Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C1C=CC=CC=1>[CH3:19][O:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of N-t-butoxycarbonyl isonipecotic acid (8.8 g, 34.9 mmol), in a 10% mixture of methanol in benzene (250 ml), was added a 2.0M solution of trimethylsilyldiazomethane in hexanes, dropwise, until a consistent yellow color was obtained (~30 ml). After vigorous gas evolution had ceased, the reaction mixture was stirred for 1 hr at room temperature. The mixture was then treated dropwise with glacial acetic acid until the yellow color had dissipated. The reaction was stirred 15 min. and concentrated in vacuo to a pale yellow oil. The residue was purified by chromatography (SiO2, eluting with 20% EtOAc in hexanes). Evaporation of the solvent in vacuo afforded the product as a colorless oil.
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](#[N:23])[CH:21]=[CH2:22].[ClH:24]>CCOCC>[ClH:24].[C:20]([CH2:21][CH2:22][N:10]1[CH2:11][CH2:12][C@:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C@@H:8]2[CH2:9]1)#[N:23]
Reactant: C=CC#N
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Agent: Cl
Solvent: CCOCC
Product: N#CCCN1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A 10 ml round bottom flask was charged with 0.503 g of cis 1,2,3,4,4a,9b-hexahydro-4a-phenyl-benzofuro[3,2-c]pyridine followed by 1 ml of acrylonitrile. The resulting mixture was stirred for 1/2 hour at room temperature under nitrogen and then heated at 60° for 1 hour. The reaction mixture was diluted with 10 ml of ether and treated with 4 ml of ether saturated with HCl. After stirring for 15 minutes, the precipitated salt was filtered, washed with ether, and dried to give 0.68 g (99.8%) of crystalline solid, m.p. s 205, 213°-216°. Recrystallization from ethanol afforded 0.50 g (73.3%) of crystals, m.p. s 213, 216°-219°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[C:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O>[Pd].CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2c3ccccc3c(=CCCc3ccccc3)c2n2ccnc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)C(CCCc1ccccc1)c1ccccc1-2
Yield: 28 %

Procedure:
The procedure is performed as in Example 13, but starting with 3.9 g of 10-(phenylpropylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 180 ml of dimethylformamide, 20 ml of methanol and 0.5 g of 10% palladium on charcoal. The crude product (3.8 g) is purified by chromatography on a column of silica (380 g partially deactivated with 10 ml of water), eluting with a mixture of dichloromethane and methanol (90/10 by volume). After trituration in 10 ml of dichloromethane, filtration and drying at 100° C., 1.1 g of 10-(phenylpropyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one are obtained, in the form of a beige solid melting at 232° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH2:14][OH:15].CCN(C(C)C)C(C)C>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:13][C:9]1[C:8]([CH2:14][OH:15])=[C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(Br)c1CO
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)Nc1cccc(Br)c1CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloroacetyl chloride (380 mg, 3.37 mmol) in DCM (10 mL) was added (2-amino-6-bromophenyl)methanol (630 mg, 3.12 mmol) followed by DIPEA (1.253 mL, 7.17 mmol). The reaction was stirred at room temperature for 3 d. The mixture was diluted with a solution of saturated sodium bicarbonate (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate and concentrated to give N-(3-bromo-2-(hydroxymethyl)phenyl)-2-chloroacetamide. The above product was dissolved in IPA (10 mL), and added 50% w/w aqueous NaOH (374 mg, 4.68 mmol). The mixture was stirred at room temperature for 3 h and concentrated. The residue was diluted with a solution of saturated sodium bicarbonate (15 mL) and extracted with DCM (80 mL). The organic layer was dried over sodium sulfate and concentrated to give 6-bromo-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one. The above intermediate was dissolved in THF (60 mL) and added 2.0 M borane dimethyl sulfide methyl sulfide complex in THF (6.24 mL, 12.47 mmol). The reaction was refluxed for 60 min, cooled to room temperature, and added MeOH (5.0 mL) dropwise. The mixture was refluxed for 30 min concentrated. The residue was diluted with a solution of saturated sodium bicarbonate (60 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (237 mg, 32% yield) as clear gum. LCMS, [M+H]+=229.9. 1H NMR (400 MHz, CDCl3) δ 7.13 (dd, J=7.9, 1.1 Hz, 1H), 6.94 (t, J=7.9 Hz, 1H), 6.74 (dd, J=7.9, 0.9 Hz, 1H), 4.92 (s, 2H), 4.06 (br. s., 1H), 3.89-3.81 (m, 2H), 3.24-3.17 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:39])[CH2:36][CH2:37][CH3:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 82.2 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by butyric acid (27 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction, was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-(cis-4-Butyrylamino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (89 mg) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][N+]([O-])=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].[OH:15]P([O-])(O)=O.[K+].[OH-].[Na+]>CO.[Cl-].[Cl-].[Ti+2].CCOCC>[CH3:1][CH:2]([CH:8]=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)C[N+](=O)[O-]
Reactant: O=P([O-])(O)O
Agent: [Ti+2]
Agent: C[O-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)CC(C)C=O
Reaction time: 1 h

