Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1)[S:9]([NH:12][C:13](=[O:28])[C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([C:42]1[CH:47]=[CH:46]C=C(C(C)(C)C)N=1)(C)(C)[CH3:39].ICCCCC>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH2:1]([N:8]([CH2:29][CH:30]1[CH2:31][CH2:32][CH:33]([CH2:36][O:37][CH2:39][CH2:38][CH2:42][CH2:47][CH3:46])[CH2:34][CH2:35]1)[S:9]([NH:12][C:13](=[O:28])[C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([C:24]([F:25])([F:26])[F:27])[CH:15]=1)(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NS(=O)(=O)N(Cc1ccccc1)CC1CCC(CO)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCI
Product: CCCCCOCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Yield: 73.9 %

Procedure:
Intermediate (4) (27.6 mg, 50 μmole, 1.0 eq) was dissolved in dichloromethane (250 μL), after which 2,6-di-t-butyl pyridine (36 μL, 160 μmole, 3.2 eq), silver triflate (38.5 mg, 150 μmole, 3.0 eq) and iodopentane (23 μL, 175 μmole, 3.5 eq) were added. After 45 minutes the reaction mixture was directly purified to give 23 mg of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.15 (s, 1H), 7.36 (d, 2H), 7.24 (t, 2H), 7.17 (t, 1H), 4.39 (s, 2H), 3.30 (water), 3.23 (t, 2H), 3.01 (d, 2H), 2.92 (d, 2H), 2.48 (DMSO), 1.61 (m, 2H), 1.54 (m, 2H), 1.41 (m, 2H), 1.34-1.19 (m, 6H), 0.82 (t, 3H), 0.62 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=2)[CH:3]=[CH:2]1.C1CCN2C(=NCCC2)CC1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O>C(Cl)Cl>[Si:23]([O:11][CH2:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: OCc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc2cc[nH]c2c1
Yield: 90.1 %

Procedure:
1 g (1H-indole-6-yl)-methanol (1.0 g, 6.79 mmol) in DCM (25 mL) was added DBU (1.24 g, 8.15 mmol) and tert-butyldimethylsilylchloride (1.14 g, 7.54 mmol). The reaction mixture was stirred 16 hours before water (25 mL) was added. The phases were separated and the organic phase was washed with HCl (0.1 N, 25 mL) and sodium bicarbonate (sat., 25 mL) and dried MgSO4. The solvent was removed in vacuo to give 1.6 g (90%) 6-(tert-butyldimethylsilanyloxymethyl)-indole. This was converted to 1-cyclopropylmethyl-6-hydroxymethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide using general procedure A where R5X=cyclopropyl-methylbromide; NH2A=2-aminothiazole.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:18])[CH:6]=[C:7]([CH:15]([CH3:17])[CH3:16])[C:8](=[O:14])[C:9]=1[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH3:3].C[SiH](C)O[SiH](C)C.II>C(Cl)Cl>[CH2:1]([C:4]1[C:9]([C:10]([CH3:12])([CH3:11])[CH3:13])=[C:8]([OH:14])[C:7]([CH:15]([CH3:17])[CH3:16])=[CH:6][C:5]=1[OH:18])[CH2:2][CH3:3]
Reactant: CCCC1=C(C(C)(C)C)C(=O)C(C(C)C)=CC1=O
Agent: C[SiH](C)O[SiH](C)C
Agent: II
Solvent: ClCCl
Product: CCCc1c(O)cc(C(C)C)c(O)c1C(C)(C)C

