Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:32]=1.O>CCOCC>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)([OH:31])[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:32]=1
Reactant: COc1ccc2c(c1)CCCCC2=O
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)CCCCC2(O)c1cc(OC)c(OC)c(OC)c1
Temperature: -30 °C
Yield: 49.6 %

Procedure:
200 mL of anhydrous ether was, added to 3,4,5-trimethoxybromobenzene (1.23 g, 4.97 mmol) in a 500 mL round bottom flask under nitrogen. The temperature of the reaction mixture was brought to −78° C. n-Butyllithium (4.5 mL, 11.25 mmol) was added dropwise. The reaction mixture was then stirred until the temperature was raised gradually to −30° C. 30 (0.86 g, 4.5 mmol) dissolved in 25 mL of dry ether was added dropwise and the reaction mixture was allowed to stir until the temperature warmed up to room temperature. 25 mL of water was added and the product was extracted with ether (3×50), combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Purification by column chromatography (silica gel, 20:80 EtOAc:Hexanes) yielded 800 mg (49%) of 32 as pale yellow oil Rf: 0.16 (30:70, EtOAc:Hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[C:23]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=[CH:6][CH:7]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Reaction time: 20 h
Yield: 50.7 %

Procedure:
2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (100 mg, 0.34 mmol) was dissolved in 2 mL of dry pyridine under nitrogen. Then 4-acetamid obenzene-1-sulfonyl chloride (209 mg, 0.85 mmol) was added drop wise to the reaction mixture. The reaction mixture was allowed to stir for 20 h. Thin layer chromatography (petroleum ether:ethyl acetate=1:1, Rf=0.5) showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to afford 85 mg of 2-(3-(4-acetamidophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 51%. MS (ES+APCI) M+1=494.2.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]([Cl:21])(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]>>[ClH:21].[C:9]1([N:6]2[CH:7]=[CH:8][C:3](=[N:2][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:4]=[N:5]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: CCCCC(=O)Cl
Agent: Cl
Product: CCCCC(=O)N=c1ccn(-c2ccccc2)nc1
Yield: 40 %

