Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24](Cl)=[O:25]>>[Cl:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:25]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)C(Cl)c1ccccc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)C(Cl)c3ccccc3)CC1)O2

Procedure:
Compound 50 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, chloro(phenyl)acetyl chloride and conditions outlined in procedure N. M.p.=125-126° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.62-7.88 (m, 3H), 7.35-7.55 (m, 6H), 6.44 (d, 1H), 4.15 (m, 2H), 3.30 (m, 2H), 3.0-3.13 (2s, 2H), 2.0 (m, 2H), 1.65 (m, 2H); LCMS: 454 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][Mg]Cl)=[CH:5][CH:4]=1.[CH3:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:21]([C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]([NH:13][CH3:12])=[O:23])=[O:22])=[CH:5][CH:4]=1
Reactant: CN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1C(=O)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At 0° C., (4-methoxybenzyl)magnesium chloride (0.25 M in THF) (37 ml, 9.3 mmol) was added to 2-methylisoindoline-1,3-dione (1.00 g, 6.2 mmol) in THF (3.0 mL) (Reference: Synthetic Comm. 2004, 34(7), 1301-1308). The mixture was stirred at 0° C. for 5 minutes, then quenched with 10 mL of water. The reaction was warmed to RT and concentrated to yield 2-(2-(4-methoxyphenyl)acetyl)-N-methylbenzamide as a white solid (crude). The material was carried on to next step without further purification. MS m/z=284 [M+1]+. Calc'd for C17H17NO3: 283.33.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8].CO.[CH3:36][NH:37][CH3:38]>C1COCC1>[CH3:36][N:37]([CH3:38])[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8]
Reactant: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Step 4): A mixture of 5-fluoro-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)-methyl]benzamide (13.4 g, 30 mmol) and 2.0M MeOH solution of dimethylamine (45 ml, 90 mmol) in THF (100 ml) was refluxed for 22 hours. The resulting solution was evaporated to give 5-dimethylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as yellow powders, 14.1 g (99.6%).
Reaction SMILES: C([O:8][C:9]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:10]=1[CH2:11][N:12]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=1)[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:15][N:14]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:40][C:37]([F:38])([F:39])[C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=1)[CH2:26][N:12]([CH2:11][C:10]1[CH:41]=[C:42]([C:45]([F:48])([F:47])[F:46])[CH:43]=[CH:44][C:9]=1[OH:8])[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:15][N:14]=1
Reactant: CS(=O)(=O)CCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)CCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 42.8 %

Procedure:
(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-amine (1.07 g) is dissolved in ethanol (15 ml) and thereto is added 10% palladium-carbon (320 mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 7 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenol (400 mg). MS (m/z): 618 [M+H]+
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:7][CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:9]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(N2CCC(NC(C)=O)CC2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(=O)NC1CCN(c2ccc(CO)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
A solution of ethyl 4-(4-acetamidopiperidin-1-yl)benzoate (0.123 g, 0.42 mmol) in CH2Cl2 (10 mL) under nitrogen at −78° C. was treated with DIBAL-H (1.0M in hexanes, 0.950 mL, 0.95 mmol) dropwise, via a syringe. After 20 minutes, the mixture was warmed to room temperature, stirred for 1 hour, and quenched with 10% Rochelle's salt. After stirring for 10 minutes, CH2Cl2 (50 mL) was added, and the stirring was continued for 15 additional minutes. The layers were separated and the aqueous phase was extracted with CH2Cl2 (50 mL) and ethyl acetate (50 mL). The combined organic phases were dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% MeOH/ethyl acetate to afford N-(1-(4-(hydroxymethyl)phenyl)piperidin-4-yl)acetamide as a white solid (0.025 g, 24%).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[BH4-].[Na+].CCCCCC>C(O)C>[CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: CCCCCCCCCOc1ccccc1CO
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
2-Hydroxybenzaldehyde (110 g), was alkylated by mixing this compound with 1-bromononane (180 g), anhydrous potassium carbonate and dimethylformamide (800 mL). This mixture was heated at 80° C. for 14 hours. Hexane and water were then added and the hexane extract was concentrated and the residue was distilled to yield the 2-nonyloxybenzaldehyde (210 g), bp 121° C. (0.3 mm Hg). A solution of 2-nonyloxybenzaldehyde prepared above (100 g) in ethanol (1000 mL) at 10° C. was reduced by treating with an excess of sodium borohydride (6 g) and after stirring the mixture for a further 15-20 min. at room temperature, the compound 2-nonyloxybenzylalcohol was isolated by extraction into hexane. Removal of the hexane in vacuo yielded the crude 2-nonyloxybenzylalcohol (98 g). The resulting 2-nonyloxybenzylalcohol was added to a mixture of triphenylphosphine hydrobromide (144 g) in acetonitrile (500 mL) and the resultant solution was heated at reflux for 14 hours. Removal of the solvents in vacuo and crystallization of the residue from a tetrahydrofuran/ethyl ether mixture gave the pure [[2-(nonyloxy)phenyl]methyl]triphenylphosphonium bromide (208 g).
Reaction SMILES: [ClH:1].Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:4]2.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[ClH:1].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1)[CH2:4]2
Reactant: Nc1ccc(OC2CN3CCC2CC3)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OC2CN3CCC2CC3)cc1

