Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]([CH3:37])([CH2:35][CH3:36])[CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]1([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1)=O>>[CH3:6][C:7]([CH3:37])([CH2:35][CH3:36])[CH2:8][C:9]1[N:5]=[C:12]([C:14]2([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=4)=[CH:23][CH:22]=3)[NH:15][C:16](=[O:19])[CH2:17][CH2:18]2)[NH:11][CH:10]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCC(=O)N1
Agent: CC(=O)[O-]
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CCC(=O)N2)n1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (1.18 g, 15.4 mmol) was added to an ambient temperature solution of N-(4,4-dimethyl-2-oxohexyl)-2-[4-(5-fluoropyridin-2-yl)benzyl]-5-oxopyrrolidine-2-carboxamide in xylenes (minimal volume). After stirring in a sealed tube at 160° C. for 1 hr, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded the title compound. (M+H) found: 421.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=S)[CH2:15][C:16](=O)[CH3:17])=[O:4].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:28]([C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:27][CH:26]=2)[N:29]=[C:16]([CH3:17])[CH:15]=1)=[O:4]
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-methanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 448c) was reacted with 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound. MS (ESI): m/z=432.0 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.O>C(#N)C>[CH2:1]([NH:17][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: CCCCCCCCCCCCCCCCNC(=O)c1cccnc1
Reaction time: 3 h
Yield: 82.4 %

Procedure:
30.7 g of cetylamine and 33.2 g of pyridine were dispersed in 200 ml of acetonitrile, and 25 g of nicotinic acid chloride hydrochloride was added thereto under cooling with water. After reacting for 3 hours at 55° C., 800 ml of water was added thereto. The thus formed crystals were collected by filtration. Recrystallization from 500 ml of ethanol yielded 36.3 g of the end product. m.p. 85°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[N:8][C:7]=2[CH:6]=[C:5]([O:15]C)[CH:4]=1.Br.C>CO>[OH:15][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]2[NH:10][C:9]([CH:12]([CH3:13])[CH3:14])=[N:8][C:7]=2[CH:6]=1
Reactant: COc1cc(OC)c2[nH]c(C(C)C)nc2c1
Agent: Br
Solvent: CO
Product: COc1cc(O)cc2nc(C(C)C)[nH]c12
Temperature: 25 °C

Procedure:
Alternatively, a solution of 4,6-dimethoxy-2-isopropylbenzimidazole (12.70 g, 57.66 mmol) and 48% HBr (100 mL) was refluxed for 3 hours, and then the solution was cooled to ambient temperature and concentrated. The resulting solids were dissolved in H2O (100 mL) and neutralized (NaHCO3). A brown precipitate formed which was isolated by filtration. The precipitate was dissolved in MeOH (100 mL), treated with charcoal and concentrated to afford 6-hydroxy-2-isopropyl-4-methoxybenzimidazole as a brown solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2.Cl.[CH2:16]([N:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][Cl:22])[CH3:17]>>[CH2:16]([N:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][N:7]1[C:8]2[C:4]3[C:3](=[CH:14][CH:13]=[CH:12][C:5]=3[C:6]1=[O:11])[CH:2]=[CH:10][CH:9]=2)[CH3:17].[ClH:22]
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Reactant: CCN(CC)CCCCl
Agent: Cl
Product: CCN(CC)CCCN1C(=O)c2cccc3cccc1c23

