Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:26])/[C:21]([O:23]CC)=[O:22])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10]1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:26])/[C:21]([OH:23])=[O:22])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:10]1
Reactant: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Temperature: 77.5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of ethyl (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (710 mg) and 1N NaOH solution (3.8 ml) in MeOH (20 ml) was stirred at 75-80° C. for 2 hours. To the reaction mixture was added 1N HCl solution (3.8 ml) and the resultant solution was evaporated in vacuo and the residue was dissolved in a mixture of MeOH and toluene and evaporated in vacuo and the residue was dried to give (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (658 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[C:11]([C:17]([O:19]C)=[O:18])[CH:10]=1.CO.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=1
Reactant: C=Cc1cc(C(=O)OC)cc(-c2ccc(C)cc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=Cc1cc(C(=O)O)cc(-c2ccc(C)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500 mL flask charged with methyl ester from step C above (20 g, 74 mmol) in THF (250 mL) was added MeOH (100 mL) and aq. 3N NaOH (74 mmol, 25 mL). The mixture was stirred overnight at rt and an additional 15 mL NaOH added. Reaction stirred for 16 h, the pH was then adjusted 4-5 and the mixture extracted repeatedly with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give 18.5 g of product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][N:20]([CH3:25])[C:21](=[O:24])[CH:22]=[CH2:23])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][C:34]([F:46])=[CH:33][C:32]=1[N:47]1[C:59](=[O:60])[C:58]2[S:57][C:56]3[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=3[C:50]=2[CH:49]=[N:48]1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O.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]>[F:46][C:34]1[CH:33]=[C:32]([N:47]2[C:59](=[O:60])[C:58]3[S:57][C:56]4[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=4[C:50]=3[CH:49]=[N:48]2)[C:31]([CH2:30][O:29][C:26](=[O:28])[CH3:27])=[C:36]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[N:16]=[C:15]([O:17][CH2:18][CH2:19][N:20]([CH3:25])[C:21](=[O:24])[CH:22]=[CH2:23])[CH:14]=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:35]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: C=CC(=O)N(C)CCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C=CC(=O)N(C)CCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
A mixture of N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)-N-methylacrylamide 112e (100 mg, 0.25 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-triene-5-yl}-6-(tetra-methyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 108c (187 mg, 0.375 mmol), Pd(dppf)Cl2 (19 mg, 0.025 mmol) and K3PO4 (133 mg, 0.625 mmol) in acetonitrile (5 mL) and water (0.5 mL) was stirred at 90° C. for 6 h under N2. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep-TLC (PE/EA=1/4) to give N-[2-[[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]-N-methyl-prop-2-enamide 113a (100 mg, 57%) as light yellow solid. MS-ESI: [M+H]+ 699.2
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].FC(F)(F)C(O)=O.[CH3:19][C:20]1[S:24][C:23]([C:25]([N:27]2[CH2:32][C:31]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[O:30][CH2:29][CH2:28]2)=[O:26])=[CH:22][CH:21]=1.C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]1[CH2:36][CH2:37][C:31]2([O:30][CH2:29][CH2:28][N:27]([C:25]([C:23]3[S:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[O:26])[CH2:32]2)[CH2:33][CH2:34]1
Reactant: OCCCCCCCCCBr
Reactant: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 9-bromo-1-nonanol (0.314 g) in MeCN (3 mL) was added to solution of (5-methylthiophen-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 9, step b) (0.263 g) and triethylamine (0.261 mL) in MeCN (7 mL). The resulting mixture was stirred at 60° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine (×2), dried over sodium sulphate, filtered and evaporated in vacuo. The white solid was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the subtitled compound as a white solid. Yield 0.352 g.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:14][CH:15]=[O:16])[CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1>CO>[F:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:14][CH2:15][OH:16])[CH2:12][CH2:13]2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=CCC1(c2cc(F)cc(F)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCC1(c2cc(F)cc(F)c2)CC1
Reaction time: 8 h