Procedure:
4-[(1-azabicyclo[2.2.2]oct-3-yl)oxy]benzenamine (Example 3) was acetylated with acetic anhydride in dry pyridine at -10° C. The crude product was converted into the hydrochloric salt to obtain N-[4-[(1-azabicyclo[2.2.2]-oct-3-yl)oxy]phenyl]acetamide hydrochloride. M.p. >250° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:20]>O.[Cu]Br>[Br:20][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Nc1cc(C(=O)O)ccc1OC(F)(F)F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1

Procedure:
To a stirred solution of 3-amino-4-trifluoromethoxybenzoic acid (2 g) in a mixture of water (16 ml) and 48% HBr (12 ml) at 0° C. was added a solution of sodium nitrite (0.64 g) in water (8 ml) drop-wise. After 15 min at 0° C. the reaction mixture was diluted with water (12 ml) and carefully poured onto a stirred solution of copper (I) bromide (1.32 g) in 48% HBr (8 ml) at room temperature. The resulting suspension was filtered, and the residue washed with water (3×5 ml) and dried in vacuo to give the title compound as a beige solid (2.08 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[C:17]1([N:23]2[C:27]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)=[CH:26][C:25]([CH:33]=O)=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:33][C:25]2[CH:26]=[C:27]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)[N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:24]=2)[CH2:12][CH2:13]1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Product: Fc1ccccc1N1CCN(CCNCc2cc(-c3ccco3)n(-c3ccccc3)n2)CC1
Yield: 86.3 %

Procedure:
Compound 67 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:37])[CH2:34][NH:35][CH3:36])[CH:30]=[CH:31][CH:32]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:37])[CH2:34][N:35]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[C:17]=2[CH3:22])[CH3:36])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(C)CC(O)c2cccc(N)c2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 5 h
Yield: 65.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (90 mg, 0.23 mmol), 1-(3-aminophenyl)-2-(methylamino)ethanol (Khim.-Farm. Zh 1983, 17, 1093)(69 mg, 0.42 mmol) and diisopropylethylamine (60 μL, 0.34 mmol) in dry DMF (4.6 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with ice (6 g). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the tide compound (79 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4]>CO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])=[CH:7][CH:8]=1
Reactant: CN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(N)cc1
Yield: 94.9 %

Procedure:
Under H2, N,N-dimethyl-4-nitrobenzenesulfonamide (879 mg, 3.8 mmol, 1.0 equiv.) was catalytically hydrogenated in the presence of Pd/C (40 mg) in MeOH (25 mL). When no more H2 was consumed, the reaction mixture was filtered. The filtrate was concentrated and crystallized to afford compound 4-amino-N,N-dimethyl benzenesulfonamide (722 mg, 95%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([S:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:52][CH2:53][CH3:54].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH:51]([S:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:52][CH2:53][CH3:54])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCSCCCC
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCSC(CCC)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of the compound of Example 1 (3.0 g, 4.2 mmol) and butyl sulfide (18 mL) in acetonitrile (24 mL) at 0° C. was added benzoyl peroxide (2.0 g) in three portions over 3 hours, and the reaction was stirred at 0° C. for 1 hour and then at room temperature for 1 hour. Additional benzoyl peroxide (4.0 g) was added in two portions over 2 hours at room temperature. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic phase was dried over MgSO4, filtered and evaporated. The concentrate was chromatographed on silica gel eluting with a gradient starting with 50% ethyl acetate in chloroform and ending with ethyl acetate to give the title compound (2.43 g, 68% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[C:11]([NH2:15])(=O)[CH:12]=[CH2:13].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.P(Cl)(Cl)(Cl)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:11]([CH:12]=[CH:13][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1)#[N:15]
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C=CC#N)cc(C)c1N
Yield: 67 %

Procedure:
The third route disclosed in WO 03/016306 involved reaction of 4-bromo-2,6-dimethylphenylamine with acrylamide in presence of palladium acetate, tris(2-methylphenyl)phosphine and N,N-diethylethanamine. The resulting amide was dehydrated using phosphoryl chloride to give 4-(2-cyanoethenyl)-2,6-dimethylphenylamine in a moderate yield of 67% without mentioning the E/Z ratio.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)O)=[CH:4][CH:3]=1.[C:16]1([NH:22][C:23](=[O:25])[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)=O.OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:19]2[CH:20]=[CH:21][C:16]([NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1cccnc1
Reactant: CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(c2ccc(Cl)cc2)c2cccnc2)cc1
Yield: 100 %