Procedure:
By the procedure described for Compound I, 6-bromobenz[cd]indol-2(1H)-one and 3-diethylaminopropyl chloride hydrochloride yield 6-bromo-1-(3-diethylaminopropylbenz[cd]-indol-2 (1H)-one (Ie), HCl salt, mp. 183°-185° C., while 3-dimethylaminopropyl chloride hydrochloride yields 6bromo-1-(3-dimethylaminopropyl) benz[cd]-2(1H)-one (If), HCl salt, mp. 264°-267° C. Similarly, 6-chlorobenz[cd]indol-2(1H)-one and methyl iodide yield 6-chloro-1-methylbenz[cd]-2(1H)-one (Ig), while benz[cd]indol-2(1H)-one and 4-chlorobenzyl chloride yield 1-(4-chlorobenzyl)benz[cd]indol-2(1H)-one (Ih), mp. 128°-129.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([O:31][C:32]([N:34]([CH2:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][NH:47][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:48][CH:49]=1)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CN)cc1)C1CCCCC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CCCCC1
Yield: 75.9 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.71 mmol) and 4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamine (335 mg, 1.05 mmol). Purify by chromatography on silica gel (150 g) eluting with hexane/EtOAc (1:0 to 9:1 gradient) to obtain 6-{-4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (320 mg, 76%). MS (ES+) m/z: 494 (M-Boc+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:16]([CH:17]=[CH:18][C:4]1[C:3]2[C:7](=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]=1[C:12]([O:14][CH3:15])=[O:13])=[O:19]
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COC(=O)C=Cc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
In 23 ml of anhydrous acetonitrile were dissolved 1.5 g (7.4 mmol) of methyl 4,7-dimethylindole-2-carboxylate and 7.6 ml of methyl acrylate. The air in the reaction system was substituted with nitrogen. After cooling the reaction mixture to 0° C., 1.66 g (7.4 mmol) of palladium acetate was added and the reaction mixture was stirred for 30 minutes. Stirring was further continued at room temperature for 19 hours. After addition of 60 ml of acetonitrile, the reaction mixture was subjected to Celite filtration. The filtrate was concentrated under reduced pressure and the solids thus obtained were purified by silica gel column chromatography to provide 680 mg of yellow crystals. Yield: 48%
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:24]=[CH:23][N:22]([CH2:25][C:26](O)=[O:27])[N:21]=1>>[F:30][C:19]([F:18])([F:29])[C:20]1[CH:24]=[CH:23][N:22]([CH2:25][C:26]([N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13][CH2:14]2)=[O:27])[N:21]=1
Reactant: CCOC(=O)c1csc(C2CC[NH2+]CC2)n1
Reactant: O=C(O)Cn1ccc(C(F)(F)F)n1
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3ccc(C(F)(F)F)n3)CC2)n1

Procedure:
4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 5.50 g) is reacted analogously to Example IV-1 with [3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.86 g). This gives, after chromatographic purification, ethyl 2-(1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.1 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:16])[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C(Cc1ccccc1)c1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CC(C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A stirred solution of benzyl 3-benzyloxyphenyl ketone (3.02 g) in dry tetrahydrofuran (70 mL) at −40° C. is treated with potassium tert-butoxide (1.12 g), portionwise during 10 minutes. The reaction is stirred at −40° C. for 1 hour and is then treated dropwise with a solution of methyl bromoacetate (1.04 g) in tetrahydrofuran (10 mL). The mixture is allowed to stir at ambient temperature for 18 hours. After this time, the reaction is concentrated to dryness and partitioned between ethyl acetate and water. The organic layer is dried over magnesium sulphate and concentrated under reduced pressure. The residue is recrystallised from a mixture of ethyl acetate and pentane, to give methyl (RS)-4-(3-benzyloxyphenyl)-4-oxo-3-phenylbutanoate (1.4 g), m.p. 88-89° C.
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][O:4][NH2:5].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[C:13]1([NH:19][C:20]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: NOCC(O)CN1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(NOCC(O)CN1CCCCC1)Nc1ccccc1

Procedure:
O-(2-hydroxy-3-piperidino-propyl)-hydroxylamine (1,74 g, 0,01 mol) was dissolved in 40 ml chloroform and 1,09 ml (0,01 mol) phenyl isocyanate was added thereto while stirring. The reaction was monitored by chromatography. After the end of reaction the solution was evaporated and the oily residue was purified by column chromatography. The oil thus obtained was crystallized from diethyl ether. Yield: 0,6 g (20%). Mp: 101-103° C.
Reaction SMILES: Br[CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:23][C:24]([NH2:26])=[S:25].C([O-])(=O)C.[Na+]>C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:23]=[C:24]([NH2:26])[S:25][C:2]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C(Br)Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc(N)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 79.1 %