Procedure:
To a stirred, cooled (0° C.) solution of sodium borohydride (1.0 g) in methanol (20 ml) under an argon atmosphere was added slowly a solution of [1-(3,5-difluoro-phenyl)-cyclopropyl]-acetaldehyde in methanol (10 ml). Stirring was continued at room temperature overnight, then the reaction mixture was quenched by slow addition of water. Methanol was evaporated and the aqueous phase was extracted with ethyl acetate twice. The combined organic layers were dried over MgSO4 and concentrated to give 2-[1-(3,5-difluoro-phenyl)-cyclopropyl]-ethanol as yellow liquid (2.37 g). 1H-NMR (300 MHz, CDCl3, δ): 0.76-0.86 (m, 4H), 1.85 (t, J=7 Hz, 2H), 3.61-3.62 (m, 2H), 6.60-6.67 (m, 1H), 6.78-6.85 (m, 2H).
Reaction SMILES: [C:1]([CH:5]1[CH2:8][C:7](=[O:9])[C:6]1(Cl)Cl)([CH3:4])([CH3:3])[CH3:2]>[Zn]>[C:1]([CH:5]1[CH2:8][C:7](=[O:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CC(=O)C1(Cl)Cl
Agent: [Zn]
Product: CC(C)(C)C1CC(=O)C1
Reaction time: 1.5 h
Yield: 55.9 %

Procedure:
Saturate dry methanol by stirring with excess ammonium chloride under nitrogen for 1.5 h. Add this saturated solution (150 mL) to 3-tert-butyl-2,2-dichlorocyclobutanone (7.5 g, 38.4 mmol) under nitrogen. To the resulting suspension add freshly activated zinc (15.4 g, 236 mmol). Stir for 5 hours, filter and concentrate. Partition the residue between diethyl ether and water. Discard the aqueous phase and wash the diethyl ether layer with water (twice), saturated aqueous sodium chloride solution, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the desired compound as a clear liquid (2.71 g, 56%).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[CH3:10][C:11]1([CH3:32])[CH:20]=[C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[C:18]2[C:13](=[CH:14][C:15]([OH:31])=[CH:16][CH:17]=2)[O:12]1.CC1(C)CC(C2C=CC(C(F)(F)F)=CC=2)C2C(=CC(OCCN(C)C)=CC=2)O1>>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:31][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:20][C:11]([CH3:32])([CH3:10])[O:12]2)=[CH:17][CH:16]=1)[CH3:3]
Reactant: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Reactant: CCN(CC)CCCl
Agent: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc2ccccc2c1
Yield: 49 %

Procedure:
Reaction of 2-diethylaminoethylchloride hydrochloride with 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7-ol by an analogous method to that described in Preparation 18 (c) gave the title compound as a colourless oil in 49% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.[H-].[Na+].Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1.O.CN(C)C=O>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[C:9]3[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2](=[O:1])[N:11]2[C:34]([O:36][CH3:37])=[O:35])=[CH:19][CH:18]=1)#[N:17]
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 60 mg, 0.146 mmol) in tetrahydrofuran (0.8 mL) is added to a suspension of sodium hydride (60% in mineral oil, 7 mg, 0.17 mmol) in tetrahydrofuran (0.5 mL). After 20 min methyl chloroformate (11 μL, 0.15 mmol) is added and the mixture is stirred at room temperature over night. Another portion of sodium hydride (60% in mineral oil, 3 mg, 0.07 mmol) is added. After 2 h, the mixture is diluted with water and N,N-dimethylformamide and then purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 8 mg; ESI mass spectrum [M+H]+=470, Retention time HPLC: 1.14 min (V011_S01).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].CCOCC.[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[Cl:28][CH2:29][C:30]([N:7]([CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(C)c1NCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCc1cccc(C)c1N(CC1OCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)-2-ethyl-6-methylaniline (7.5 grams), sodium carbonate (5.0 grams), ether (100 ml) and water (40 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to a temperature of about 0° C. and chloroacetyl chloride (4.5 grams) was added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for a period of about one hour. After this time the resulting solution was washed with water and the washed solution was dried over anhydrous magnesium sulfate and stripped of solvent under reduced pressure to yield the desired product N-α-chloroacetyl-N-(1,3-dioxolan-2-ylmethyl)-2-ethyl-6-methylaniline.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]2[CH:7]([CH:8]2[N:11]([CH3:13])[CH3:12])[CH2:6]1.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([OH:39])[CH:37]=3)[N:32]=[CH:31][N:30]=2)[CH:24]=[CH:25][C:26]=1[F:27]>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([O:39][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH:9]5[CH:7]([CH:8]5[N:11]([CH3:13])[CH3:12])[CH2:6]4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: CN(C)C1C2CN(CCCCl)CC21
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2C(C1)C2N(C)C
Temperature: 80 °C
Reaction time: 7 h
Yield: 44.2 %

