Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=2)=[CH:13][CH:12]=1)([CH2:9][CH3:10])[CH3:8].Br[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>CN(C=O)C>[Si:40]([O:39][CH2:38][CH2:37][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:18]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([CH:7]([CH2:9][CH3:10])[CH3:8])=[CH:16][CH:15]=3)[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:29][C:30]=1[CH3:35])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(O)c(C)c3)nc3ccccc3c2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3ccc(OCCO[Si](C)(C)C(C)(C)C)c(C)c3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
K2CO3 (0.135 g, 0.97 mmol) was added to a solution of 3-(4-sec-butylphenyl)-2-(4-hydroxy-3-methylphenyl)quinazolin-4(3H)-one (0.250 g, 0.65 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 30 min, then (2-bromoethoxy)(tert-butyl)dimethylsilane (0.16 mL, 0.78 mmol) was added and the reaction was heated at reflux temperature for 3 hours, before concentrating in vacuo and dissolving the residue in EtOAc. The organics were washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 40% EtOAc in heptane, afforded 2-(4-(2-(tert-butyldimethylsilyloxy)-ethoxy)-3-methylphenyl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one (0.320 g, 90%).
Reaction SMILES: Cl[C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][S:17]([O-:19])=[O:18].[Na+].O.Cl>CN(C)C=O>[CH3:16][S:17]([C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:15])[CH:3]=1)(=[O:19])=[O:18]
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Reactant: CS(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)O
Temperature: 0 °C
Yield: 53.9 %

Procedure:
6 kg of 4-chloro-2-methyl-5-(methylsulfonyl)benzoic acid are dissolved in 15 l of N,N-dimethylformamide (DMF) at room temperature (25°) and subsequently warmed to 50°. 3.6 kg of sodium methanesulfinate are added to this solution. The internal temperature is then raised to 120° and stirred at this temperature for 2 days, with a further 3 kg of sodium methanesulfinate being added after 24 hours. After cooling to 25°, the reaction mixture is introduced into 40 l of water, and 300 g of activated carbon and 1 kg of kieselguhr are added. 5 l of ice are added to the filtrate, and 3.5 l of concentrated hydrochloric acid are added dropwise (pH=1). Recrystallisation from 2-propanol gives 3.8 kg of 4,5-bismethanesulfonyl-2-methylbenzoic acid; m.p. 234-235°.
Reaction SMILES: [F:1][C:2]([F:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[F:1][C:2]([F:28])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOCC(F)(F)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCOCC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of Intermediate 8 (6.41 g, 16.5 mmol) in ethanol (50 mL) was added hydrazine monohydrate (12 mL, 247 mmol). The mixture was stirred at room temperature overnight, concentrated, and the residue was triturated with isopropyl alcohol. The resulting solid was filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel, eluting with methylene chloride/ethanol/ammonium hydroxide (80:8:1) to give the title compound (2.31 g, 54%) as oil.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[C:11]1([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:11]1([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:24]=2)[C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CNc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(=O)c2cccnc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.8 %

Procedure:
To a room temperature slurry of 1.03 g of nicotinoyl chloride hydrochloride in 20 ml of methylene chloride is added, via cannula, 2.0 g of product from Example 145 in 30 ml of methylene chloride. After 5 minutes, 2.05 g of triethylamine is added and the reaction stirred at room temperature for 72 hours. The solution is poured into saturated sodium bicarbonate and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 40% ethyl acetate/hexane) to give 2.35 g of the desired product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)=O.[CH:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28].C(COC)OC.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]([O:17][C:8]1[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=1[C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:27]=[O:28])[CH:34]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)c1cccc(OS(=O)(=O)C(F)(F)F)c1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cccc(-c2cccc(C=O)c2)c1OCc1ccccc1
Yield: 96 %

