Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[O:18][CH2:19][C:20](=[O:27])[C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:3][CH2:2]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][N:35]=2)[C:30]([CH:37]=O)=[CH:29]1.[OH-].[Na+]>C(O)C.Cl>[NH:28]1[C:36]2=[N:35][CH:34]=[CH:33][CH:32]=[C:31]2[C:30]([CH:37]=[C:19]2[O:18][C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]2=[O:27])=[CH:29]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2OCCN2CCOCC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2OCCN2CCOCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a solution of ethyl 2-{[2-(2-morpholinoethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.021 g, 0.054 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0070 g, 0.048 mmol) in ethanol (0.5 mL), 2M hydrochloric acid in ethanol (0.024 mL, 0.048 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. The reaction mixture was cooled with ice bath. Aqueous 2M sodium hydroxide solution (0.024 mL, 0.048 mmol) was added dropwise to neutralize and the mixture was stirred for 1 h. The precipitate was collected by filtration then purified by preparative HPLC to afford the titled compound as solid (0.0054 g, y. 21%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@@H:14]2[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]2[OH:24])=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].[N:25]([O-])=O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:25][N:13]([C@@H:14]3[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]3[OH:24])[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: O=N[O-]
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@@H](O)[C@H]2O)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a stirring solution of (1S,2S,3R,5S)-3-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLACINA; 1.14 g, 3 mmol) in acetic acid (5 mL) was added sodium nitrite (0.23 g, 3.3 mmol) while maintaining the reaction temperature at 20-30° C. The reaction mixture was stirred for 30 minutes. It was then diluted with ethyl acetate (50 mL), washed with water (2×35 mL) and evaporated under reduced pressure. The crude product was triturated in hexane (20 mL) and filtered to give CLTOL as an off-white powder (1.00 g, 86% yield): 98 area % by HPLC; mp 98-107° C.; 13C NMR (CDCl3, 125 MHz) δ13.4, 22.0, 33.5, 33.7, 61.75, 61.77, 71.1, 74.9, 75.4, 82.0, 131.8, 150.7, 152.9, 171.8.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.C(NCC)C>[NH2:1][C@H:2]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCNCC
Product: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Fmoc-Asn(Trt)-OBn (3.5 g, 5.1 mmol) in DCM (14.0 mL), diethylamine (14.0 mL) was added and stirred for 1 h at rt. The resulting solution was concentrated in vacuo and the thick-residue was purified by neutral alumina column chromatography (eluent: 0-50% EtOAc in Hexane then 0-5% MeOH in CHCl3) to yield NH2-Asn(Trt)-OBn D (yield: 1.75 g, 73.0%; Mass: Cal. 464.21, Obs—465.3 (M+1), 487.2 (M+Na]).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:27])/[CH:12]=[CH:13]/[C:14](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:15]/[C:16]([O:18]CC)=[O:17].C(O)C.C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:27])/[CH:12]=[CH:13]/[C:14](/[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:15]/[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)/C=C(/C=C/C(=O)c1cc(OC)ccc1OC)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(C(=O)/C=C/C(=C/C(=O)O)c2ccccc2)c1