Procedure:
6.0 g (28.9 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 40 ml of valeryl chloride were kept at 120° C. for 20 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized first from ethanol/methyl tert.-butyl ether and then from ethanol/acetone. 3.4 g (40% of theory) of 1,4-dihydro-1-phenyl-4-(valerylimino)-pyridazine hydrochloride were isolated as pale yellowish crystals of melting point 180°-182° C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:28][C:27]([C:26]3[CH:25]=[CH:24][C:23]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Reactant: NCc1ccc(N2CCCC2)cc1
Product: CCOC(=O)c1nc(-c2ccc(N3CCCC3)cc2)[nH]c1-c1ccc(C)cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate and 4-(1-pyrrolidinyl)benzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. Ethyl 5-(4-methylphenyl)-2-(4-(1-pyrrolidinyl)-phenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid. 5-(4-Methylphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid is reacted and treated in the same manner as in Example 1 to give 5-(4-methylphenyl)-2-(4-(1-pyrrolidinyl)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[N+](C1C=CC([N:43]([CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:44](=O)[O-:45])=CC=1)([O-])=O>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:44]([NH:43][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:45])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)C1CCCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.9 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in acetonitrile (50 mL). After stirring for 20 min, 4-nitrophenyl-N-cyclopentylcarbamate (0.44 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered to afford N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclopentylamino)carboxamide (0.2 g, 27%) as a white solid: mp 151-153° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.68 (m, 3H), 6.31 (t, 1H), 6.17 (d, J=6.9 Hz, 1H), 5.18-5.11 (dd, J=4.6 and 12.3 Hz, 1H), 4.62 (d, J=5.4 Hz, 2H), 3.83 (q, J=6.4 Hz, 2H), 2.96-2.85 (m, 1H), 2.64-2.50 (m, 2H), 2.07-2.04 (m, 1H), 1.70-1.29 (m, 8H); 13C NMR (DMSO-d6) δ 172.77, 169.83, 167.59, 167.04, 157.63, 141.12, 134.64, 133.43, 131.52, 128.99, 121.64, 51.09, 48.83, 38.70, 32.91, 30.94, 23.16, 21.99; Anal. Calcd. For C20H22N4O5: C, 60.29; H, 5.57; N, 14.06. Found: C, 60.09; H, 5.66; N; 14.15.
Reaction SMILES: [CH:1]1([N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8](=[O:23])[NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]=2[OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>ClCCl>[C:31]([O:22][C:11]1[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[NH:9][C:8]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:23])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(NC(=O)N(Cc2ccccc2)C2CCCCC2)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)N(Cc2ccccc2)C2CCCCC2)c(OC(C)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4.00 g of 2-(3-cyclohexyl-3-phenylmethylureido)-4-methoxy-6-tert-butylphenol, 2.0 ml of acetic anhydride, 3.2 ml of triethylamine and 80 ml of dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was washed and dried, and the solvent was removed under reduced pressure. The residue was applied to silica gel column chromatography (solvent; chloroform:ethyl acetate=9:1) to give 735 mg of O-acetyl-2-(3-cyclohexyl-3-phenylmethylureido)-4-methoxy-6-tert-butylphenol (Rf=0.75, melting point: 129°-132° C. (recrystallized from hexane)).
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:6]1[CH:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:3][C:2]2=1.[H-].[Na+].Br[CH2:19][C:20]#[N:21].O>CN(C=O)C>[C:20]([CH2:19][N:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:6]2[CH:7]3[CH2:10][CH:1]([CH2:9][CH2:8]3)[C:2]1=2)#[N:21]
Reactant: CCOC(=O)c1cc2c([nH]1)C1CCC2C1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC#N)C1CCC2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Into a solution of 167c (3.0 g, 14.6 mmol) in anhydrous DMF (30 mL) was added NaH (880 mg, 22 mmol). The mixture was stirred at room temperature for 30 minutes. 2-Bromoacetonitrile (3.5 g, 29.3 mmol) was added and the resulting mixture was heated at 65° C. for 1 hour. It was then stirred at room temperature overnight. After reaction water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase was evaporated under reduced pressure to dryness. The residue was purified by silica-gel column chromatography eluting with 20:1 methylene chloride/methanol to afford 167d as a brown solid (2.6 g, 72%). MS: [M+H]+ 245.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1>CC(N(C)C)=O>[OH:9][CH2:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=1)[O:1][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1
Reactant: OCc1cc(O)cc(CO)c1
Reactant: CC(=O)c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(OCCOc2cc(CO)cc(CO)c2)cc1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a stirred solution of (5-hydroxy-1,3-phenylene)dimethanol (3.0, 20.0 mmol), sodium carbonate (2.5 g, 29.0 mmol) and sodium iodide (0.45 g, 2.9 mmol) in 60 ml of DMA was added 1-(4-(2-bromoethoxy)phenyl)ethanone (5.0, 20.57 mmol). The mixture was stirred overnight, evaporated and purified on SiO2 chromatography eluted with EtAc/Hexane (4:1 to 5:1) to afford 5.41 g (86%) of the title compound. 1H NMR (CD3OD) 7.99 (ddd, 2H, J=2.8, 4.8, 9.8 Hz), 7.07 (ddd, 2H, J=2.8, 4.7, 9.8 Hz), 6.94 (s, 1H), 6.89 (s, 2H), 4.58 (s, 4H), 4.42 (dd, 2H, J=2.2, 6.1 Hz), 4.37 (m, 2H), 2.55 (s, 3H); 13C NMR 199.55, 164.66, 160.59, 144.72, 132.03, 131.74, 119.16, 115.64, 113.11, 68.36, 67.87, 65.20, 26.53; MS m/z+339.2 (M+Na).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[F:19])=[O:23])[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccccc4F)CC3)cccc2n1
Yield: 55 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-fluorobenzoyl chloride (65 mg; 0.41 mmol) to obtain 40.2 mg. (55% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.50 (m, 2H), 7.34 (m, 3H), 7.09 (br s, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 5.93 (br s, 2H), 4.60 (br d, J=13.5 Hz, 1H), 3.46 (br s, 2H), 3.17 (m, 2H), 3.02 (m, 1H), 2.72 (m, 2H). ESIMS+368.0 m/z
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:10]=O)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:18]([O:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:10]=[N:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: COC(=O)C1(C=O)CCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C=NOCc2ccccc2)CCCC1
Yield: 43.7 %