Procedure:
Dissolve 2-propyl-3-t-butyl-5-isopropylbenzoquinone (10 mmol), 1,1,3,3-tetramethyldisiloxane (1.79 mL, 10 mmol) and iodine (0.05 g) in methylene chloride (30 mL). Stir at reflux for 30 minutes and extract with 1N sodium hydroxide (30 mL). Acidify the aqueous phase with concentrated hydrochloric acid and extract into ethyl acetate (4×10 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 2-propyl-3-t-butyl-4-hydroxy-5-isopropylphenol.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1>O1CCCC1>[Br:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=2)=[CH2:23])[CH:8]=1
Reactant: Brc1cccc(Br)c1
Reactant: CSc1ccc(C(C)=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(SC)cc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 4.50 mL, 7.20 mmol, 1.2 eq) was added over 20 min to a solution of 1,3-dibromobenzene (0.80 mL, 6.61 mmol, 1.1 eq) in 15 mL of dry tetrahydrofuran at −78° C. and under an inert atmosphere. The white suspension formed and was stirred at −78° C. for 30 min. A solution of 1-(4-methylsulfanyl-phenyl)-ethanone (1 g, 6.01 mmol, 1.0 eq.) in 10 mL of tetrahydrofuran was then added dropwise and the reaction stirred for 1 h. The reaction mixture was examined by LC-MS which showed the complete formation of tertiary alcohol. The solution was quenched with a saturated aqueous solution of ammonium chloride and then water was added. 2N hydrochloric acid was added to adjust the pH=5. The two phases were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude was dissolved in a mixture of acetic acid/sulfuric acid (10 mL of acetic acid, 0.3 mL of sulfuric acid) and the reaction mixture was stirred for 1 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and then brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography eluting with cyclohexane. The desired product was obtained as an orange liquid (1.61 g, Yield: 88% over two steps).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([CH3:20])[CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][CH:8]([CH3:20])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:18][CH:19]=1
Reactant: CC(C)CCOc1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Lithium aluminum hydride (350 mg) was added gradually to a solution of 1.35 g of p-(3-methylbutoxy)-benzaldehyde in 50 ml of tetrahydrofuran at -10° C. After stirring at room temperature for 1 hour, the excess lithium aluminum hydride was decomposed with sodium sulfate decahydrate. The insoluble matter was filtered off from the mixture, and the filtrate was concentrated to give 1.33 g of p-(3-methylbutoxy)benzyl alcohol. Thionyl chloride (3 g) was added to a solution of the compound obtained in 25 ml of benzene, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 1.45 g of p-(3-methylbutoxy)benzyl chloride. To a solution of this compound in 50 ml of N,N-dimethylformamide, there was added a solution of 3.3 g of sodium azide in 14 ml of water with ice cooling. After overnight stirring at room temperature, the reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.48 g of p-(3-methylbutoxy)benzyl azide. To a solution of this compound in 30 ml of tetrahydrofuran was added 500 mg of lithium aluminum hydride with ice cooling. The temperature of the reaction mixture was allowed to gradually rise to room temperature, and the mixture was stirred for 2 hours. The excess lithium aluminum hydride was decomposed with sodium sulfate decahydrate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give 1.13 g of p-(3-methylbutoxy)benzylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]2[CH2:14][C:15]3[C:20]([CH2:21][C@@H:9]12)=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]2[C@H:9]1[CH2:21][C:20]1[C:15]([CH2:14]2)=[C:16]2[O:23][CH2:24][O:22][C:17]2=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2Cc3c(ccc(O)c3O)C[C@H]21
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H]2Cc3c(ccc4c3OCO4)C[C@H]21
Temperature: 110 °C

Procedure:
Intermediate VI (60 mg), Cs2CO3 (33 mg) and CH2BrCl (48 mg) and DMF (1 mL) were heated to 110° C. for 0.5 h in a sealed microwave reactor vial. More CH2BrCl (33 mg in 0.2 mL DMF) was added and the mixture was heated 110° C. for 0.5 h. The reaction mixture was purified by silica gel chromatography (EtOAc/heptane). Yield: 18 mg of intermediate VII.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=[CH:5][CH:4]=1.[NH:44]1[CH2:48][CH2:47][C@@H:46]([CH2:49][OH:50])[CH2:45]1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH2:21][N:44]4[CH2:48][CH2:47][C@@H:46]([CH2:49][OH:50])[CH2:45]4)[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: OC[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CC[C@@H](CO)C4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.310 g, 0.537 mmol) and (R)-pyrrolidin-3-yl-methanol (0.163 mL, 1.610 mmol) in dichloromethane (0.035 mL, 0.537 mmol) and methanol (0.022 mL, 0.537 mmol) was treated with sodium triacetoxyborohydride (0.341 g, 1.610 mmol). The solution was stirred at room temperature overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 5% to 10% 2 M NH3.MeOH in CH2Cl2 to give (R)-(1-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)pyrrolidin-3-yl)methanol (0.188 g, 0.284 mmol, 52.9% yield). m/z (ESI, +ve ion) 663.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CC(N(C)C)=O>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH2:18][CH2:17]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: COCCN1CCNCC1
Solvent: CC(=O)N(C)C
Product: COCCN1CCN(c2ccc([N+](=O)[O-])cc2C)CC1

Procedure:
A solution of 0.95 g (6.06 mmol) 2-fluoro-5-nitrotoluene and 0.99 g (6.67 mmol) 1-(2-methoxyethyl)piperazine in 10 ml dimethylacetamide is stirred at 120° C. for 20 h. After that the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[N+:24]([O-])=O)(=[O:16])=[O:15])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.O.NN>[Ni]>[NH2:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[S:14]([NH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2)(=[O:15])=[O:16]
Reactant: COc1cc(NS(=O)(=O)c2ccc(C)cc2[N+](=O)[O-])c2ncccc2c1
Agent: [Ni]
Agent: NN
Solvent: O
Product: COc1cc(NS(=O)(=O)c2ccc(C)cc2N)c2ncccc2c1
Yield: 43.7 %