Procedure:
To a 50 ml eggplant-shaped flask were added 0.45 g (1.24 mmol) 2-bromo-1-(4-methoxy-phenyl)-3-(4-nitro-phenyl)-propan-1-one prepared in the step 4 and 15 ml anhydrous ethanol, added 94 mg (1.24 mmol) thiourea and 101 mg (1.24 mmol) anhydrous sodium acetate under stirring. The resulting mixture was refluxed for 3 hours, distilled under a reduced pressure to remove the solvent, added 20 ml ethyl acetate and 20 ml 5% NaHCO3 aqueous solution, the organic layer was separated, washed with saturated brine until neutrality, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was recrystallized with ethyl acetate to obtain a 0.34 product in a yield of 79.1%, mp: 209-210 └(Dec.). 1H-NMR (DMSO-d6, 400 MHz) δ: 3.34 (3H, s, OCH3), 4.20 (2H, s, CH2), 6.93 (2H, s, NH2), 6.95 (2H, d, J=8.72 Hz, ArH), 7.43˜7.46 (4H, m, ArH), 8.19 (2H, d, J=8.72 Hz, ArH); EI-MS m/e (%): 341.2 (M+, 100), 219.1 (14); HREI-MS Calcd. for C17H15N3O3S: 341.0834. found: 341.0834. Anal. Calcd. for C17H15N3O3S: C, 59.81; H, 4.43; N, 12.31. found: C, 59.76; H, 4.36; N, 12.05.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:25])[CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[N:18]1[CH:19]=[C:20]([C:24]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C@H:2]3[CH2:7][CH2:6][C@H:5]([N:8]4[C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[NH:10][C:9]4=[O:17])[CH2:4][CH2:3]3)[CH2:31][CH2:32]2)=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NC1CCNCC1)c1cccnc1
Reactant: O=C1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(NC1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 0.13 g of 1,3-dihydro-1-(4-oxocyclohexyl)-2H-benzimidazol-2-one, 0.12 g of 4-(3-pyridinecarbonylamino)piperidine, 5 mL of 1,2-dichloroethane, 0.04 mL of glacial acetic acid and 0.161 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 50 mL chloroform and 50 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with 10% methanol in choroform gave 0.015 g of 1,3-dihydro-1-{trans-4-[4-(5-pyridinecarbonylamino)piperidin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one: 1H NMR (400 MHz, CDCl3) 9.01 (d, J=2 Hz, 1H), 8.75 (dd, J=2 and 4.5 Hz, 1H), 8.40 (br s, 1H), 8.16 (dd, J=2 and 8 Hz, 1H), 7.43 (m, 2H), 7.08 (m, 3H), 6.16 (br m, 1H), 4.47 (m, 1H), 4.12 (m, 2H), 3.1 (br s, 2H), 2.8 (m, 1H), 2.5 (m, 1H), 2.2 (br m, 4H), 1.60 (br m, 8H). The dihydrochloride salt was precipitated from ether: Analysis calculated for C24H29N5O2.2HCl.0.75 CHCl3.1.0 H2O C: 49.54, H: 5.67, N: 11.67 found C: 49.55, H: 5.85, N: 11.88.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1>O>[C:3]1([CH3:13])[CH:4]=[CH:5][C:6]([S:9]([O-:12])(=[O:10])=[O:11])=[CH:7][CH:8]=1.[Zn+2:2].[C:3]1([CH3:13])[CH:4]=[CH:5][C:6]([S:9]([O-:12])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an appropriate vessel there is charged 618 gms (7.6 moles) of zinc oxide in an aqueous slurry. With vigorous stirring there is slowly added to the charge 650 gms (3.8 moles) of p-toluene sulfonic acid in 1 liter of water. The resulting reaction mixture produces an exotherm and heats up to a temperature of circa 100° C. With continued stirring, the mixture is allowed to cool to room temperature and then stood overnight. The crystal precipitate is then separated by filtration, washed and dried to obtain zinc p-toluene sulfonate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)(=[O:3])N.N([O-])=[O:22].[Na+].O>[N+]([O-])(O)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)([OH:22])=[O:3]
Reactant: NC(=O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C(O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
2-carbamoyl-4H-pyrido[3,2,1-jk]carbazole-4-one (350 mg) produced in Example 174 was suspended in conc. nitric acid (13 ml), and sodium nitrite (1.84 g) was added to the suspension in an ice bath. The mixture was stirred at room temperature for 12 hours, and water was added to the reaction mixture. The crystals precipitated were recovered by filtration, and washed with methanol and ether in succession to obtain the title compound (300 mg, 85%).
Reaction SMILES: [OH:1][B:2]1[O:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][O:3]1.[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)#[N:14].N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:1][B:2]2[O:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][O:7]2)=[O:20])=[CH:17][CH:16]=1)#[N:14]
Reactant: CCCCCC1COB(O)OC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1COB(OC(=O)c2ccc(C#N)cc2)OC1