Procedure:
A solution of methyl 3-methyl-4-nitrobutanoate (24.55 g) in methanol (10 ml) is added dropwise to a solution of sodium methoxide (6.37 g) in methanol (250 ml) at room temperature under nitrogen. The resulting mixture is stirred for one hour, added to a mixture of 20% titanous chloride (170 ml), and pH 7 buffer (potassium phosphate monobasic--sodium hydroxide buffer) solution (340 ml) and stirred for 30 minutes. The mixture is then treated with ether (1 l). The organic phase is separated, dried (Na2SO4) and evaporated in vacuo to give the crude product. The crude material is purified by column chromatography on silica gel (300 g, 2% ethyl acetate in hexane) to give methyl 3-methyl-4-oxo-butanoate as a colorless liquid. This material is used directly in the next step.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1>CN(C)C=O>[CH3:1][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2C)C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 5 h
Yield: 33.5 %

Procedure:
Potassium carbonate (166 mg) and methyl iodide (170 mg) were added to a solution of tert-butyl 5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate (362 mg) obtained in Reference Example 50 in dimethylformamide (2 ml), and the mixture was stirred at 60 to 70° C. for 5 hours. The solvent was evaporated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give the title compound as a pale yellow oil (125 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].CS(O[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[N:6]=[CH:5]2
Reactant: Cc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C

Procedure:
To a solution of 5-methylindazole (901 mg) in DMF (10 mL) was added sodium hydride (327 mg) at 0° C., and the mixture was stirred with heating at 40° C. for 30 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (2.28 g), and the mixture was stirred with heating at 90° C. for 19 hours. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:5 as the eluting solvent) to give Compound Q1 (1.04 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12]S(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH:17]3[CH2:18][CH2:19]3)=[CH:23][CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(OCC2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(OCC3CC3)cc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.6 g (10.4 mmol) 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester, 1.7 g (10.4 mmol) 4-cyclopropylmethoxy-phenol and 6.7 g (20.7 mmol) Cs2CO3 in 60 mL DMF is stirred for 12 h at 80° C. Water is added and the mixture is extracted with ethyl acetate (2×). The combined organic layers are washed with NaHCO3 solution and are dried over MgSO4. The solvent is evaporated and the residue is purified by column chromatography (silica gel; PE/ethyl acetate; gradient 9:1→8:2) to yield the desired product.
Reaction SMILES: [Li][CH2:2]CCC.[CH3:6][C:7]1[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:9][CH:10]=[CH:11][CH:12]=1.CI>C1COCC1>[CH2:6]([C:7]1[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: [Li]CCCC
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cccnc1NC(=O)OC(C)(C)C
Temperature: -5 °C
Yield: 85.2 %

Procedure:
Following a literature procedure (Synthesis 1996, 877), n-BuLi (2.2 M in hexane, 9.1 mL, 20 mmol) was added dropwise to solution of tert-butyl 3-methylpyridin-2-ylcarbamate (1.98 g, 9.5 mmol) in dry THF (21 mL) at −5° C. The reaction was maintained at −5° C. for 1 h, then cooled to −78° C. in a dry ice-acetone bath. A solution of MeI (0.62 mL, 10 mmol) in dry THF (3 mL) was added over 20 min. The reaction was maintained at −78° C. for 1 h and then raised slowly to −55° C. The reaction was quenched with water (20 mL) and the resulting mixture was partitioned and the layers separated. The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organic portions were washed with brine, dried (Na2CO3), and concentrated to furnish 1.8 g of tert-butyl 3-ethylpyridin-2-ylcarbamate: LCMS (m/z): 223.1 (MH+), tR=0.54 min
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cccs1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 71 (379 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 398 mg (82%) of white solids. M.P. 266° C. 1H NMR (DMSO-d6): δ 3.70 (m, 4H), 3.93 (m, 4H), 5.48 (s, 2H), 7.15 (m, 1H), 7.19-7.26 (m, 3H), 7.32 (m, 2H), 7.42 (d, J=8.9 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.68 (dd, J=2.6, 8.9 Hz, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.88 (s, 1H). EIMS m/z 512 (M+23). Anal. (C26H21ClN4O2S) C,H, N,
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1>>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:24]2[CH:25]=[C:20]([Cl:19])[N:21]=[CH:22][N:23]=2)=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(Nc2cc(Cl)ncn2)ccc1OCc1ccccc1

Procedure:
The reaction of 4-benzyloxy-3-nitro-aniline with 4,6-dichloropyrimidine to afford 4-(4′benzyloxy-3-nitrophenyl)amino-6-chloro-pyrimidine is performed according to Preparation method 1. δH (d6DMSO): 5.34 (2H, s, CH2Ar), 6.84, (1H, s, HetH), 7.30-7.75 (7H, m, ArH), 8.30 (1H, m, ArH), 8.55 (1H, s, Het H), 10.10 (1H, s, NH)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Reactant: Nc1ccc(Sc2ccccn2)c(Cl)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 642.1 mg (2.81 mmol) of 3-chloro-4-(pyridin-2-ylsulfanyl)-phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to yield 4-[3-chloro-4-(pyridin-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile as a yellow solid, mp 225-228° C.
Reaction SMILES: ClC[C:3]1[C:12]2[C:7](=[CH:8][C:9](OC)=[C:10](OC)[CH:11]=2)[C:6](CC2C=CC(OC)=C(OC)C=2)=[N:5][CH:4]=1.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(N(CC)CC)C>CS(C)=O.O>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=[CH:4][N:5]=1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2cnccc2c1