Procedure:
A mixture of 1-formyl-cyclopentanecarboxylic acid methyl ester (3.1 g, 19.8 mmol), sodium acetate (2.74 g, 39.72 mmol) and O-benzylhydroxylamine hydrochloride (6.34 g, 39.7 mmol) were stirred in methanol (120 mL) for 18 h. The methanol was removed in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. Purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5 to 90:10) provided the title compound as a clear colorless oil (2.26 g, 44%). MH+262.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: C1CCNCC1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: Cc1sc2cc(OCCCCN3CCCCC3)ccc2c1-c1ccc(Br)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and piperidine were converted to yield 1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-piperidine, MS: 458 (MH+,1Br).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]=O)=[CH:7][CH:8]=2)[NH:3]1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][N:14]3[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]3)=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=Cc1ccc2c(c1)NC(=O)CC2
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of the compound (19.8 g) obtained in Step 1-4 and tert-butyl piperidin-4-ylcarbamate (24.8 g) in CHCl3 (450 mL) was stirred at 70° C. for 1.5 hours and allowed to cool to room temperature. Thereafter, NaBH(OAc)3 (35.9 g) was added to the mixture under ice cooling and the mixture was stirred at room temperature for 12 hours. A saturated aqueous NaHCO3 solution was added to the reaction mixture and then a water layer and an organic layer were separated. The water layer was extracted three times with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60 N, mobile phase: MeOH/CHCl3=33/66 to 100/0; v/v) to obtain tert-butyl {1-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]piperidin-4-yl}carbamate (37.8 g, a colorless solid).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([NH2:8])[CH:3]([CH2:4]2)[CH2:2]1.[CH3:9][CH:10]1[S:14](=[O:16])(=[O:15])[O:13][CH2:12][CH2:11]1>O1CCCC1>[CH:3]12[CH2:4][CH:5]([CH2:1][CH2:2]1)[CH2:6][CH:7]2[NH:8][CH2:12][CH2:11][CH:10]([S:14]([OH:16])(=[O:15])=[O:13])[CH3:9]
Reactant: CC1CCOS1(=O)=O
Reactant: NC1CC2CCC1C2
Solvent: C1CCOC1
Product: CC(CCNC1CC2CCC1C2)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of exo-2-aminonorbornane (1.0 g, 9.0 mmol) in tetrahydrofuran (THF, 10 mL) was added 2,4-butane sultone (1.28 g, 9.3 mmol). The solution was stirred at reflux for 3 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with THF (2×20 mL) and dried in vacuo. 1H NMR (DMSO, 500 MHz) δ ppm 8.43 (s (broad), 1H), 2.96 (m, 3H), 2.62 (m, 1H), 2.38 (m, 1H), 2.28, (m, 1H), 1.91 (m, 1H), 1.82 (m, 1H), 1.61 (m, 1H), 1.54 (m, 2H), 1.42 (m, 2H), 1.12 (m, 6H). 13C (DMSO, 125 MHz) δ ppm 60.92, 60.79, 53.61, 53.21, 44.55, 44.36, 39.80, 39.55, 36.27, 36.15, 36.11, 35.98, 35.19, 35.13, 29.62, 29.43, 28.07, 26.88, 17.56, 14.11. ES-MS 248 (M+1).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[C:10]#[N:11]>O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[C:10]([NH2:11])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)cc(Cl)c1
Solvent: O
Product: NC(=O)c1cc(F)cc(Cl)c1

Procedure:
A mixture of sulfuric acid (500 ml) and water (100 ml) is heated to 95° and 3-chloro-5-fluorobenzonitrile (94.8 gms) added. After 4 hours the mixture is cooled and poured over ice and water added to make 3.6 L. In 1.2 L portions the mixture is filtered, the solid rinsed with hexane and the aqueous rinsed with hexane (4×120 ml) then extracted with ethyl acetate (2×100 ml). The solid and the ethyl acetate extracts were combined, dried over magnesium sulfate and stripped to give 3-chloro-5-fluorobenzamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][S:15]([CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:21][CH2:22]1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)CCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (2.02 g, 10.9 mmol) and 4-[2-(methylsulfonyl)ethyl]piperidine (2.48 g, 13.0 mmol) in DMSO (75 mL) was added K2CO3 (5.26 g, 38.1 mmol). The mixture was stirred at 100° C. for 2 days. The mixture was diluted with EtOAc, washed with H2O (4×), and rotovapped down. The crude residue was taken up in DCM and dried (MgSO4), filtered, and concentrated. Purification by flash chromatography provided the title compound of Step D (3.26 g, 9.14 mmol, 84%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (q, J=11.0 Hz, 2H), 1.52 (br. s., 1H), 1.60-1.72 (m, 2H), 1.78 (d, J=12.1 Hz, 2H), 2.17 (s, 3H), 2.67 (t, J=11.6 Hz, 2H), 2.95 (s, 3H), 3.07-3.21 (m, 2H), 3.21-3.35 (m, 2H), 3.88 (s, 3H), 6.66 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH:13]=O)[CH:9]=2)[C:4](=[O:15])[O:3]1.[CH3:16][CH:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1.C([BH3-])#N.[Na+]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:21]3[CH2:20][CH2:19][NH:18][CH:17]([CH3:16])[CH2:22]3)[CH:9]=2)[C:4](=[O:15])[O:3]1
Reactant: CC1Cc2cc(CC=O)ccc2C(=O)O1
Reactant: CC1CNCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC1CN(CCc2ccc3c(c2)CC(C)OC3=O)CCN1
Reaction time: 8 h

