 0.80 mmol) in DMF (3 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with hydrochloric acid (0.5M, 2×20ml), aqueous sodium hydrogen carbonate (20 ml) and dried (magnesium sulphate). Evaporation of the solvents under vacuum gave N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-6-(4-fluorophenyl)pyrazine-2-carboxamide (117 mg, 91%). NMR; δH [2H6]—DMSO 10:64,(1H, s), 9.52,(1H, s), 9.20,(1H, s), 8.63,(1H, t), 8.54,(2H, m), 7.95,(2H, d), 7.88,(1H, dd), 7.78,(1H, d), 7.48,(2H, d), 7.42,(2H, t), 7.35,(1H, d), 3.17,(2H, t), 2.23,(3H, s), 1.05,(1H, m), 0.24,(2H, m). LCMS: retention time 3.65 min, MH+481.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[C:8]([O:12][NH:13][C:14]([C@:16]1([OH:45])[C@H:21]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[C:36]([CH3:44])[CH:35]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C.C(OCC)=O>CO>[C:8]([O:12][NH:13][C:14]([C@:16]1([OH:45])[C@H:21]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[C:36]([CH3:44])[CH:35]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:20][CH2:19][N:18]([CH:3]=[O:4])[CH2:17]1)=[O:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: CCOC=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C=O)C[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 46 °C
Yield: 61.3 %

Procedure:
(3R,4R)-N-tert-Butoxy-3-hydroxy-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide trifluoroacetic acid salt (250 mg, 0.32 mmol) was dissolved in methanol (1 mL) and diisopropylethylamine (0.23 mL, 1.3 mmol, 4 eq) was added, followed by ethyl formate (5 mL, excess). The reaction was heated at 46° C. for 5 h, and then concentrated in vacuo. The residue was triturated with ether to yield 112 mg (62%) of (3R,4R)-N-tert-butoxy-1-formyl-3-hydroxy-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide as white waxy solid. MS: (M+H)+=571.1.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CCN(CC)CC.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(O)C.C(Cl)Cl>[O:8]=[C:6]1[NH:7][C@@H:3]([CH2:2][O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@H](CO)N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)OC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To a solution of commercially available (R)-(−)-5-(hydroxymethyl)pyrrolidin-2-one (5 g, 43.4 mmol) in ethanol-free CHCl3 (150 ml), Et3N (6.9 g, 68.3 mmol) and methanesulfonyl chloride (5.96 g, 52.0 mmol) were added dropwise at 0° C. The mixture was left stirring at room temperature for 3 hours, then it was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. After drying (Na2SO4) the solvent was removed under reduced pressure and the residue was purified by flash chromatography (DCM/MeOH 95/5 respectively) to give the title compound as a pale yellow solid (5.9 g, 70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[C:20]#[N:21]>CN(C)C=O.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=2[C:20]#[N:21])=[C:4]([CH3:9])[CH:3]=1
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Reactant: Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(Cl)ccc1OCc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
4-Chloro-2-methylphenol (0.12 g, 0.83 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.2 g, 0.83 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried to yield 155 mg of 2-(4-chloro-2-methylphenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: [C:1]1([C:7](C2C=CC=CC=2)(C2C=CC=CC=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O[C:26](=O)[C:27]([F:30])(F)F)=O.[F:34][C:35](F)(F)[C:36](O)=O>>[F:30][C:27]1[CH:26]=[C:35]([F:34])[CH:36]=[C:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[C:1]2[CH3:7]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Product: Cc1cccc2c(F)cc(F)cc12