Procedure:
0.45 g (1.22 mmol) of ethyl (2Z, 4E)-6-(2,5-dimethoxyphenyl)-6-oxo-3-phenylhexa-2,4-dienoate, 20 ml of ethanol, 0.206 g (2.44 mmol) of sodium bicarbonate and 20 ml of water are mixed together and refluxed for three hours. After evaporating off the solvents, the residue is poured into water, acidified with normal hydrochloric acid solution and extracted with dichloromethane. The organic phase is dried (Na2SO4), the solvent is evaporated off and the pasty product obtained is purified by flash chromatography (20/80 heptane/ethyl acetate) (yellow solid; diisopropyl ether; m.p.: 165° C.; 170 mg) and recrystallized (10/6 hexane/ethyl acetate) (0.3 g of yellow solid; 22%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH:22]1[C:35]2[C:26](=[CH:27][C:28]3[C:33]([C:34]=2[CH2:36]O)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br:20][CH2:36][C:34]1[C:35]2[C:26]([CH:27]=[C:28]3[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of triphenylphosphine (16.44 g, 100.8 mmol) in acetonitrile (120 mL) was flushed with nitrogen for 20 minutes. Bromine (3.3 mL) was added and a solution of anthracen-9-yl-methanol (15.0 g, 72.0 mmol) in acetonitrile (100 mL) was added dropwise. The mixture was stirred for 2 hours at room temperature and refrigerated at 5° C. overnight. The solution was cooled to 0° C. for 30 minutes and filtered. The residue was washed with cold acetonitrile and purified by recrystallization from chloroform to give 9-bromomethyl-anthracene as yellow crystals (13.47 g, 69% yield). 1H NMR (CDCl3) δ 8.51 (1H, s), 8.32 (2H, d), 8.05 (2H, d), 7.66 (2H, dd), 7.52 (2H, dd), 5.56 (2H, s).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[N+:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([O-:28])=[O:27].N>CN(C=O)C>[N+:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: N
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
Prepared analogously to Example 77 from 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-nitroaniline in DMF and subsequent treatment with methanolic ammonia.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[OH:22]>C(O)(=O)C>[OH:13][C:9]1([C:19]2[CH:18]=[C:17]([CH3:21])[C:16]([OH:22])=[C:15]([CH3:14])[CH:20]=2)[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: Cc1cccc(C)c1O
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CC(=O)O
Product: Cc1cc(C2(O)C(=O)c3ccccc3C2=O)cc(C)c1O
Yield: 19.6 %

Procedure:
Ninhydrin (1.00 g, 5.61 mmol) and 2,6-dimethylphenol (686 mg, 5.61 mmol) was dissolved in acetic acid (15 ml), and this solution was heated for 13 hrs. The reaction mixture was concentrated, and extracted with dichloromethane, and then concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.31 g, 20%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[Cl:10].CC1(C)C(C)(C)OB([C:19]2[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])O1.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1(C)C(C)(C)OB(C2C=CC=CC=2C(OCC)=O)O1>[Cl:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:19]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(Br)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(OC)cc1Cl
Temperature: 120 °C
Reaction time: 7 h
Yield: 116.4 %

Procedure:
Under an argon atmosphere, 1-bromo-2-chloro-4-methoxybenzene (44.3 g) was dissolved in toluene (220 ml), ethyl 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoate (60.8 g), water (132 ml), sodium hydrogen carbonate (33.6 g) and dichlorobis(triphenylphosphine)palladium(II) (2.8 g) were added, and the mixture was stirred at an oil bath temperature of 120° C. for 7 hr. To the reaction mixture was added ethyl 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoate (5.2 g), and the mixture was further stirred for 2 hr. The reaction mixture was cooled to room temperature, toluene (100 ml) and water (200 ml) were added, and the mixture was stirred overnight. To the reaction mixture was added activated carbon (3 g), and the mixture was further stirred for 1 hr. The insoluble material was filtered off through celite, and the insoluble material was washed with toluene (100 ml) and water (200 ml). The obtained filtrates were combined to allow for layer separation. The obtained organic layer was washed with water (100 ml), and the solvent was evaporated to give the title compound (67.7 g).
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1.C(Cl)Cl.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(N(CC)CC)C>[CH3:30][S:31]([O:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1)(=[O:33])=[O:32]
Reactant: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2.48 g. of ethyl 15-hydroxy-9-oxo-prostanoate (Example 50) in 18 ml. of methylene chloride containing 1.4 ml. of triethylamine, cooled in an ice-salt bath is added dropwise 0.58 ml. of methanesulfonyl chloride. The resulting mixture is stirred for 15 minutes and is then washed successively with ice cold water, 10% hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 2.7 g. (90%) of oil; λmax. 5.78 (carbonyl groups), 7.45 and 8.55 μ (sulfonate).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])O.[Na+].[N:30]#[C:31]Br>ClCCl.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]#[N:30])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:23][CH:24]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(C3CCNCC3)cn2)cc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(C#N)CC3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidine (124 mg, 0.358 mmol) in dichloromethane (1 mL) was added a solution of sodium hydrogen carbonate (60 mg, 0.716 mmol) in water (0.5 mL). The mixture was cooled in an ice bath followed by the addition of a solution of cyanogen bromide (45 mg, 0.430 mmol) in dichloromethane (1 mL). The mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature for an additional 1 hour. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (114 mg, yield 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7][CH2:6][CH2:5]2.C([O:21]O)(C)(C)C>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:8]([CH3:15])([CH3:16])[CH2:7][CH2:6][C:5]2=[O:21])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14]
Reactant: CC(C)(C)OO
Reactant: CCOc1cc2c(cc1Br)CCCC2(C)C
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Product: CCOc1cc2c(cc1Br)C(=O)CCC2(C)C
Reaction time: 8 h