Procedure:
In a similar fashion using route 6 general procedure 14, N-(6-methoxyquinolin-8-yl)-4-methyl-2-nitro-benzenesulfonamide (Intermediate 153) (150 mg, 0.40 mmol), Raney nickel (30 mg, 20% wt) and hydrazine hydrate (64 mg, 1.21 mmol) gave title compound (60 mg, 44%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9](Cl)=[O:10].[CH3:19][C:20]1([CH3:28])[CH2:25][C@H:24]([CH3:26])[CH2:23][C@H:22]([OH:27])[CH2:21]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]([O:27][C@H:22]1[CH2:23][C@@H:24]([CH3:26])[CH2:25][C:20]([CH3:28])([CH3:19])[CH2:21]1)=[O:10]
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Reactant: C[C@@H]1C[C@H](O)CC(C)(C)C1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)O[C@H]2C[C@@H](C)CC(C)(C)C2)c1

Procedure:
25 g of 2-(3-(2,5-dimethylphenoxy)propyl)-2-methylpropionyl chloride are added to 14 g of (cis) 3,3,5-trimethylcyclohexanol dissolved in 100 ml of toluene. The mixture is refluxed for three hours and then evaporated to dryness. The evaporation residue is chromatographed on a silica column with chloroform. The title product is obtained in the amorphous state and in thin layer chromatography gives a single spot under the above conditions; the characteristic bands of its IR spectrum run in KBr are as follows: 3000-2850 cm-1, group of fine bands; 1730 cm-1, strong band for the carbonyl.
Reaction SMILES: [CH3:1][N:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[N:19]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][NH:13][C:14](OC)=[O:15])=[O:11])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].CO>C1COCC1>[CH3:1][N:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[N:19]=1)[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10](=[O:11])[NH:12][NH:13][C:14]2=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)NNC(=O)Nc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N(C)c2ccc(-n3c(=O)[nH][nH]c3=O)cc2)c2ccccc2n1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2-[({4-[methyl(2-methylquinazolin-4-yl)amino]phenyl}amino)carbonyl]hydrazine carboxylate 0.150 g (0.4 mmol) in THF 5 mL was added K2CO3 0.138 g (1.0 mol), and the reaction mixture was stirred for 48 h under reflux. Due to the incompletion of the reaction, the reaction was further heated under microwave irradiation at 120° C. for 20 min. The reaction mixture was filtrated with a short silica-get column using methanol, and methanol was evaporated under reduced pressure to obtain a crude product, which was purified with preparative HPLC to give the titled compound in pure form. 1H NMR (CD3OD, 400 MHz): δ 8.21, 8.19 (dd, 1H, J=8.0, 1.2 Hz), 7.87-7.83 (m, 2H), 7.79-7.75 (m, 1H), 7.71, 7.69 (dd, 1H, J=8.4, 0.8 Hz), 7.65-7.59 (m, 2H), 7.59-7.53 (m, 1H), 7.30-7.26 (m, 1H), 6.98 (d, 1H, J=8.4 Hz), 3.87 (s, 3H), 2.80 (s, 3H). m/e: 349.30 (M+1), 347.25 (M−1).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])([O-])=O.[Na+].[Na+].[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.[OH-].[Na+]>C1COCC1.O.O1CCOCC1>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([NH:4][O:3][CH3:2])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: CONS(=O)(=O)c1cccc(Br)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a solution of commercially available methoxyamine hydrochloride (1.96 g, 23.4 mmol) and 2 M Na2CO3-solution (20 mL, 40 mmol) in THF (100 mL) at 0° C. was added dropwise added commercially available 3-bromobenzenesulfonyl chloride (2.5 g, 9.8 mmol) and the mixture was stirred at 23° C. for 18 h. The reaction is diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated to give a light brown solid, which was refluxed with 1 M NaOH (10 mL) in dioxane (10 mL) for 30 min to cleave disulfonylated product. Cooled to rt, diluted with water, extracted with EtOAc, washed organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left a light brown solid, which was purified by trituration with heptane/diethyl ether gave the title compound as a light yellow solid (1.30 g, 50%). MS (ISN) 264.0 [(M−H)−] and 266.0 [(M+2−H)−].
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.C([Li])CCC>O1CCCC1>[CH2:1]([NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:14][OH:15])[CH:17]=[C:16]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[C:18]([F:19])([F:21])[F:20])=[CH:9][C:8]=1[CH3:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCNC(=O)c1ccc(C(C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)=NO)cc1C
Temperature: 0 °C
Yield: 60.4 %