Procedure:
2.5 g of 5,7-Difluoro-1-methyl-tetralol, 3.6 g of triphenylmethanol and 2.6 g of trifluoroacetic acid anhydride are refluxed for 5 hours in 16 ml of trifluoroacetic acid. The mixture is poured onto ice-water and extracted with dichloromethane. The organic phase is washed neutral with sodium bicarbonate solution, dried and concentrated. The oily crude product can be purified by chromatography over silica gel (eluant:hexane).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6]1)[CH:2]([CH3:4])[CH3:3].[F:15][C:16]([F:21])([F:20])[C:17](O)=[O:18]>>[CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:17](=[O:18])[C:16]([F:21])([F:20])[F:15])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1Cc2ccccc2CN1
Reactant: O=C(O)C(F)(F)F
Product: CC(C)CC1Cc2ccccc2CN1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To 206 mg of 3-isobutyl-1,2,3,4-tetrahydroisoquinoline obtained in Example 20 was added 458 mg of anhydrous trifluoroacetic acid, followed by stirring at room temperature for 2 hours. Further, 200 mg of anhydrous trifluoroacetic acid was added thereto, followed by stirring at 40° C. for 1 hour. After completion of the reaction, the reaction liquid was concentrated under reduced pressure, added with ethyl acetate, and washed with an aqueous sodium bicarbonate solution and then with brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation to obtain 283 mg (yield 91%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [CH:1]([N:14]=[C:15]=[S:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH2:21][C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)(Cl)Cl.CCOCC>[CH:1]([NH:14][C:15]([N:19]([CH3:18])[O:20][CH2:21][C:22]([OH:24])=[O:23])=[S:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOCC(=O)O
Reactant: S=C=NC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(OCC(=O)O)C(=S)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of benzhydryl-isothiocyanate (13.75 g), N-methyl aminooxy acetic acid hydrochloride (8.6 g), triethylamine (16 g) and chloroform (200 mL) was heated at reflux for three hours, stirred at ambient temperature for one hour. The mixture was diluted with chloroform (200 mL) and washed with 2N HCl (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give a solid. The solid was stirred in ether (200 mL) and filtered to give 18.8 g of [[[[(benzhydryl)amino]thioxomethyl]methylamino]oxy]acetic acid as a white solid, m.p. 160-162° C. Mass spectrum (−FAB, [M−H]−) m/z 329. 1H-NMR (DMSO-d6; 400 MHz) δ13.55 (br s, 1H), 9.75 (d, 1H), 7.35-7.23 (m, 10H), 6.63 (d, 1H), 4.63 (s, 2H), and 3.42 ppm (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:43]([O:44][CH3:45])=[CH:42][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:43]([O:44][CH3:45])=[CH:42][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)=[O:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCN(C)CC1)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(=O)N1CCN(C)CC1)CC2
Yield: 36 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-(4-methyl-piperazin-1-yl)-ethanone. Product was isolated as a white foam (40 mg, 36%). mp: ˜140° C. (glass 100), MS (ESI+): 643.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=8 HZ, 1H), 7.58 (t, 1H), 7.52 (s, 1H), 7.25 (m, 1H), 6.67 (s, 1H), 3.89 (s, 3H), 3.72 (m, 2H), 3.68 (m, 2H), 3.30 (s, 2H), 2.88 (m, 2H), 2.76 (s, 8H), 2.70 (m, 2H), 2.66 (m, 2H), 2.46 (m, 2H), 2.42 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2.[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].C(N(CC)CC)C.O>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31])[C:24]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2)=[O:25]
Reactant: CC(=O)c1ccc(-c2cnc3c(c2)NCCO3)cc1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(C(C)=O)cc4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
In a 10 ml flask, 1-[4-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-phenyl]-ethanone (59 mg, 0.23 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (287 mg, 0.87 mmol) were dissolved in dichloromethane. Triethylamine (0.32 ml, 2.3 mmol) was added thereto and then stirred at room temperature for 12 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain 1-{4-[1-(3,5-dibromo-4-methoxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-phenyl}-ethanone as white solid (119 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:5][C:4]=1[N+:26]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.C(OCC)(=O)C>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])/[CH:11]=[CH:12]/[C:13]2[C:14]([O:23][CH3:24])=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=2[O:19][CH3:20])=[CH:5][C:4]=1[NH2:26]
Reactant: COc1cc(OC)c(C=CC(=O)Nc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc(OC)c(/C=C/C(=O)Nc2ccc(OC)c(N)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of N-(4-methoxy-3-nitrophenyl)-3-(2,4,6-trimethoxyphenyl) -2-propenamide (example 5) (1.3mmol) in acetone/water (10:5) was heated to 50° C. After 30 min, sodium hydrosulfite (Na2S2O4) 26.3 mmol) was added slowly. The resulting mixture was heated at reflux (50° C.) for one hour. The mixture was then cooled to room temperature and water was added. The product was isolated by extraction with ethyl acetate. The organic layer washed with 10% aqueous NaHCO3 and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product thereby obtained was recrystallized from 2-propanol to yield the title compound, melting point 92-94° C., in 48% yield.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[N:15]1([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Reactant: c1cn[nH]c1
Product: N#Cc1ccc(S(=O)(=O)CCn2cccn2)cc1

