Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:18])[CH:14]=[C:13](Cl)[N:12]=1>C1COCC1>[Cl:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:18])[CH:14]=[C:13]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:12]=1
Reactant: OC1CCCCC1
Reactant: O=C(OC1CCCCC1)c1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OC1CCCCC1)c1cc(OC2CCCCC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 111.4 %

Procedure:
A cold (0° C.) solution of cyclohexanol (2.35 ml; 22.3 mmol) was treated with sodium hydride (534 mg; 22.3 mmol) in dry THF (25 ml) and stirred for 30 min at 0° C. It was slowly added to a cooled (0° C.) solution of cyclohexyl 2,6-dichloropyrimidine-4-carboxylate (Intermediate 31, 3.50 g; 12.72 mmol) in dry THF (70 ml) and the resulting mixture was stirred at 50° C. After 4 h the reaction was treated again with a solution cyclohexanol (0.34 ml; 3.18 mmol) and sodium hydride (76.3 mg; 3.18 mmol) in dry THF (3 mL) obtained as described above and it was stirred for an additional hour. The reaction mixture was concentrated under vacuum and the residue was taken up in EtOAc and the organic layer was washed with water, then brine, dried over MgSO4, filtered off and concentrated under vacuum to afford the title compound (4.80 g, 99%) without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:8][C:4]1[CH:3]=[C:2]([O:1][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([Cl:9])[CH:11]=2)[CH:7]=[CH:6][N:5]=1)=[O:14]
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: c1ccncc1
Product: O=C(Oc1ccnc(OC(=O)c2cccc(Cl)c2)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
A 1.00 g quantity of 4-hydroxy-2-pyridone was suspended in 30 ml of pyridine and 3.46 g of 3-chlorobenzoyl chloride was added to the suspension. The mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and the filtrate was concentrated and the concentrate was extracted with ethyl acetate. The extract was concentrated and the concentrate was washed with water and with methanol, giving 1.74 g of the title compound in a yield of 50%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]2)[CH:6]=[CH:5][C:4]=1[C:15]([N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][N:20]2[CH:28]=[CH:29][CH:30]=[C:19]2[CH2:18]1)=[O:16].C(O)(=O)C.C=O>CO>[CH3:15][N:17]([CH2:23][C:28]1[N:20]2[C:19]([CH2:18][N:17]([C:15]([C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]4)=[CH:8][C:3]=3[O:2][CH3:1])=[O:16])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1)[CH3:18]
Reactant: COc1cc(-n2ccc(C)n2)ccc1C(=O)N1Cc2cccn2Cc2ccccc21
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(-n2ccc(C)n2)ccc1C(=O)N1Cc2ccc(CN(C)C)n2Cc2ccccc21

