Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:33])[C@H:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)[O:17][NH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=O)[C:41]([OH:43])=[O:42])[N:39]=1.O.Cl>CN(C)C=O>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:18]/[O:17][C@H:16]([C:15]([O:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)/[C:41]([OH:43])=[O:42])[N:39]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: CC(=O)Oc1ccc([C@H](ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc([C@H](O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To an ice-cooled solution of the product obtained in Step 4 (20.3 g) in dimethylformamide (60 ml) was added 2-(2-amino-4-thiazolyl)glyoxylic acid (7.8 g). the mixture was allowed to stand until it reached room temperature, and stirred overnight. The reaction mixture was then poured into ice-cooled water (400 ml), and the pH of the resulting mixture was adjusted to 2.0 with 1 N hydrochloric acid. The mixture was extracted twice with ethyl acetate (500 ml). The combined organic layer was washed with brine (200 ml) and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was dissolved in a small amount of chloroform. This solution was added dropwise to ether. The formed crystals were collected by filtration and washed with ether, giving 22.3 g of the objective compound as pale yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:25][C:26]([O:28]CC)=[O:27])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:12]=[CH:11][CH:10]=2)=[O:5])C>O>[NH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:8]=[C:7]([CH2:25][C:26]([OH:28])=[O:27])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1nc2cccc(CCC3CCCCC3)c2c(N)c1C(=O)OCC
Solvent: O
Product: Nc1c(C(=O)O)c(CC(=O)O)nc2cccc(CCC3CCCCC3)c12

Procedure:
Prepared as in Example 1 from ethyl-4-amino-5-(2-cyclohexylethyl)-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate (Example 113a) as an orange solid (69%). 1H NMR (400 MHz, DMSO-d6) δ 0.89-0.92 (m, 2H), 1.14-1.29 (m, 4H), 1.44-1.49 (m, 2H), 1.56-1.66 (m, 4H), 1.73-1.76 (m, 1H), 3.15 (t, J=8.0 Hz, 2H), 3.70 (s, 2H), 7.09-7.11 (m, 1H), 7.38-7.42 (m, 1H), 7.46-7.51 (m, 2H). MS 338 (MH+-H2O).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]=1[CH3:30])C.[NH2:32][NH2:33].O>C(O)C>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([CH2:5][C:4]([NH:32][NH2:33])=[O:3])=[C:7]1[CH3:30]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2-c2ccccc2)c2ccc(OC)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1-c1ccccc1

Procedure:
A mixture of 1.18 g (2.86 mmol) of 1-([1,1-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester and 3 mL of hydrazine in 20 mL of ethanol was heated to maintain reflux for 16 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated to give 1.02 g of 1-([1,1′-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid hydrazide. A mixture of 576 mg (1.44 mmol) of this material and 300 mg of Raney Ni in 20 mL of ethanol was heated to maintain reflux for 3 hours. After cooling the solvent was decanted and the Raney Ni washed twice with methylene chloride. The combined organic solvents were concentrated at reduced pressure and the residue chromatographed on silica gel and eluted with ethyl acetate to give 369 mg (67% yield) of 1-([1,1′-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][C:7]2=[O:12].[C:13]1([CH2:19][CH2:20][CH:21]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CO>[C:13]1([CH2:19][CH2:20][C:21]2[N:10]3[C:11]4[C:6]([C:7](=[O:12])[CH2:8][CH2:9]3)=[CH:5][CH:4]=[CH:3][C:2]=4[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=CCCc1ccccc1
Reactant: Nc1cccc2c1NCCC2=O
Agent: Cl
Solvent: CO
Product: O=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fifteen grams of 8-amino-2,3-dihydro-4(1H) -quinolinone was dissolved in methanol (300 mL), and after addition of 3-phenylpropionaldehyde (14.6 mL) and 1N HCl (3 mL), the mixture was stirred at room temperature for 2 hrs, followed by addition of silica gel (60 g) to the reaction mixture, and the solvent was removed under reduced pressure. The residue was heated at 100° C. for 2 hrs and purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to yield the titled compound as yellow crystals (13.2 g).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C:13]([CH2:15][C@:16]4([CH3:22])[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:14]>O1CCOCC1.Cl>[CH3:22][C@:16]12[CH2:15][C:13](=[O:14])[C@H:12]3[C@@H:11]([CH:10]=[CH:9][C:8]4[C@:2]3([CH3:1])[CH2:3][CH2:4][C:5](=[O:6])[CH:7]=4)[C@@H:17]1[CH2:18][CH2:19][C:20]2=[O:21]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Solvent: C1COCCO1
Product: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 1.5 h