Procedure:
A mixture of 1.16 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline, 0.8 of 1-(para-methoxyphenyl)piperazine hydrochloride, and 1.3 ml of triethylamine in 10 ml dimethylsulfoxide was heated at 80° for one hour under argon. The cooled solution was then diluted with water and extracted with methylene chloride. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, charcoaled, and evaporated. The residue was crystallized from ethanol to give 1.3 g of 6,7-dimethoxy-1-{(3,4-dimethoxyphenyl)methyl}-4-[[4-methoxyphenyl)-1-piperazinyl]methyl]isoquinoline as a yellow solid, mp 176°-177°. Recrystallization from ethanol provided the analytical sample, mp 176-177°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2I.C(N(CC)CC)C.[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1
Reactant: Cn1cc(I)c2cc(F)ccc21
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cc(F)ccc21
Temperature: 100 °C

Procedure:
A solution of 5-fluoro-3-iodo-1-methyl-1H-indole (11.5 g, 41.8 mmol) in dioxane (200 mL) was treated with triethyl amine (27 mL, 194 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (1.707 g, 2.090 mmol). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (39.4 mL, 272 mmol) was added carefully to the reaction (gas evolution was observed). The mixture was heated to 100° C. for 30 minutes, cooled, and diluted with about 250 mL ethyl acetate. The precipitate was filtered and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was purifed on silica gel, eluting with 8:2 heptane:ethyl acetate, to give the title compound. MS ESI(+) m/z 276.0 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>[Cu](I)I.O.C(OCC)(=O)C>[CH3:19][Si:20]([CH3:22])([CH3:21])[C:23]#[C:24][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COCOc1ccc(I)cc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.74 g (21.7 mmol) of 1-iodo-4-methoxymethoxybenzene, 100 ml of triethylamine and a mixture of 1.53 g (2.18 mmol) of dichloro-bis(triphenylphosphine)palladium and 831 mg (4.37 mmol) of copper iodide are introduced into a three-necked flask. 6.14 ml (43.5 mmol) of trimethylsilylacetylene are then added and the medium is stirred for 48 h at room temperature. It is then poured into a water/ethyl acetate mixture. The organic phase is washed twice with water and, after separation of the phases by settling, it is washed with magnesium sulphate and concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:20])([C:13]#[C:14][C:15]2OC=[CH:18][CH:19]=2)[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:21])=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-].[Cs+].[Cs+].[I-].[Li+].[H-].[Na+]>>[Cl:21][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:8](=[O:20])[C@H:7]([CH2:6][CH3:5])[O:20][C@:8]([C:13]#[C:14][C:15]3[CH:19]=[CH:18][O:25][CH:22]=3)([C:9]([F:10])([F:11])[F:12])[C:7]=2[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Cl)cc1C(O)(C#Cc1ccco1)C(F)(F)F
Agent: [Cs+]
Agent: [H-]
Agent: [I-]
Product: CC[C@@H]1O[C@](C#Cc2ccoc2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O

Procedure:
The title compound was prepared in a manner similar to the product of Example 11 except that cesium carbonate/lithium iodide rather than sodium hydride was used in the final reaction step: mp 169-170°; HRMS: Calcd. for C18H14NO3F3Cl (M+H)+ : 384.061431. Found: 384.058632.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:19])[CH3:2].O.NN.N>CO.[Ni].CO.C(Cl)Cl>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[CH2:8][CH2:9]2
Reactant: CCN(CC)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: N
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCN1C(=O)CCc2cc(N)ccc21
Yield: 81.2 %

Procedure:
A solution of 1-(2-(diethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.72 mmol) in 10 mL methanol was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was treated with hydrazine hydrate (534 μL, 17.2 mmol) and heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad was rinsed with 10 mL methanol. The filtrate was concentrated to give a dark brown residue which was subjected to flash silica gel chromatography using 5% 2M NH3 in MeOH/CH2Cl2 to give a colorless oil (365 mg, 81.2%). 1H-NMR (CDCl3) δ: 6.88 (d, J=8.4 Hz, 1H), 6.58 (d, J=2.7 Hz, 1H), 6.51 (dd, J=2.7, 9 Hz, 1H), 3.98 (t, J=7.8 Hz, 2H), 3.54 (br s, 2H), 2.78 (t, J=7.8 Hz, 2H), 2.66-2.55 (m, 8H), 1.04 (t, J=7.2 Hz, 6H). MS (ESI): 262.2 (M+1, 100%).
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:29]1([CH2:35][CH2:36][CH2:37]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:37][CH2:36][CH2:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: BrCCCc1ccccc1
Agent: Cl
Product: O=C1N(CCCc2ccccc2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m.p. 164° C. and MS: m/e=488.4 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3-phenyl-1-propylbromide.