Procedure:
To a stirred solution of [2-methoxy-4-(3-methyl-pyrazol-1-yl)-phenyl](5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl) methanone from Example 107 (0.57 g) in warm methanol (10 ml) was added N,N,N,N′-tetramethyl-diaminomethane (0.392 ml) and acetic acid (0.164 ml). Following the addition of aqueous 37% formalin solution (2.9 ml) the reaction was stirred for fifteen minutes. The mixture was concentrated in vacuo and partitioned between dichloromethane and sodium hydrogen carbonate. The organic phase was removed, washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica eluting with chloroform/methanol (50/1) to afford a solid. Recrystallisation of the solid from acetone gave the title compound as a colorless solid, m.p. 196-198° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: CC(N)c1oc2ccccc2c1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1oc2ccccc2c1-c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-(3-phenylbenzofuran-2-yl)ethylamine Example 24 (0.706 mmol), 6-chloro-9H-purine (213 mg, 1.38 mmol) and DIPEA (0.24 mL, 1.38 mmol) in n-butanol (5 mL) was heated at 100° C. for 18 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) and then triturated from MeOH with water affording 103 as an off-white solid (107 mg, 43% over two steps). LCMS: RT 4.15 min [M+H]+ 356.1. 1H NMR (DMSO, 400 MHz): δ 8.21-7.95 (3H, m), 7.73-7.60 (3H, m), 7.58-7.49 (3H, m), 7.46-7.23 (3H, m), 5.84 (1H, s), 1.67 (3H, d, J=6.99 Hz)
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([NH:20][C:21]3[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]([NH:33][C:34]4[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=4)[N:22]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[NH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH:45]1[CH2:49][NH:50][C:51](=[O:57])[C:52]([O:54][CH2:55][CH3:56])=[O:53].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([NH:20][C:21]3[N:26]=[C:25]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])[N:24]=[C:23]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:38]([NH:43][CH:44]5[CH2:48][CH2:47][CH2:46][CH:45]5[CH2:49][NH:50][C:51](=[O:57])[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:39])=[CH:41][CH:42]=4)[N:22]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)NCC1CCCC1N
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)NCC1CCCC1NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (300 mg), ethyl 2-(((2-aminocyclopentyl)methyl)amino)-2-oxoacetate (205 mg) and TBTU (201 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude ethyl 2-(((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)amino)-2-oxoacetate which was used as was.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccccn2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2-pyridyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 90% overall yield. FDMS m/e=352 (M+ of free base). α[D]589=−31.14 (c=0.86, methanol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cnc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of 3-methyl-5-nitro-2-(4-(trifluoromethyl)phenyl)pyridine (223 mg, 0.79 mmol) in ethanol (30 mL) was added 10 wt % palladium on carbon (100 mg). The reaction was pressurized to 50 psi hydrogen and was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite and concentrated to give 5-methyl-6-(4-(trifluoromethyl)phenyl)pyridin-3-amine (198 mg, 99%). 1H NMR (400 MHz, CDCl3, δ): 8.04 (s, 1H), 7.67 (m, 2H), 7.60 (m, 2H), 6.91 (s, 1H), 3.72 (br s, 2H), 2.30 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 98.5 %

Procedure:
Palladium on carbon (5%, 0.80 g) was added to a solution of ethyl 3-(4-benzyloxyphenyl)-2-(phenylamino)propionate (3.94 g), which is the product of Reference example 55(a), in a mixture of ethanol (40 ml) and tetrahydrofuran (20 ml). The mixture was stirred under an atmosphere of hydrogen at 50° C. for 6 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified via chromatography on a silica gel column using ethyl acetate/hexane=1/2 as the eluant to afford the title compound (2.95 g) as a syrup.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:23]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:24])[CH2:10][N:9]=2)=[C:18](I)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2].C([Sn](CCCC)(CCCC)[C:30]1[O:31][CH2:32][CH2:33][CH:34]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:31]1[CH2:32][CH2:33][CH:34]=[C:30]1[C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][CH2:21][N:12]1[C:11](=[O:24])[CH2:10][N:9]=[C:8]([N:6]3[CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=[CH:5]3)[CH:23]=[C:13]12
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCc1cn(C2=NCC(=O)N3CCc4c(C5=CCCO5)cccc4C3=C2)cn1
Temperature: 150 °C
Yield: 56.5 %