Procedure:
Freshly prepared (3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)acetaldehyde was dissolved in DCM. To the solution was added 2-methyl piperazine (221 mg, 2.2 mmol) followed by sodium cyanoborohydride (165 mg, 2.64 mmol). The reaction mixture was allowed to stir overnight before being quenched with 10 mL of 1N HCl followed by stirring for 30 minutes. The reaction mixture was then treated with 50 mL of saturated sodium bicarbonate solution and extracted with DCM (3×50 mL). The combined organic layers were washed with water and brine, dried with magnesium sulfate, filtered, concentrated and purified via MPLC (30-100% (10% IPA in DCM/DCM) to afford 3-methyl-6-[2-(3-methylpiperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one. LC-MS (IE, m/z): 289 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[C:25](OC)([CH3:27])[CH3:26].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]2[CH2:20][O:21][C:25]([CH3:27])([CH3:26])[O:22]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)nc1)N(CC(O)CO)c1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN(c2ccccc2)S(=O)(=O)c2ccc(Cl)nc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A mixture of 0.67 g (1.96 mmol) of 6-chloro-N-(2,3-dihydroxypropyl)-N-phenylpyridine-3-sulfonamide, 0.53 mL (4.3 mmol) of 2,2-dimethoxypropane and 37 mg of pTsOH in 4 mL of DMF is stirred for 3 hours at room temperature. The medium is taken up in 100 mL of EtOAc, washed with 50 mL of saturated NaHCO3 solution and 50 mL of water and then dried over Na2SO4, filtered and concentrated under reduced pressure. 0.54 g 6-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-N-phenylpyridine-3-sulfonamide is obtained in the form of a brown solid, which is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:15]=[CH:14][NH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:17][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:19][CH3:20]>>[NH2:21][C@H:18]([CH2:19][CH3:20])[CH2:17][N:13]1[CH:14]=[CH:15][C:11]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=2[CH3:10])=[N:12]1
Reactant: Cc1c(-c2cc[nH]n2)ccc(C#N)c1Cl
Reactant: CC[C@H](CO)NC(=O)OC(C)(C)C
Product: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2C)n1
Yield: 56.5 %

Procedure:
(R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile was prepared using the method of Example 99 starting from 2-chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.0 g, 9.19 mmol) and (R)-tert-butyl 1-hydroxybutan-2-ylcarbamate (3.48 g, 18.38 mmol). Yield 56.5%. m/z [288.8+1].
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:24]3[CH2:25][C:20]4([C:27](=[O:29])[NH2:28])[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)=[O:15])[CH2:10]1)=O)(C)(C)C.ClC1[S:32][C:33]([C:36]#[N:37])=[CH:34][N:35]=1>>[C:36]([C:33]1[S:32][C:6]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]3[CH:24]4[CH2:25][C:20]5([C:27](=[O:29])[NH2:28])[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)=[O:15])[CH2:10]2)=[N:35][CH:34]=1)#[N:37]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OC2C3CC4CC2CC(C(N)=O)(C4)C3)C1
Product: N#Cc1cnc(NC2CCN(C(=O)OC3C4CC5CC3CC(C(N)=O)(C5)C4)C2)s1

Procedure:
The title compound was prepared from (3R) (1-carbamoyl-4-adamantyl) 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate isomer 2 following procedures analogous to those described in Example 33 using 2-chloro-5-cyanothiazole in Step 2. LC-MS Method 1 tR=1.32 min, m/z=415; 1H NMR (CD3OD) 1.55 (2H), 1.85-2.15 (12H), 2.25 (m, 1H), 3.35-3.80 (4H), 4.40 (br s, 1H), 4.78 (s, 1H), 7.74 (s, 1H).