Procedure:
To 6-bromo-7-ethoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Compound A-3, 5.83 g, 20.6 mmol) in dichloromethane (25 mL) and tert-butyl hydroperoxide (25 mL) at room temperature was added a catalytic amount of chromium (VI) oxide. The reaction was stirred overnight. Quenched the reaction with water and followed by extraction with diethylether. The organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (silica gel, 2% ethyl acetate/hexane) yielded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)CCC>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH:3]=[C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(-c2nc(Cl)cc(Nc3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCCCO
Product: Fc1ccc(-c2nc(Nc3ccc(OC(F)(F)F)cc3)cc(N3CCOCC3)n2)cc1
Temperature: 30 °C
Yield: 55.6 %

Procedure:
A mixture of compound [6-chloro-2-(4-fluoro-phenyl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine (0.25 g, 0.65 mmol) and morpholine (0.113 g, 8.20 mmol) in n-butanol (10 mL) was refluxed for 12 hours under nitrogen. The mixture was then cooled to temperature in the range of 20-40° C. and evaporated under reduced pressure. The crude compound was passed through the silicagel by using 20% ethylacetate—petroleum ether to afford the compound [2-(4-fluoro-phenyl)-6-morpholin-4-yl-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine (0.157 g, 56%) as off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]#N)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C1C=CC(C2(C=[O:30])CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:14]=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: O=CC1(c2ccc(Cl)c(Cl)c2)CCCC1

Procedure:
1-(3,4-Dichlorophenyl)cyclopentanecarbaldehyde (482) was synthesized from 1-(3,4-dichlorophenyl)cyclopentanecarbonitrile (481) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbaldehyde (238).
Reaction SMILES: [C:1]([C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:13]=3)[C:8]=2[CH:7]=[C:6]([CH:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)[CH:5]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCCl>[N:19]1([C:17]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]4[CH:7]=[C:6]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]=4[NH:15]3)=[CH:10][CH:11]=2)=[O:18])[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)CC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(C2CCNCC2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Yield: 54.4 %

Procedure:
tert-Butyl 4-(1-carbamoyl-7-(morpholine-4-carbonyl)-9H-carbazol-3-yl)piperidine-1-carboxylate (Example 393, 50 mg, 0.099 mmol) was dissolved in 1,2-Dichloroethane (3 ml) and trifluoroacetic acid (1 ml, 12.98 mmol) and stirred for 1 hour at room temperature. Evaporation of volatiles and purification by reversed phase preparative HPLC, followed by filtration of product containing fractions through a PHENOMENEX® Strata-X cartridge (2 g adsorbent), a wash with Methanol, and elution with 2M NH3 in MeOH gave 21.9 mg 7-(morpholine-4-carbonyl)-3-(piperidin-4-yl)-9H-carbazole-1-carboxamide. MS (ESI) m/e−=405 and m/e=407 consistent with [M−H]− and [M+H]+. HPLC retention time 7.61 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (CD3OD) δ ppm 8.21 (s, 1H), 8.20 (d, 1H, J=8.0), 7.87 (d, 1H, J=1.5), 7.69 (s, 1H), 7.27 (dd, 1H, J=8.0, 1.5), 3.90-3.50 (b, 8H), 3.23 (br. d., 2H, J˜12), 2.91 (m, 1H), 2.83 (m, 2H), 1.97 (br. d., 2H, J˜12), 1.85 (m, 2H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@H:15]([CH3:26])[O:14][C@@H:6]1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+]>CO>[S:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@H:6]1[O:14][C@@H:15]([CH3:26])[C@@H:16]([OH:22])[C@@H:17]([OH:18])[C@@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](Sc2ccccc2)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 40 °C
Yield: 73.3 %