Procedure:
111-2. A mixture of 2-(4-ethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (520 mg, 1.20 mmol), tributyl(4,5-dihydrofuran-2-yl)stannane (864 mg, 2.41 mmol) and Pd(PPh3)4 (70 mg, 0.06 mmol) in dioxane (10 mL) was heated to 150° C. for 1.5 h. The mixture was filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (SiO2, DCM to DCM/MeOH 95:5) afforded the title compound (254 mg) as a beige solid. UPLC-MS: MS 375.3 (M+H+); UPLC rt 0.91 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([O:15]C)=[O:14])[C:9]=2[CH3:17])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]=2[CH3:17])=[C:4]([C:18]([F:21])([F:19])[F:20])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(-c2ccc(F)cc2C(F)(F)F)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)O)c[nH]c1-c1ccc(F)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of methyl 5-[4-fluoro-2-(trifluoromethyl)phenyl]-4-methyl-1H-pyrrole-3-carboxylate (0.23 g, 0.77 mmol) in methanol (4.0 ml) was added 5N NaOH (3.0 ml) and the mixture was stirred at 80° C. for 2.0 h. The reaction mixture was cooled to room temperature and added 2N HCl (8.0 ml). The mixture was diluted with ethyl acetate and washed with water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (1:1 to 1:9 hexane:ethyl acetate) to give the title compound (211 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([NH:18][C:19](=O)[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[N:35]=[C:34]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:42])[CH:21]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:7][C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[N:35]=[C:34]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:42])[CH:21]=2)=[N:18]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C[C@@H](COC(C)=O)NC(=O)c2ccnc(-n3nc(-c4cccnc4)c4ccccc4c3=O)c2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)C(c1ccnc(-n3nc(-c4cccnc4)c4ccccc4c3=O)c1)=N[C@H](COC(C)=O)C2
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a solution of (2S)-1-acetoxy-3-(3,4-dimethoxyphenyl)-2-{2-[4-(3-pyridyl)phthalazin-1(2H)-on-2-yl]isonicotinoylamino}propane (150 mg) in acetonitrile (5 ml) is added phosphorus oxychloride (0.29 ml), and the mixture is heated under reflux overnight. The reaction mixture is cooled to room temperature, and neutralized with an aqueous sodium hydrogen carbonate solution. The mixture is extracted with chloroform, and the extract is washed, dried, and concentrated. The residue is crystallized from ethyl acetate to give (3S)-4-(3-acetoxymethyl-3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl)-2-[4-(3-pyridyl)phthalazin-1(2H)-on-2-yl]pyridine (136 mg), as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCCOC1CCN(c2ccc(N)cc2C#N)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: COCCOC1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 19.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.13 g) and 5-amino-2-[4-(2-methoxyethoxy)piperidin-1-yl]benzonitrile (0.14 g), the title compound (0.05 g) was obtained, melting point: 180–182° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].N1CCCCC1.Cl>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[NH:10][C:11](=[O:12])[NH:13][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)N1
Temperature: 130 °C
Yield: 87.9 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (100 g, 0.819 M), hydantoin (90 g, 0.9 M) and piperidine (165 ml) was heated to 130° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 60° C. and 3.2 l water was added. The reaction mixture was acidified with 12N HCl. The precipitated solid was filtered and washed with cold water to yield the title compound of the formula (18) (147 g, 88%), (Org. Syn. Vol. V., pp627).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][O:38][CH3:39])[N:31]=[CH:30][N:29]=[C:28]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][N:29]=3)[CH:42]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COc1cc(NC(=O)Oc2ccccc2)ccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(C(F)(F)F)c(OC)c4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react with phenyl 3-methoxy-4-(trifluoromethyl)phenylcarbamate described in Example 190B (140 mg, 0.45 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (103 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with dichloromethane to give 52 mg. 1H (DMSO-d6) 9.30 (s, 1H), 9.15 (s, 1H), 8.60 (s, 1H), 7.60 (m, 2H), 7.50 (s, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.00 (m, 2H), 4.35 (m, 2H), 4.00 (s, 3H), 3.84 (s, 3H), 3.70 (m, 2H), 3.40 (m, 3H). LCMS (ESI) m/z 559 (M+H)
Reaction SMILES: N1C=CC=CC=1.[N:7]1([CH2:12]/[CH:13]=[C:14](/[C:22]2[N:27]=[C:26](/[CH:28]=[CH:29]/[CH2:30][OH:31])[CH:25]=[CH:24][CH:23]=2)\[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([O:31][CH2:30]/[CH:29]=[CH:28]/[C:26]1[CH:25]=[CH:24][CH:23]=[C:22](/[C:14](/[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13]/[CH2:12][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:27]=1)(=[O:34])[CH3:33]
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/CO)n2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC/C=C/c1cccc(/C(=C/CN2CCCC2)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
Pyridine (110 μl, 1.36 mmol) was added to a solution of 3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-en-1-ol (227 mg, 0.68 mmol) in DCM (3 ml) under an inert atmosphere. Acetyl chloride (72 μl, 1.02 mmol) was added and the reaction stirred for 18 hours at room temperature. The reaction mixture was partitioned between DCM and brine. The organic layer was separated, dried over sodium sulphate, filtered and concentrated under vacuum to leave a brown oil. The product was purified by column chromatography on silica gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed to yield 3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-en-1-yl acetate as a brown gum (184 mg, 73%). 1H-NMR; δ (CDCl3), 7.49 (1H, t, J=7.8 Hz), 7.24 (2H, d, J=7.9 Hz), 7.18-7.11 (2H, m), 7.06 (2H, d, J=7.9 Hz), 6.91-6.66 (3H, m), 4.79 (2H, dd, J=5.4, 0.7 Hz), 3.72 (2H, m), 3.20 (4H, bm), 2.40 (3H, s), 2.12 (3H, s) and 2.11-2.02 (4H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH2:16][C:15]3[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:23][N:24](C)C=O.[C-]#N.[Na+]>C(Cl)(Cl)Cl>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[CH2:16][C:15]3[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(Br)cc1)C2
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(C#N)cc1)C2