Procedure:
250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with pyrazole to yield 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-pyrazol-1-yl)ethylsulfonyl)-K-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.0 (M)+.
Reaction SMILES: [ClH:1].[CH:2](=[NH:6])[O:3]CC.[C:7]1([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[OH2:3].[ClH:1].[C:7]1([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]2[CH2:15][CH2:16][N:17]([CH:2]=[NH:6])[CH2:18][CH2:19]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC=N
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Product: N=CN1CCC(C(c2ccccc2)c2ccccc2)CC1
Product: O

Procedure:
A suspension of 27.39 g (0.25 mole) of ethyl formimidate hydrochloride [prepared by the method of Ohme, et al., Angew. Chem. Intl. Ed., 6, 566(1967)] and 52.71 g (0.20 mole) of diphenyl-4-piperidylmethane in 80 ml of freshly-opened absolute ethanol was stirred magnetically under a calcium chloride tube overnight. The suspension was filtered and diethylether was added to the filtrate. The filtrate was stripped to dryness and the resulting oil was crystallized from isopropanol. The solid was then suspended in boiling ethyl acetate to obtain a higher melting form. Two recrystallizations from ethanol-ether yielded pure 4-diphenylmethyl-1-iminomethylpiperidine hydrochloride hydrate; m.p. 220°-221° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11](Cl)=[O:12])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:11]([C:7]4[N:8]([CH3:10])[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=4)=[O:12])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A dry flask was charged with 5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (0.207 g, 1.03 mmol) and THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.390 g, 0.94 mmol, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](=S)[NH:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[C:6]([NH:22][C:23](=[O:25])[CH3:24])[CH:5]=1)[CH3:2].C([N:29](C(C)C)CC)(C)C.CI.N.CO>C(#N)C>[NH2:29][C:18]1[S:19][C:15](=[CH:14][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[C:6]([NH:22][C:23](=[O:25])[CH3:24])[CH:5]=[C:4]3[O:3][CH2:1][CH3:2])[C:16](=[O:21])[N:17]=1
Reactant: CCOc1cc(NC(C)=O)nc2ccc(C=C3SC(=S)NC3=O)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: CI
Solvent: CO
Solvent: CC#N
Product: CCOc1cc(NC(C)=O)nc2ccc(C=C3SC(N)=NC3=O)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
A suspension of N-[4-ethoxy-6-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-quinolin-2-yl]-acetamide (example 6a, 80 mg, 0.21 mmol) in acetonitrile (3 ml) was reacted with diisopropylethyl amine (0.40 ml, 2.2 mmol) and methyl iodide (0.30 ml, 4.6 mmol) at rt for 30 min. The mixture was concentrated to dryness and the residue suspended in DMF (0.5 ml). A solution of ammonia in methanol (7N, 5 ml, 35 mmol) was added at rt, and the mixture was stirred at rt for 24 h. The mixture was concentrated to dryness and the solid was triturated with water. The precipitate was collected by suction filtration, successively washed with water and ether, and then air dried to afford the product as a light brown solid (50 mg, 663%). LC-MS m/e 357 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8]CC)=O)=[CH:2]1.[NH2:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH3:22]>>[CH3:22][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][CH2:14][C:13]1[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=1[NH:11][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: CCOC(=O)c1ccoc1
Reactant: CN1CCCCC1CCc1ccccc1N
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccoc1