Procedure:
Adrenosterone (androst-4-ene-3,11,17-trione, A-1, 50 g, 166.7 mmol) was dissolved in dioxane (1200 mL, dry), which had been saturated with HCl gas at 10° C. under argon, and a chilled solution of 2,3-dichloro-5,6-dicyanoquionone (DDQ, 50 g, 220 mmol) in hydrogen chloride saturated dioxane (450 mL) was added slowly to the stirred solution. Solid dihydro-DDQ rapidly separated from the solution. After 1.5 h, the mixture was filtered through a sintered glass funnel, most of the dioxane was evaporated under reduced pressure and the residue was chromatographed over silica gel (1000 g) using chloroform as the eluting solvent. The light-yellowish material from evaporation of the eluate was 48.7 g of the dienone compound A-2: mp 237° C.; UV (MeOH) λmax 278 nm (ε 24,600); IR (CHCl3) 1745 (17-C=0), 1705 (11-C=0) and 1650 (3-conjugated C=0) cm−1; 1H NMR(CDCl3) δ 0.92 (s, 3, 18-CH3), 1.32 (s, 3, 19-CH 3), 5.63 (s, 1, 4-H) and 6.13 (s, 2, 6- and 7-H); m/z 298 (M+).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH2:34][CH:35]([CH3:37])[CH3:36]>CS(C)=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][CH2:5][CH:6]([CH3:14])[CH3:7])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: CC(C)CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)CCc1cn(CC(C)C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (64 mg) was added to a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (100 mg) and 1-iodo-2-methylpropane (0.2 mL) in dimethyl sulfoxide (DMSO) (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over sodium sulfate. After concentration, the residue was purified via column chromatography to afford 2-methylpropyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(2-methylpropyl)-1H-indol-3-yl]propanoate (D124) (77 mg). MS (ES): C30H36ClN3O4 requires 537; found 538.3 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=O)=[CH:17][CH:16]=1>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:23]([CH2:22][CH2:21][C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:25])[F:26])=[CH:20][CH:19]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(OC(F)(F)F)cc1
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(OC(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (5.621 mmol) and 3-(4-trifluoromethoxy-phenyl)-propionaldehyde (1.206 g; 5.528 mmol) afforded 3-ethyl-1-iodo-8-[2-(4-trifluoromethoxy-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.78 min.; [M+H]+=465.87 g/mol.
Reaction SMILES: [C:1]([C:9]1[S:10][C:11]2[CH:23]=[C:22]([O:24]C)[CH:21]=[CH:20][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[C:1]([C:9]1[S:10][C:11]2[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3)sc2c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1sc2cc(O)ccc2c1-c1ccccc1
Temperature: 0 °C
Yield: 88 %

Procedure:
A mixture of 2.5 g. (0.0073 mole) of the product from Example 5 and 10 g. of pyridine hydrochloride was refluxed in a 220° C. oil bath for 1.5 hours. The hot reaction mixture then was poured over an ice-water mixture in a blender, and the resulting yellow crystals were collected. The crystals then were dissolved in ethyl acetate, and the ethyl acetate solution was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The ethyl acetate solution then was filtered over silica, and the silica was washed with ethyl acetate which was added to the original ethyl acetate solution. The ethyl acetate was evaporated and the resulting residue was crystallized from methanol to give 2.1 g. (88 percent) of the title compound as yellow crystals, m.p. 187°-190° C. The product was recrystallized from methanol to give a purified product having melting point 191°-191.5° C.
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>CO>[CH3:1][O:17][C:16](=[O:18])[CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Trimethylsilyl chloride (5.6 mL, 2.0 equiv.) was added to a stirred solution of (3-nitrophenyl)acetic acid (4.0 g) in methanol (60 ml). The resulting solution was stirred at room temperature for 18 hours, then concentrated at reduced pressure and partitioned between DCM and aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound as a colourless liquid (4.2 g, 100%).
Reaction SMILES: F[C:2]1[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-:30].[Na+]>CN(C)C=O>[F:30][C:22]1[C:23]([F:28])=[C:24]([F:27])[C:25]([F:26])=[C:2]2[C:3]=1[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: [F-]
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Temperature: 0 °C
Yield: 94.6 %