Procedure:
A mixture of 3-(3-chloropropyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-6-amine (0.70 g), K2CO3 (0.78 g) and 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.70 g) in 30 mL of DMF was stirred at 80° C. for 7 h, and cooled to rt. To this, 50 mL of ice-water was added, and the resulted mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (diluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.47 g, 35.00%), HPLC: 96.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 9.45 (s, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.54 (s, 2H), 7.12 (d, J=4.2 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H), 4.19-4.12 (m, 2H), 3.93 (s, 3H), 2.45-3.30 (m, 6H), 2.51 (s, 6H), 2.14-1.93 (m, 6H), 1.33 (m, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:3]=1.[OH:17]O>[C].[Pd].C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:17])=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Cc1ccnc(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: OO
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(-c2ccc([N+](=O)[O-])cc2)c1
Reaction time: 17 h

Procedure:
A mixture of 4-methyl-2-(4-nitrophenyl)pyridine (25.8 g), acetic acid (130 ml) and 30% hydrogen peroxide (27.5 ml) is agitated at 75°-85° C. for 17 hours. To the mixture is added 10% palladium-carbon in order to decompose excess amount of hydrogen peroxide, and then the palladium-carbon is removed by filtration. The filtrate is concentrated, and the concentrated solution is made alkaline with potassium carbonate and extracted with ethyl acetate. The extract is washed with water and dried, and ethyl acetate is distilled off to give 4-methyl-2-(4-nitrophenyl)pyridine N-oxide (26.6 g). M.P. 158°-160° C.
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[CH:11]=[C:12]([CH3:14])[CH3:13])=[O:5].B(Br)(Br)Br>O1CCOCC1>[CH3:13][C:12]([CH3:14])=[CH:11][CH:7]1[C:8]([CH3:9])([CH3:10])[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(C)C)C1(C)C
Agent: BrB(Br)Br
Solvent: C1COCCO1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Temperature: 15 °C

Procedure:
In a 50 ml flask, there were charged ethyl chrysanthemate (composition: (+)-cis, 2.5%; (-)-cis, 16.8%; (+)-trans, 12.3%; (-)-trans, 68.4%) (2.0 g) and dioxane (18.0 g) under nitrogen. Boron tribromide (0.26 g) was added thereto at 15° C. with stirring and stirred for 4 hours. Then a small amount of the reaction mixture was hydrolyzed to obtain chrysanthemic acid. The composition of the optical isomers in the product was determined by the same method as described in EXAMPLE 1. The result was as follows: (+)-cis, 2.4%; (-)-cis, 2.6%; (+)-trans, 46.2%; (-)-trans, 48.8%.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(O)c2ncccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-Chloromethyl-8-hydroxyquinoline hydrochloride (2.145 g; 9.3 mmol) was added to a mixture of sodium methoxide (1.763 g; 32.6 mmol) in MeOH (40 ml). The reaction mixture was stirred for about 4 h at room temperature, and then evaporated to dryness. The residue was dissolved in CHCl3 (100 ml, the solution was washed with water until a neutral pH was obtained, and was then washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was extracted with hexane (100 ml). The hexane solution was evaporated to give the title product, 0.36 g (20%). M.p. 75-760° C. TLC (CHCl3/MeOH/NH3.9.5:0.5:0.1). Rf=0.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:13]O)[CH2:6]2.C1(C)C=CC(S(Cl)(=O)=[O:22])=CC=1>[OH-].[Na+]>[C:7]([CH2:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=1[C:8]([OH:12])=[O:22])#[N:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CC(=NO)C2=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(CC#N)c1
Temperature: 50 °C
Yield: 95.9 %

Procedure:
5-Methoxy-indan-1,2-dione-2-oxime (22 g, 0.12 mol) was added to a solution of 230 ml 8% NaOH. The mixture was heated to 50° C., and then p-toluenesulfonyl chloride (30 g, 0.16 mol) was added in portions. The mixture was heated at 80° C. for 15 min. After cooled to room temperature, the precipitate was removed, and the filtrate was acidified with concentrated HCl to pH=3-4. The precipitate was collected and dried to give colorless solid (22 g, 100% yield). LC-MS: 192 (MH+)
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH:14]12[O:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]2.Cl>CN(C)C=O>[Cl:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]3[OH:20])[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: C1CCC2OC2C1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O[C@@H]1CCCC[C@H]1n1cnc2cc(Cl)c(Cl)cc21
Yield: 88 %