Procedure:
A solution of 8 (3.75 g, 9.65 mmol), 3-formylphenylboronic acid (2.89 g, 19.3 mmol, 2 equiv.), bis(triphenylphosphine) palladium(II) dichloride (0.20 g), glyme (10 mL) and a solution of sodium bicarbonate (2.9 g, 34.5 mmol) in water (50 mL) was stirred well at reflux under nitrogen for 4 hr. After cooling the reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (2×100 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator. The crude product was purified by chromatography on silica (120 g) with heptane (3 L) to afford pure 9 (3.19 g, 99%).
Reaction SMILES: [CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[NH:9][C:10]=31)[CH2:4][CH2:3]2.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:20]([N:9]1[C:10]2[C@@:2]3([CH3:1])[C:17]([CH3:19])([CH3:18])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:16])[N:8]1[CH2:11][C:12]([F:13])([F:14])[F:15])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(CC(F)(F)F)n1Cc1ccccc1
Temperature: 100 °C
Yield: 69.4 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 47; 150 mg, 0.55 mmol), tetrabutylammonium iodide (220 mg, 0.60 mmol) and benzyl bromide (580 μL, 4.9 mmol) in dimethylformamide (2 mL) was heated in a pressure tube in an oil-bath at 100° C. for 20 h. Dichloromethane (75 mL) was added and the solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with petroleum ether, triturated with petroleum ether, evaporated, and dried under high vacuum at 70° C. overnight to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (139 mg, 70%) as a white solid. ES(+)-MS (M+H) 365.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](/[N:8]=[CH:9]/[N:10](C)C)=O)=[CH:4][CH:3]=1.O.[NH2:16]N>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[N:8]=[CH:9][NH:10][N:16]=2)=[CH:4][CH:3]=1
Reactant: CN(C)/C=N/C(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(-c2nc[nH]n2)cc1
Temperature: 120 °C

Procedure:
To a stirred solution of (E)-4-chloro-N-((dimethylamino)methylene)benzamide (9.4 g, 44.6 mmol) in acetic Acid (13.5 ml) was added hydrazine hydrate (1.524 ml, 49.1 mmol). The reaction mixture immediately solidified and was heated to 120° C. for 2 hours. Whereupon was cooled to room temperature and azeotroped with toluene. The crystalline residue was stirred with water for a while. The precipitate was filtered off, washed with water and dried under vacuum. (Yield: 7.27 g, 91%).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:5])[CH3:4].[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+]([O-])=O)[C:19]=1[C:20]#[N:21])([O-:17])=[O:16]>>[C:20]([C:19]1[C:18]([N+:15]([O-:17])=[O:16])=[CH:25][CH:24]=[CH:23][C:22]=1[O:1][CH2:2][C:3]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:5])[CH3:4])#[N:21]
Reactant: CC(C)(CO)NC(=O)c1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(COc1cccc([N+](=O)[O-])c1C#N)NC(=O)c1ccccc1
Yield: 91 %