Procedure:
A mixture of 135.4 g of ethyl 2-(2,3,4,5,6-pentafluorobenzoyl)-3-(2,4-difluorophenylamino)acrylate, 20.6 g of sodium fluoride and 300 ml of anhydrous dimethylformamide is heated at 140°-150° C. for 3 hours. The suspension is poured hot onto 2 kg of ice and the precipitate is filtered off with suction, washed with water and dried. 122 g of the title compound of melting point 160°-162° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CC(C)([O-])C.[K+].[NH2:18]Cl>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([NH2:18])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A solution of 5-methoxy-1H-indole (16.9 mmol) and potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (169.2 mL) is added drop-wise for 15 minutes at rt. The reaction mixture is stirred at rt for 2 h, quenched with 5% Na2S2O3 aqueous solution (100 mL), and stirred at rt overnight. The mixture is extracted with ether. The organic layer is separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-20% EtOAc in heptane to afford 5-methoxy-indole-1-ylamine (388 mg, 14%) as a solid. 1H NMR (300 MHz, CDCl3): δ 4.78 (br, 2N—H), 6.35 (d, H), 6.94 (d, H), 7.08 (d, H), 7.17 (d, H), 7.30-7.39 (d, H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([O:8][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(Br)c[nH]c1=O
Reactant: Fc1cccc(F)c1CBr
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Oc1cc(Br)cnc1OCc1c(F)cccc1F

Procedure:
To a solution of 5-bromo-3-hydroxy-2(1H)-pyridinone (U.S. Pat. No. 3,471,506, 10.0 g, 52.6 mmol) in dioxane (30 mL) and H2O (15 mL) was added NaOH (2.1 g, 52.5 mol) dissolved in H2O (12.5 mL). To this mixture is added di-t-butyl-dicarbonate (12.5 g, 57.5 mmol), and the mixture is stirred at room temperature for 6 hours. At this time, the mixture is filtered, and the solid is washed with H2O (50 mL), and is dissolved in CH2Cl2 (100 mL). This organic solution is washed with brine, dried over MgSO4, and concentrated to yield 5-bromo-3-(t-butoxycarbonyloxy)-2(1H)pyridinone. A solution of 5-bromo-3-(t-butoxycarbonyloxy)-2(1H)-pyridinone (5.0 g, 17.2 mmol), AG2CO3 (4.74 g, 17.2 mmol) and α-bromo-2,6-difluorotoluene (3.56 g, 17.2 mmol) in toluene (60 mL) is heated to 42° for 24 hours in the dark. At this time the mixtut is filtered. The filtrate is concentrated in vacuo, and the residue is dissolved in EtOAc (150 mL) and washed with H2O (50 mL) and brine (50 mL), dried over MgSO4 and concentrates in vacuo. Chromatography (silica, 9:1 EtOAc/hexane) yields 5-bromo-3-(t-butoxycarbonyloxy)-2-(2,6-difluorobenzyloxy)-pyridine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([C:28](Cl)=[O:29])[CH:23]=1>C1(C)C=CC=CC=1>[CH3:31][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[C:28]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:29]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Yield: 65 %