Procedure:
5,6-Dichlorobenzimidazole (Townsend and Revankar, Chem. Rev. 1970, 70:389, and references cited therein) (5.00 g, 26.0 mmol) was dissolved in N,N-dimethylformamide (65 ml) and sodium hydride (60% oil dispersion, 50 mg) was added. The solution was heated to 145° and cyclohexene oxide (Aldrich, 7.8 g, 26 mmol) was added in 3 portions over 3 hours. The solution was neutralized with 1 N hydrochloric acid, and evaporated to a purple solid. The solid was recrystallized from ethanol to give title compound as pink crystals (12.55 g, 88%); m.p. 236-238° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1>[Ni].C(O)C.C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Raney nickel was added to a flask containing ethanol (20 mL). The catalyst was triturated with ethanol (3×20 mL) and the a suspension of ethyl 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (4.0 g, 12.2 mmol) in ethanol (600 mL) and THF (200 mL) was added. The reaction was then placed under a hydrogen atmosphere (1 atm) and allowed to stir at rt overnight. The reaction was filtered through a pad of Celite® using a mixture of ethanol and THF (3:1) to rinse. The filtrate was concentrated in vacuo to afford the desired product (3.60 g, 96%). 1H-NMR (DMSO-d6) 8.05 (s, 1H), 8.04 (br s, 2H), 7.88 (s, 1H), 7.01 (d, J=8.0 Hz, 2H), 6.61 (d, J=8.0 Hz, 2H), 5.31 (br s, 2H), 4.07 (q, J=7.3 Hz, 2H), 1.12 (t, J=7.3 Hz, 3H); ES-MS m/z 298.2 (MH)+; HPLC RT (Method A) 1.64 min; TLC Rf=0.30 (Acetone/CH2Cl2 1:3).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][N:17]([CH3:36])[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:27]=2)[CH:22]=[CH:21]1)=[O:19]>C(Cl)Cl>[CH3:16][N:17]([CH3:36])[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:27]=2)[C:22]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)=[CH:21]1)=[O:19]
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CN(C)C(=O)n1ccc2ccc(-c3ccc(F)cc3)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)C(=O)n1cc(C(=O)c2ccc(CCl)cc2)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19 %

Procedure:
To a solution of 4-(chloromethyl)benzoyl chloride (804 mg, 4.26 mmol) in CH2Cl2 (21 mL) was added AlCl3 (850 mg, 6.39 mmol) in a single portion, and the yellow solution was stirred for 15 min at ambient temperature. A solution of 6-(4-fluorophenyl)indole-1-carboxylic acid dimethylamide (1.00 g, 3.55 mmol), prepared as in step 1, in CH2Cl2 was added dropwise and the dark solution was stirred for 2 hours at ambient temperature. Additional AlCl3 (0.24 g, 1.78 mmol) was added and the reaction mixture was stirred for 0.5 hours. The reaction mixture was poured into a separatory funnel containing ice water and CH2Cl2. The layers were separated and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. Pure 6-(4-fluorophenyl)-3-(4 -chloromethylbenzoyl)indole-1-carboxylic acid dimethylamide (294 mg) was obtained by chromatography on silica gel (25%, then 50% ethyl acetate/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:38][CH3:39])([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][C:29](=[O:37])[NH:28]3)[CH2:24][CH2:23]2)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[CH2:13][C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>C(#N)C>[F:16][C:14]([F:15])([F:17])[CH2:13][C:12]([N:11]([CH2:10][C@@:9]([N:38]([CH3:39])[C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][C:25]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C:29](=[O:37])[NH:28]2)[CH2:26][CH2:27]1)[CH3:19])=[O:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN[C@](CCN1CCC2(CC1)NC(=O)Cc1ccccc12)(CN(C)C(=O)CC(F)(F)F)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CN(C[C@](CCN1CCC2(CC1)NC(=O)Cc1ccccc12)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)c1ccccc1)C(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 85.5 %

Procedure:
N-{2-(S)-(3,4-Dichlorophenyl)-2-methylamino-4-[3-oxo-3,4-dihydro-2H-spiro(isoquinoline-1,4′-piperidin)-1′-yl]butyl}-3,3,3-trifluoro-N-methylpropanamide (440 mg) was dissolved in acetonitrile (5 mL). Under cooling with ice, triethylamine (314 μL) and benzoyl chloride (174 μL) were added thereto, and the mixture was stirred for 1 hour at the same temperature. Water was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate, sequentially washed with 0.5N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated brine, and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (n-hexane ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=10:1), to thereby give the title compound (442 mg, 85.5%) as white powder.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1)=[CH2:2].[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16]>C(Cl)(Cl)Cl>[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)[CH2:24][CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C=Cc1ccnc2ccc(C#N)cc12
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCc2ccnc3ccc(C#N)cc23)CC1
Temperature: 50 °C
Yield: 99.9 %

Procedure:
A mixture of (d) (150 mg, 0.8 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (166 mg, 0.8 mmol) and chloroform (0.5 ml) were heated at 50° C. in a loosely capped vial for 6 hours. The product was purified by flash silica chromatography eluting with a 0-2% methanol in chloroform gradient affording the product as a foam (304 mg, 96%).