Procedure:
17.2 g of 2-hydroxy-5-pentyl-1,3,2-dioxaborinane (prepared from trichloroborane and 2-hydroxymethylheptan-1-ol, followed by hydrolysis), 16.6 g of 4-cyanobenzoyl chloride and 15 ml of pyridine in 500 ml of toluene are heated at reflux temperature for 4 hours. Water is added to the mixture, the phases are separated, the organic phase is washed with water, dried over sodium sulphate and evaporated, and (5-pentyl-1,3,2-dioxaborinan-2-yl) 4-cyanobenzoate is obtained.
Reaction SMILES: [OH-].[Na+:2].C[O:4][C:5](=[O:41])[C@@H:6]([NH2:40])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1>CO>[NH2:40][C@@H:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:20][CH3:21])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:32])([CH3:33])[CH3:34])=[C:24]([CH3:36])[CH:23]=3)[CH2:37][CH3:38])=[CH:15][C:14]=2[CH3:39])=[CH:11][CH:12]=1)[C:5]([O-:41])=[O:4].[Na+:2]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](N)C(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](N)C(=O)[O-])cc2)c(C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
A 0.5 N sodium hydroxide aqueous solution (0.064 mL) was added to a solution of (S)-amino-(4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 166-(3); 12.0 mg, 0.0226 mmol) in methanol (0.50 mL) at room temperature, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (12.5 mg, 100%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:12]=3[S:11][C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[OH-].[K+].O.C(O)C>O1CCOCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]=3[S:11][C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1N=C2N1CCOCC1

Procedure:
Stir a mixture of 1.77 gm. (5 mmole) of the ester of Example 11, 1.12 gm. (10 mmole) of 85% aqueous potassium hydroxide, 5.5 ml. of water, 27.5 ml. of ethanol and 2.75 ml. of dioxane under argon at room temperature for 21/2 hours. Evaporate to a small volume and dilute with 18 ml. of water. Filter and acidify with acetic acid to pH 4.5. Separate the precipitate by filtration, wash with water and dry in vacuo over calcium chloride. Recrystallize from acetonitrile to obtain the title product, (m.p. 267°-269° C.).
Reaction SMILES: [CH:1]12[CH2:8][NH:7][CH2:6][CH:5]1[CH2:4][N:3]([C:9]1[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:22])[C:11]=3[CH:10]=1)[CH2:2]2.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:27](C)=O.[Na+]>>[CH3:27][N:7]1[CH2:8][CH:1]2[CH:5]([CH2:4][N:3]([C:9]3[CH:21]=[CH:20][C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12](=[O:22])[C:11]=4[CH:10]=3)[CH2:2]2)[CH2:6]1
Reactant: O=C1c2ccccc2-c2ccc(N3CC4CNCC4C3)cc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Product: CN1CC2CN(c3ccc4c(c3)C(=O)c3ccccc3-4)CC2C1
Reaction time: 3 h
Yield: 100 %

Procedure:
The product of Example 13B (130 mg, 0.46 mmol) was treated with aqueous formaldehyde (5 mL, 37%; EM Science) and NaBH(OAc)3 (163 mg, 0.77 mmol; Aldrich). After stirring for 3 h, the reaction was quenched with saturated NaHCO3 (5 mL) and diluted with CH2Cl2 (5 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure and purified via column chromatography (silica gel, 1:9:90 NH4OH/CH3OH/CH2Cl2) to give the title compound (>100%, impure). MS (DCI/NH3) m/z 305 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.CN(C)CCN(C)C.C([Li])CCC.[CH:29](=[O:42])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]#[CH:41]>C1COCC1>[CH3:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[C:7]=1[CH:29]([OH:42])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]#[CH:41]
Reactant: C#CCCCCCCCCCCC=O
Reactant: COc1cc(C)c(OC)c(OC)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCCCCCCCCCC(O)c1c(C)c(OC)c(OC)c(OC)c1OC

Procedure:
A solution of 5-methyl-1,2,3,4-tetramethoxybenzene (2.12 g, 10 mmol, Hansen, C. A.; Dean, A. B.; Draths, K. M.; Frost, J. W. J. Am. Chem. Soc. 1999, 121(15), 3799-3800.) and tetramethylethylenediamine (TMEDA, 2.96 mL, 20 mmol) in hexanes (25 mL) is cooled at 0° C. in an ice bath while a solution of n-butyllithium (2.0M in hexanes, 5 mL) is added dropwise. The yellow reaction mixture is stirred for thirty minutes and is then diluted with THF (20 mL). A solution of 12-tridecynal (4.27 g, 22 mmol, J. Org. Chem. 2001, 66(14), 4766-4770) in THF (10 mL) is added, and the mixture stirred for two hours. The reaction is quenched by the addition of saturated aqueous NH4Cl (20 mL). Water (30 mL) is added and the aqueous phase is separated and extracted with ethyl acetate (2×50 mL). The combined organic fractions are washed (1× water), dried (saturated aqueous NaCl, sodium sulfate), filtered, and concentrated. Chromatography (hexane-2:1 hexane:ethyl acetate gradient over silica gel 230-400 mesh) provides the desired product.