Procedure:
1.0 g (0.00532 mol) of 1-benzyl-4-hydroxypiperidine and 0.72 ml (0.00532 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.7 ml (0.00532 mol) of m-toluoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3→1:2). 1.07 g (65%) of 1-benzyl-piperidin-4-yl 3-methyl-benzoate were obtained as a yellow solid: m.p. 45°-46°.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:7](=[O:18])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[CH3:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39]Br>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:7](=[O:18])[CH:8]([CH2:36][C:37]3[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=3[CH3:39])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: Cc1ccccc1CBr
Reactant: COc1ccc(CN2C(=O)CN=C(c3ccc(F)cc3)c3cc(Cl)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3C)N=C(c3ccc(F)cc3)c3cc(Cl)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
7-Chloro-5-(4-fluorophenyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (90 mg, 0.220 mmol) was dissolved in dry THF (2 mL) and cooled to −78° C. under nitrogen. Potassium tert-butoxide (49 mg, 0.437 mmol) was added as a solid in one portion and the resulting red solution was stirred vigorously for 5 min. To this solution was added 2-methylbenzyl bromide (25 μL, 0.262 mmol) by syringe. The mixture was stirred for 1 h at −78° C., then the cold bath was removed. After another 1 h (warming to room temperature), the reaction was quenched with MeOH and diluted with ethyl acetate. The organic layer was washed twice with water and once with brine, and then dried over MgSO4. Chromatography on silica gel eluting with 100% hexanes to 30% ethyl acetate in hexanes provided 7-chloro-5-(4-fluorophenyl)-1-(4-methoxybenzyl)-3-(2-methylbenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (44 mg, 39%). APCI MS m/z 535.2 [M+Na+], 513.3 [M+]; 1H NMR (300 MHz, CDCl3) δ 7.43-6.98 (m, 11H), 6.88 (d, J=9 Hz, 2H), 6.61 (dd, J=7 Hz, 2 Hz, 2H), 5.69 (d, J=15 Hz, 1H), 4.55 (d, J=15 Hz, 1H), 3.85 (t, J=7 Hz, 1H), 3.70 (s, 3H), 3.63 (d, J=7 Hz, 2H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([OH:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][C@@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[CH2:15][CH2:14]1)(=[O:27])=[O:26]
Reactant: O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-ol (1.476 g, 6.79 mmol) from Step B and triethylamine (1.420 mL, 10.19 mmol) were combined in dichloromethane (30 mL). Methanesulfonyl chloride (0.635 mL, 8.15 mmol) was added as a solution in 20 mL of dichloromethane dropwise via addition funnel. The reaction was stirred at room temperature for 30 minutes and concentrated. The crude material was absorbed onto silica gel and chromatographed on a silica gel cartridge (Analogix®, Burlington, Wis., RS25-25) eluting with 20-100% ethyl acetate/hexanes to give (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate: 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.27 (m, 4H), 7.27-7.20 (m, 1H), 4.96 (ddd, J=6.1, 7.6, 9.1, 1H), 3.71-3.44 (m, 1H), 2.94 (s, J=13.5, 3H), 2.85 (ddd, J=4.9, 8.1, 16.0, 1H), 2.75-2.68 (m, 2H), 2.67-2.55 (m, 1H), 2.54-2.44 (m, 1H), 2.31 (dd, J=4.1, 8.7, 1H), 2.20-2.04 (m, 1H), 1.97 (dtd, J=3.4, 6.2, 9.6, 1H), 1.79-1.63 (m, 1H), 1.61-1.49 (m, 2H).
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([CH3:10])=[C:6]([CH3:9])[C:7]=1[CH3:8].C(#N)C.[Br-:14].[C:15]1([PH+:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[Br-:14].[CH3:8][C:7]1[C:6]([CH3:9])=[C:5]([CH3:10])[S:4][C:3]=1[CH2:2][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1sc(CO)c(C)c1C
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Temperature: 50 °C

Procedure:
2.2 G. of 2-hydroxymethyl-3,4,5-trimethyl-thiophene were dissolved in 25 ml. of acetonitrile and 4.6 g. of triphenylphosphonium bromide were added. The resulting reaction mixture was heated to 50° C. for 3 hours. After evaporation of the solvent, the residue which formed was diluted with ethyl acetate, heated briefly and filtered. The crystalline (3,4,5-trimethyl-2-thenyl)-triphenyl phosphonium bromide obtained was dried at 50° C. under high vacuum and had m.p. 208°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:26](O)=[O:27].O1CCCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[N:8][CH:7]=[C:6]2[CH2:26][OH:27]
Reactant: COc1ccc(Cc2ncc(C(=O)O)c3cc(OC)c(OC)cc23)cc1OC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A slurry of 25.2 g of 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid and 100 of dry tetrahydrofuran was stirred at 15° in an inert atmosphere while cautiously adding 200 ml of 1 molar borane/tetrahydrofuran complex. After stirring for 2 hours at room temperature, the initial solids had dissolved and were replaced by a second precipitate. The mixture was cautiously treated with 200 ml of water and the tetrahydrofuran was removed in vacuo at 40°. The chilled reaction mixture was then filtered, washed with water, and the damp stable borane complex was added portionwise with stirring to 200 ml of 2 N hydrochloric acid previously heated to 70°-80°. The resulting solution was heated an additional 15 minutes on the steam bath and was then chilled extracted with 100 ml of diethyl ether. The aqueous layer was added dropwise to 250 ml of cold 2 N sodium hydroxide with stirring. The resulting solids were removed by filtration, washed well with water, and dried to give 20.6 g of crude 6,7-dimethoxy-1[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline methanol, mp 146°-148°. Recrystallization from methylene chloride/ethyl acetate gave 19.2 g of purified 6,7-dimethoxy-1-(3,4-dimethoxyphenyl)methyl]-4-isoquinoline methanol, mp 141°-143°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[CH2:22]([O:26][C:27]1(OCCCC)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([O:26][C:27]1([O:1][CH2:2][C:3]2[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOC1(OCCCC)CCCCC1
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCCCOC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC)CCCCC1
Yield: 34.4 %

Procedure:
The compound 19 (345 mg, 1.00 mmol) was converted to the acetal with 1,1-dibutoxycyclohexane (2.28 g, 10.0 mmol) in the same manner as the example 18 to give the compound 21 (172 mg, 35%) as oil. Rf 0.41 (Al2O3 60, Type E, toluene).