Procedure:
2-(4-Bromophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone (8.00 g., 0.02 mole), cuprous cyanide (3.94 g., 0.04 mole) and dimethylformamide (100 ml.) are heated at reflux for 8 hours, added to warm sodium cyanide solution (3 g. in 400 ml. water), extracted with benzene, the benzene solution dried over anhydrous magnesium sulfate, then concentrated in vacuo to give an oily residue. Chromatographing with chloroform on silica gel gives 1.13 g. of 2-(4-cyanophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone melting at 161°-163° C. after crystallization from benzene:hexane, 2:1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([N:16]2[C@@H:20]([C:21]3[CH:26]=CC=CC=3)COC2=O)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(N)CC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([NH:16][CH:20]2[CH2:21][CH2:26]2)=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Agent: NC1CC1
Product: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 49.1 %

Procedure:
1-Benzyl-4-(R)-methyl-3-(R)-[(4-(S)-phenyl-2-oxazolidinon-3-yl)carbonyl]pyrrolidine (150 g) was dissolved in cyclopropylamine (650 mL). The mixture was stirred at room temperature for 23 hours and was concentrated under reduced pressure. Diisopropyl ether (800 mL) was added to the residue and the solution was stirred at room temperature for 70 min. The resulting crystals were filtered. The collected crystals were then dissolved in dichloromethane (800 mL) and the solution was extracted with 1 mol/L hydrochloric acid (2×400 mL). The layers of 1 mol/L hydrochloric acid were combined. While the combined layer was chilled in an ice water bath, a 30% aqueous NaOH solution was added to make the solution basic (pH 13). The resulting crystals were filtered, washed sequentially with water and diisopropyl ether, and dried under reduced pressure to give (3R,4R)-1-benzyl-N-cyclopropyl-4-methyl-3-pyrrolidinecarboxamide as white crystals (52.2 g).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:6]2[CH2:7][CH2:8][C:9]3[S:1][CH:2]=[CH:3][C:4]=3[C:5]2=[O:10])[CH:13]=1
Reactant: Brc1cccnc1
Reactant: O=C1NCCc2sccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2ccsc2CCN1c1cccnc1
Yield: 49.9 %

Procedure:
Using analogous reaction conditions as described in Example 1, 6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-7d: 80 mg, 0.5221 mmol) was reacted with 3-bromo-pyridine (99 mg, 0.6266 mmol), 1,4-dioxane (15 mL), copper iodide (9.9 mg, 0.05221 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (22.2 mg, 0.15667 mmol) and potassium phosphate (277.1 mg, 1.3054 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 60 mg of the product (50% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:11]([O:13]C)=[O:12])[C:7]([O:9][CH3:10])=[O:8].[OH-].[K+]>CO.O>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(C(=O)OC)=C1SC=CS1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C(C(=O)O)=C1SC=CS1
Temperature: 50 °C
Yield: 84.4 %

Procedure:
Dimethyl 2-(1,3-dithiol-2-ylidene)malonate (2) (116 g) was suspended in methanol (2 l), to which a solution of 33.5 g of 85% potassium hydroxide in water (250 ml) was added. The resulting mixture was heated under reflux for 8 hours. After the solvent was removed, water (2.5 l) was added and the resulting mixture was heated to 50° C. Insoluble matter was filtered off. Concentrated hydrochloric acid (50 ml) was added to the filtrate to acidify the same. The resultant precipitate was collected by filtration and after washing, was dried at 40° C. in air, whereby 2-(1,3-dithiol-2-ylidene)-3-methoxy-3-oxopropionic acid (3) (92 g, yield: 84%) was obtained.