Procedure:
A mixture of α-(4-chlorophenyl)-3-pyridinemethanol (0.364 mol) and N-phenyl acetamide (0.364 mol) in HOAc (360 ml) and H2SO4 36N (38.6 ml) was stirred and refluxed for 6 days. The solvent was evaporated, yielding 122.6 g (±)—N-[4-[(4-chloro-phenyl)(3-pyridinyl)methyl]phenyl]acetamide (compound 673).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].O>CO>[Cl:3][C:4]1[C:5]([CH2:6][OH:7])=[CH:8][CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: O=Cc1cccc(O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1cccc(O)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of sodium borohydride (724 mg, 19.2 mmol) in anhydrous methanol (10 mL) was added a solution of 2-chloro-3-hydroxybenzaldehyde (1.0 g, 6.4 mmol) in anhydrous methanol (5 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, 2-chloro-3-(hydroxymethyl)phenol was obtained (710 mg, 70% yield) and used for next step without further purification; 1H NMR (400 MHz, DMSO-d6): δ 4.51 (d, J=5.8 Hz, 2H), 5.28 (t, J=5.8 Hz, 1H), 6.84-6.87 (m, 1H), 6.96-6.99 (m, 1H), 7.12 (t, J=7.8 Hz, 1H), 10.02 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:19]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])=[CH:18][CH:17]=[C:16]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].[Cl:28]N1C(=O)CCC1=O>CN(C=O)C>[Cl:28][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:16]([F:27])=[CH:17][CH:18]=[C:19]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[C:2]=3[F:1])[CH:8]=2)[NH:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(Cl)c3c2)c1F
Reaction time: 8 h

Procedure:
2,6-Difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.300 g, 0.7607 mmol) was dissolved in DMF (10 mL), and N-chlorosuccinimide (0.122 g, 0.913 mmol) was added and stirred overnight. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil. DCM was added to the oil, and a solid, N-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (217.4 mg, 66.7%), precipitated out, which was collected by filtration. 1H NMR (400 MHz, DMSO-d6) δ 12.03 (br s, 1H), 11.04 (s, 1H), 9.81 (br s, 1H), 8.40-8.43 (m, 2H), 7.72-7.74 (m, 1H), 7.53-7.59 (m, 1H), 7.26-7.30 (m, 1H), 3.11-3.15 (m, 2H), 1.75-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-neg) M−1=427.1, 429.2.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][C:16](=[O:32])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([F:31])[CH:20]=1)[CH3:18]>CN(C)C=O>[F:31][C:21]1[CH:20]=[C:19]([CH:17]([CH3:18])[C:16](=[O:32])[CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:24]=[CH:23][C:22]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C(=O)CCl)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a suspension of sodium hydride (1.88 g as 60% in oil, 47.0 mmoles) which was washed with hexane to remove mineral oil and dried, in dimethylformamide (DMF, 23 ml) was added dropwise a solution of diethyl malonate (7.52 g, 47.0 mmoles) in DMF (5 ml) at 0° C. under the stream of nitrogen gas. After elevating the temperature to 50° C., a solution of 1-chloro-3-(2-fluoro-4-biphenylyl)butan-2-one (10.0 g, 36.1 mmoles) in DMF (40 ml) was added dropwise, and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into ice water and extracted with diethyl ether. The organic layer was washed with 1M hydrochloric acid, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by medium pressure silica gel column chromatography gave the desired diethyl 2-(3-(2-fluoro-4-biphenylyl)-2-oxobutyl)malonate (8.98 g, 22.4 mmoles, yield 62%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([C:15]#[N:16])[CH2:10][C:11](OC)=[O:12])[CH:5]=[CH:6][CH:7]=1>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH:9]1[CH2:15][NH:16][C:11](=[O:12])[CH2:10]1
Reactant: COC(=O)CC(C#N)Cc1cccc(Cl)c1
Agent: [Ni]
Product: O=C1CC(Cc2cccc(Cl)c2)CN1

Procedure:
In the same manner as Example 1-(d), 5 g of methyl 4-(3-chlorophenyl)-3-cyanobutyrate was reduced with Raney's nickel as the catalyst to obtain 4-(3-chlorobenzyl)-2-pyrrolidinone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:41])[CH3:22])=[CH:29][CH:28]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:39])[CH3:40])=[CH:34][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 20.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.0 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.91 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH:4]=[CH:5][CH2:6][C:7]1[C:8](=[O:19])[C:9]2[C:14]([C:15](=[O:18])[C:16]=1[OH:17])=[CH:13][CH:12]=[CH:11][CH:10]=2.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:19])[C:9]2[C:14]([C:15](=[O:18])[C:16]=1[OH:17])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)(C)CC=CCC1=C(O)C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)CCCCC1=C(O)C(=O)c2ccccc2C1=O
Yield: 404.8 %

Procedure:
2-(5,5-dimethylhex-2-enyl)-3-hydroxynaphthalene- 1,4-dione(3 91 mg) prepared in Example 45 was dissolved in ethyl acetate (15 ml) and hydrogenated as in Example 1(c) using hydrogen and 100 mg of Pd/C catalyst to provide 371 mg title compound.