Procedure:
Prepared as in Example 215c from N-(1-hydroxy-2-methylpropan-2-yl)benzamide (Boyd, R. N.; Hansen, R. H. J. Am. Chem. Soc. 1953, 75, 5896) and 2,6-dinitrobenzonitrile in 91% yield as a pale yellow solid. MS 340 (MH+).
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][C:18]2[CH:23]=[C:22]([CH:24]3[CH2:26][CH2:25]3)[CH:21]=[C:20]([C:27]#[N:28])[CH:19]=2)[C:11]=1[F:29])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[NH2:5][CH2:9][C:10]1[C:11]([F:29])=[C:12]([O:17][C:18]2[CH:19]=[C:20]([CH:21]=[C:22]([CH:24]3[CH2:25][CH2:26]3)[CH:23]=2)[C:27]#[N:28])[C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CC(C)(C)N(Cc1ccc(Cl)c(Oc2cc(C#N)cc(C3CC3)c2)c1F)C(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 1,1-dimethylethyl({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)carbamate (880 mg, 2.111 mmol) dissolved in DCM (15 ml) was added TFA (5.0 ml) and the reaction mixture was stirred for 30 minutes at RT. The reaction mixture was neutralized with saturated sodium bicarbonate, diluted with EtOAc, and the organics layer was separated. The solvent was evaporated and the crude material was purifed via silica gel chromatography to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-cyclopropylbenzonitrile (594 mg, 1.875 mmol, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.52 (m, 2H), 7.22 (s, 1H), 7.04 (d, 2H), 3.73 (s, 2H), 1.91-2.01 (m, 1H), 1.89 (br. s., 2H), 0.89-1.04 (m, 2H), 0.64-0.81 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]1[NH:44][CH2:43][CH2:42][N:41]2[CH2:45][CH2:46][CH2:47][CH:40]12>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:43][CH2:42][N:41]4[CH2:45][CH2:46][CH2:47][CH:40]4[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CC2CNCCN2C1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN2CCCC2C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with octahydro-pyrrolo[1,2-a]pyrazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H47N4O3Cl2 [(M+H)+] 661.3071, observed 661.3073.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.CI>C1COCC1.CCCCCC.O>[Cl:13][C:14]1[C:15]([CH3:1])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: Clc1cncc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CI
Product: Cc1ncc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
N,N-Diisopropylamine (65.6 ml) was dissolved in anhydrous THF (150 ml), n-butyl lithium (a 1.54 mol/l solution in hexane, 300 ml) was dropwise added thereto at −78° C. in an argon atmosphere, and the mixture was stirred for 5 minutes. After a solution of 3,5-dichloropyridine (63 g) in anhydrous THF (600 ml) was dropwise added thereto and the mixture was stirred for 1 hour, methyl iodide (29.2 ml) was dropwise added thereto, and the mixture was stirred for 1.5 hours. Water was added thereto, the reaction mixture was extracted with ethyl acetate, the extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), the resulting residue was suspended in hexane, and the precipitated crystals were collected by filtration to give 3,5-dichloropicoline (62.8 g, 91%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:16][CH3:17])[CH:14]=3)[NH:9][C:8]=2[CH3:18])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:16][CH3:17])[CH:14]=3)[N:9]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:8]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: CSc1ccc2[nH]c(C)c(Oc3ccc(Cl)cc3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(SC)ccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of the product from step (i) (0.45 g), potassium carbonate (0.415 g) and methyl bromoacetate (0.21 ml) in DMF (3 ml) was stirred at 50° C. for 3 h. The reaction was partitioned between ethylacetate/water. The organics were washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-15% ethylacetate/iso-hexane. Yield 0.33 g
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[C:15]1([CH:21]([N:28]=[C:29]=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH:21]([NH:28][C:29]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:10][CH2:11]1)=[O:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(CN2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 1-(1-methyl-piperidin-4-ylmethyl)-piperazine (0.5 g, 2.7 mmol) in dry CH2Cl2 (12 ml) was added diphenylmethyl isocyanate (0.56 ml, 2.7 mmol) drop wise under nitrogen. The resulting mixture was stirred at room temperature over night. Removal of solvent under reduced pressure followed by column chromatography using CH2Cl2: CH3OH (10:1) gives the desired product in 82% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1Cl
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a mixture of 7-chloro-1H-indole-6-carboxylic acid (3.8 g, about 19.4 mmol) in MeOH (50 ml) at r.t. under N2 was added cyclohexanone (6.13 ml, 59.1 mmol), followed by a solution of NaOMe in MeOH (17.5 ml, 76.6 mmol, 25% wt). The reaction mixture was stirred at reflux for 16 hr. After cooling to r.t., the mixture was added another bath of cyclohexanone (6.13 ml, 59.1 mmol), followed by another solution of NaOMe in MeOH (17.5 ml, 76.5 mmol, 25% wt), and then re-stirred at reflux for another 7 hr. After cooling to r.t., the mixture was evaporated, added with water (100 ml), acidified with hydrochloric acid (5N) and left standing at r.t. overnight. The aqueous mixture was decanted, and the residue washed twice with hydrochloric acid (30 ml, 1N) and twice with water (30 ml). The residue was further washed three times with hexane, and then dried to give 5.5 g of 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid. Another 2.6 g of the product was obtained from another reaction using 2.27 g of 7-chloro-1H-indole-6-carboxylic acid. Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=275.94, 277.94, HPLC Rt=1.750 min. To a mixture of the 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid (8.1 g) obtained from above in a mixture of THF/MeOH (25 ml/25 ml) at r.t. under N2 was added Pd(OH)2/C (764 mg, 20%). The mixture was then flushed with a stream of hydrogen gas using a balloon, and then stirred under hydrogen (using a balloon) for 27 hr. After removing the hydrogen balloon, the mixture was then flushed with a stream of N2, and then filtered through a cake of celite. The filtrate was evaporated to give 7-chloro-3-cyclohexyl-1H-indole-6-carboxylic acid (7.7 g). Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=278.01, 280.00, HPLC Rt=1.773 min.
Reaction SMILES: [F:1][C:2]1([F:42])[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([O:26]C)=[O:25])=[CH:21][C:20]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:3]1.O.[OH-].[K+]>CO>[F:42][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([OH:26])=[O:25])=[CH:21][C:20]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:3]1
Reactant: COC(=O)c1c(CN2CCC(N3CCC(F)(F)C3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCC(F)(F)C4)CC3)c(C(=O)O)c2c1
Temperature: 65 °C
Yield: 75.8 %