Procedure:
To a solution of N-butyl-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (made as described in EP 1,731,512) (1670 mg, 4.13 mmol) and N,N-diisopropylamine (880 mg, 8.69 mmol) in dry tetrahydrofuran (10 ml) was added n-butyl lithium (“n-BuLi”) (1.55M in hexane) (5.6 ml, 8.69 mmol) at −90° C. The reaction mixture was allowed to warm to 0° C. over a period of 2 hours and quenched by addition of aqueous ammonium chloride (saturated). The mixture was extracted several times with diethyl ether. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate 2:1) to give N-butyl-4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-1-hydroxyimino-but-2-enyl]-2-methyl-benzamide (1180 mg, 70% yield) as a yellow resin. 1H-NMR (CDCl3, 300 MHz): 8.52 (bs, 1H), 7.45-7.36 (m, 6H), 6.75 (s, 1H), 5.81 (m, 1H), 3.46-3.43 (m, 2H), 2.47 (s, 3H), 1.54-1.39 (m, 4H), 0.97 (t, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]5[C:26]([CH3:49])=[N:27][N:28](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:29]=5)[CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[ClH:50]>>[ClH:50].[ClH:50].[ClH:50].[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]5[C:26]([CH3:49])=[N:27][NH:28][CH:29]=5)[CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(N2CCN(c3ccnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5C)cc34)CC2)n1
Agent: Cl
Product: COc1cccc(N2CCN(c3ccnc4ccc(-c5c[nH]nc5C)cc34)CC2)n1

Procedure:
120 mg 4-[4-(6-methoxy-2-pyridyl)piperazin-1-yl]-6-(3-methyl-1-trityl-1H-4-pyrazolyl)quinoline obtained in Example 178 and 1.4 mL of 5 N— hydrochloric acid were reacted in the same manner as in Example 163, to give 87 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].[CH:28]1([CH2:31]Cl)[CH2:30][CH2:29]1>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:31][CH:28]2[CH2:30][CH2:29]2)[CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2[nH]cc(C3=CCN(CC4CC4)CC3)c2c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 12.5 g of 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 120 ml of anhydrous dimethylformamide, 11.5 g of sodium carbonate and 6.5 ml of cyclopropylmethyl chloride was stirred for 24 hours under an inert atmosphere at 70° C. and was then cooled to 30° C. after which 300 ml of distilled water were added thereto while cooling in an ice bath. Precipitation occured and the mixture was stirred for 45 minutes, stood for 15 minutes and was then filtered. The product was washed 3 times with distilled water and was empasted with 20 ml of 50% aqueous ethanol. The product was dried at 50° C. under reduced pressure in the presence of a dehydrating agent to obtain 13.54 g of raw product which was dissolved in 350 ml of refluxing ethanol. The solution was filtered and the filtrate was concentrated to 300 ml for crystallization. The solution was cooled to room temperature and was held in a refrigerator for 90 minutes. The mixture was vacuum filtered and the product was rinsed with ethanol and dried under reduced pressure to obtain 7.8 g of 5-chloro-3-(1-cyclopropylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 205° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:6]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:6]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:11])[N:8]([CH3:25])[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)N(C)C(C)=C(C(C)=O)C1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21.5 %

Procedure:
1.0 g (3.2 mmol) of the compound from Example I are dissolved in 15 ml of DMF and treated under argon with 180 mg of NaH. The mixture is stirred at 0° C. for 15 minutes. 0.51 ml (6.2 mmol) of MeI is then added dropwise and the mixture is stirred again for 30 min. It is treated successively with H2O and ethyl acetate and the organic phase is washed with saturated aqueous NaCl solution. It is then concentrated and the residue is separated on silica gel (petroleum ether/AcOEt=1+1). The appropriate fractions crystallize from Et2O/petroleum ether. 230 mg of the title compound are obtained. MS:333.8 Rf =0.57 (petroleum ether/AcOEt=1+1)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]([CH2:14][C:15]([O:17]CC)=[O:16])[C:9](=[O:13])[O:10]2)=[CH:5][C:4]=1[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>C(O)C>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:8]([CH2:14][C:15]([OH:17])=[O:16])[C:9](=[O:13])[O:10]2)=[CH:5][C:4]=1[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)c2cc(CN3CCN(c4ccccc4)CC3)c(Cl)cc2oc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1c(-c2ccccc2)c2cc(CN3CCN(c4ccccc4)CC3)c(Cl)cc2oc1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Ethyl [7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]acetate.hydrochloride (40 g) was suspended in ethanol (120 ml), and combined with a 2 N aqueous solution of sodium hydroxide (144.5 ml). A yellow clear solution obtained by stirring at 70° C. for 1 hour was added dropwise to a mixture solution of ethanol (40 ml) and 6 N hydrochloric acid (49.4 ml) over 45 minutes. The reaction solution was adjusted to pH 5.5 to 6.0 with sodium hydrogen carbonate at 40° C. After pH became stable, the mixture was stirred at 35 to 40° C. internal temperature for 15 minutes, and cooled to room temperature, and stirred at room temperature for 30 minutes. The crystal formed was filtered and washed with 30% ethanol to obtain the title compound (34 g, yield: 96%) as a white crystal.