Procedure:
Compound of example 8 (224 g) is dissolved in methanol (500 ml) and NaOMe (2 g, 37 mmol) is added. The reaction mixture is stirred at 40° C. for 2½ h. Methanol (250 ml) is distilled off and CO2 is bubbled through the remaining solution for 5 min reaching pH=7. The reaction mixture is evaporated and isobutyl acetate (450 ml) is added. 50 ml of solvent is evaporated and the resulting mixture is subjected to crystallization by letting it at room temperature for 24 h. The white crystalline solid formed is filtered and washed with tert-butyl methyl ether (200 ml) giving 110 g (73%) of product after drying.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[C:22]([F:34])=[C:23]([C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C1COCC1>[Cl:20][C:21]1[C:22]([F:34])=[C:23]([C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)[C:24]([N:12]=[C:6]1[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]1)=[O:25]
Reactant: O=C(Cl)c1c(C(F)(F)F)ccc(Cl)c1F
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)sc1=NC(=O)c1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a suspension of the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF was added Et3N (0.37 mL, 2.7 mmol). This mixture was cooled to 0° C. and 3-chloro-2-fluoro-6-trifluoromethyl benzoyl chloride (Alfa Aesar, 0.35 g, 1.3 mmol) in 5 mL THF was added dropwise via syringe. The mixture was allowed to stir at ambient temperature for 1 hour, then was warmed to reflux and was allowed to stir for 8 hours. The mixture was then cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and purified via flash column chromatography (SiO2, 7:3 hexanes:EtOAc) to provide the title compound (0.20 g, 0.50 mmol, 46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.27 (s, 3H), 2.28 (s, 3H), 3.27 (s, 3H), 3.68 (t, J=4.7 Hz, 2H), 4.28-4.37 (m, 2H), 7.37-7.43 (m, 1H), 7.44-7.52 (m, 1H); MS (DCI/NH3) m/z 411 (M+H)+; Anal. calculated for C16H15ClF4N2O2S: C, 46.78; H, 3.68; N, 6.82. Found: C, 46.83; H, 3.30; N, 6.65.
Reaction SMILES: Cl[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:32]=[N:33][OH:34])[CH:17]=3)[C:12]2=[O:35])=[CH:7][CH:6]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44]#[CH:45])=[CH:39][CH:38]=1>ClCCl>[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44]2[O:34][N:33]=[C:32]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[C:12](=[O:35])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=3)[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[CH:19]4)[CH:45]=2)=[CH:39][CH:38]=1
Reactant: C#CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C=NO)ccc2c(=O)n1-c1ccc(F)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(-c3cc(Cc4ccc(F)cc4)on3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Sodium hypochlorite (1.408 mL, 0.912 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(2-(4-fluorophenyl)-6-((hydroxyimino)methyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (100 mg, 0.228 mmol) and 1-fluoro-4-(prop-2-ynyl)benzene (61.2 mg, 0.456 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for overnight. The reaction was checked with LCMS and starting material was all consumed. The mixture was diluted with dichloromethane (10 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1×8 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane=50% to give tert-butyl 5-(6-(5-(4-fluorobenzyl)isoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (102 mg, 0.179 mmol) as a yellow solid.
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].[C:5]1([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:5]1([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]2[CH2:13][CH2:14][N:15]([CH2:1][CH2:2][OH:3])[CH2:16][CH2:17]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: OCCBr
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethylene bromohydrin (0.37 ml) was added dropwise with stirring to a mixture of 4-diphenylmethylpiperidine (1 g), potassium carbonate powder (1.1 g) and N,N-dimethylformamide (10 ml), and the mixture was stirred at room temperature for 4 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure, followed by addition of water and extraction with dichloromethane. The dichloromethane layer was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was purified by silica gel chromatography [eluent: CH2Cl2 --MeOH (25:1, v/v)] to give 4-diphenylmethyl-1-piperidineethanol as an oil. Yield 1.08 g (91.9%).