Procedure:
To a solution of methyl 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.970 g, 1.586 mmol) in methanol (15.86 mL) was added water (5.29 mL) and potassium hydroxide (0.445 g, 7.93 mmol). The mixture was heated to 65° C. for 15 h. The mixture was cooled to room temperature and concentrated. The residue was acidified to pH 4-5 with 2N HCl. The resulting precipitate was collected by filtration, washed with water (2×1 mL), and dried in the vacuum oven (35° C.) overnight to provide 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.718 g, 72% yield) as a yellow solid. MS (m/z) 598.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(/C=C/c3ccc(F)cc3)c2c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(CCc3ccc(F)cc3)c2c1
Yield: 73 %

Procedure:
N-{3-[2-(4-Fluorophenyl)ethyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide can be obtained in the following way: a mixture of 300 mg of N-{3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide, of 30 mg of 10% palladium-on-charcoal and of 8 ml of dimethylformamide is autoclaved under a pressure of 10 bar of hydrogen and the mixture is stirred at a temperature in the region of 20° C. for 1 hour until complete absorption of hydrogen. The medium is then filtered through a bed of Celite® 535, this is washed with dimethylformamide and the filtrate is concentrated to dryness under reduced pressure. The solid residue is taken up with dichloromethane and the insoluble material is isolated by filtration, washed with dichloromethane and then dried under reduced pressure. 220 mg of N-{3-[2-(4-fluorophenyl)ethyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide is thus obtained in the form of an off-white solid melting at 234° C. (analysis C22H20FN3O4S2 % calculated C, 55.81; H, 4.26; F, 4.01; N, 8.87; O, 13.51; S, 13.54. % found C, 55.80; H, 4.45; F, 3.85; N, 8.97; S, 12.80).
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C.O.C(O)(=O)C>[CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([NH:26][C:21]3[C:20]([NH2:27])=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=C1CCN(C2CC3CCCc4cccc2c43)CC1
Reactant: Nc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1ccccc1NC1CCN(C2CC3CCCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 85.2 %

Procedure:
To a cooled (0° C.) solution of 1-(1,2,2a,3,4,5-hexahydroacenaphthylen-1-yl)piperidin-4-one (1.00 g, 3.92 mmol) and 1,2-phenylenediamine (642 mg) in dichloroethane (30 ml) were added sodium triacetoxyborohydride (1.99 g) and acetic acid (0.509 ml), and the mixture was stirred at room temperature for 19 hr. The reaction mixture was poured into water, and the mixture was neutralized with potassium carbonate, and extracted with chloroform. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give N-[1-(1,2,2a,3,4,5-hexahydroacenaphthylen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.16 g) as an oil.