Procedure:
Reaction of ethyl furan-3-carboxylate prepared by the method of Boyd et al, Synthesis, 545, (Oct. 1971) with 2-(2-aminophenethyl)-1-methylpiperidine according to the procedure of Example 115 provides 2'-[2-(1-methyl-2-piperidyl)ethyl]-3-furancarboxanilide, m.p. 114.5°-115.5° C. (corr.), from isopropyl ether and then ethyl acetate.
Reaction SMILES: [CH3:1][CH:2]([C:7]1[CH:8]=[C:9]([OH:25])[C:10]2[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([CH3:18])([CH3:17])[O:14][C:15]=2[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[Br:26][CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>CC(C)=O>[Br-:26].[CH3:1][CH:2]([C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[CH:24]=[CH:23][N+:22]([CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=4)=[CH:21][CH:20]=3)=[CH:12][C:13]([CH3:18])([CH3:17])[O:14]2)=[C:9]([OH:25])[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)c1cc(O)c2c(c1)OC(C)(C)C=C2c1ccncc1
Reactant: BrCc1ccc2ccccc2c1
Solvent: CC(C)=O
Product: CCCCC(C)c1cc(O)c2c(c1)OC(C)(C)C=C2c1cc[n+](Cc2ccc3ccccc3c2)cc1
Product: [Br-]
Yield: 99.1 %

Procedure:
7-(2-Hexyl)-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (5.00 g), 2-bromomethyl-naphthalene (3.54 g) and acetone (70 ml) were heated together under reflux for 6 hours. The resulting pale yellow precipitate was filtered and dried to yield 4-[7-(2-hexyl)-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl]-1-(2-naphthylmethyl) pyridinium bromide (8.20 g) m.p. 236°- 239°.
Reaction SMILES: [Cl:1][C:2]1[C:11](I)=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[K+].[F:15][C:16]([F:19])([F:18])I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:10][C:5]2[NH:6][C:7]([S:9][C:16]([F:19])([F:18])[F:15])=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)I
Reactant: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Sc1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Compound number 102 (i.e., 6-chloro-5-(4-chlorophenyl)-2-trifluoromethylthiobenzimidazole) was prepared as follows. A 250-mL 3-necked round-bottom flask was charged with a solution of 5-chloro-6-iodo-2,3-dihydro-1H-1,3-benzodiazole-2-thione (2 g, 6.44 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) and potassium hydroxide (1.1 g, 3.00 equiv). Trifluoro(iodo)methane was introduced to the above. The resulting solution was stirred for 3 h at 120° C. in an oil bath. The resulting solution was diluted with 250 mL of ethyl acetate. The resulting mixture was washed with 3×200 mL of water and 2×200 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 400 mg (16%) of 5-chloro-6-iodo-2-[(trifluoromethyl)sulfanyl]-1H-1,3-benzodiazole as a yellow solid.
Reaction SMILES: [CH2:1]1[N:6](C(OCC)=O)[CH2:5][CH2:4][N:3]2[C:12]3[CH:18]=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][C:13]=3[N:14]=[C:2]12.[OH-].[Na+].O.Cl>C(O)C>[CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:12]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:13]=3[N:14]=[C:2]12
Reactant: CCOC(=O)c1ccc2c(c1)nc1n2CCN(C(=O)OCC)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc1n2CCNC1
Yield: 67 %

Procedure:
Diethyl 3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyrazine-2,8-dicarboxylate (500 mg, 1.58 mmol) prepared in the Step 38-1-3 was suspended in ethanol (3.2 ml), and a 1 mol/L sodium hydroxide aqueous solution (1.6 ml) and then purified water (1.6 ml) were added thereto. The mixture was heated under reflux for 48 hours. After being allowed to cool, the mixture was neutralized with 3-N hydrochloric acid. The precipitate was separated by filtration and dried to give the title compound (230 mg, 67%) as a light-brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(Cl)cc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-(4-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (146.2 mg, 0.32 mmol, 1.00 equiv) in MeOH/THF (1:1)(16 mL), a solution of sodium hydroxide (64 mg, 1.60 mmol, 5.00 equiv) in water (1.5 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. The solid was dissolved in DMF and sent for prep-HPLC to purification. This resulted in 49 mg (35%) of 3-(4-(4-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.