Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:25]=[O:26])C>C1COCC1>[Si:5]([O:8][C:9]1[C:10]([F:16])=[C:11]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH:25]=[O:26])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)ccc1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
A 500 mL round bottom flask was charged with 90.A (8.60 g, 35.2 mmol) and THF (70 mL) and cooled to −78° C. under N2. To the cold solution was added sec-butyllithium (1.4 M in cyclohexane) (available from Aldrich) (27.7 mL, 38.7 mmol) dropwise. The mixture was stirred for 30 minutes, and to it was added DMF (4.09 mL, 52.8 mmol) dropwise. The mixture was stirred for 30 minutes at −78° C., warmed to room temperature over 30 minutes, quenched with 1 N HCl, and diluted with EtOAc. The organic layers were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 90.B (5.71 g, 59.6% yield) as a colorless oil.
Reaction SMILES: [NH2-].[Na+].[CH3:3][N:4]([CH3:20])[C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[NH:10][C:9]=2[CH:19]=1.[OH2:21].[CH:22]1[CH:27]=CC=C[CH:23]=1>C(Cl)(Cl)Cl>[CH3:3][N:4]([CH3:20])[C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]([CH2:23][CH2:22][CH2:27][OH:21])[C:9]=2[CH:19]=1
Reactant: c1ccccc1
Reactant: CN(C)c1ccc2c(c1)Nc1ccccc1CC2
Reactant: O
Agent: [NH2-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc2c(c1)N(CCCO)c1ccccc1CC2
Temperature: 70 °C

Procedure:
A suspension of sodium amide (2.6 g, 0.033 mol, 50%wt suspension in toluene) was added to a solution of 3-dimethylamino-10,11-dihydro-5H-dibenz[b,f]azepine (6.1 g, 0,0256 mol, prepared similarly as described in Brit. Pat., 1040739,1966) in dry benzene (60 ml). The reaction mixture was heated to 70° C. for 1 h. 3-Bromo-1-propyl-tetrahydro-2-pyranyl ether (7.35 g, 0.033 mol) was added and the mixture was heated at reflux temperature for 20 h. To the cooled reaction mixture, water (20 ml) was added, and the phases were separated. The solvent was evaporated from the organic phase and the residue was dissolved in a mixture of methanol (100 ml) and 5 N HCl (30 ml). The mixture was heated at reflux temperature for 15 minutes, and methanol was evaporated. Water (50 ml) was added, pH was adjusted to 8-9 with aqueous ammonia and the mixture was extracted with benzene (2×150 ml). The combined organic extracts were dried (K2CO3), filtered and the solvent was evaporated under vacuum. The residue, was purified by chromatography on silica gel (50 g) using first benzene as eluent to isolate the starting material. Then, using chloroform as eluent, 3.5 g of 3-(3-dimethylamino-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol as an oil was isolated.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[F:15][C:16]1[CH:17]=[C:18]([CH2:24][NH2:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22]>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:25]([CH2:24][C:18]2[CH:19]=[C:20]([F:23])[C:21]([F:22])=[C:16]([F:15])[CH:17]=2)[CH:10]=1
Reactant: NCc1cc(F)c(F)c(F)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)c(F)c(F)c1

Procedure:
According to the method of Example 160, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with 1-(3,4,5-trifluorophenyl)methanamine to give the title compound.
Reaction SMILES: CC1C=CC=C(C)C=1C(O)=O.[CH3:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[CH2:12][Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1cccc(C)c1C(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Yield: 73 %

Procedure:
To a solution of 2.3 g (15.3 mmol) of methyl o-methylbenzoate (methyl o-toluate) in 20 mL of refluxing CCl4 was added 3 g of N-bromosuccinimide and 0.10 g AIBN. After 2.5 hours the mixture was cooled, diluted with 500 mL of CH2Cl2 and washed with 200 mL of H2O and 200 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was flash chromatographed with 5:1 hexane/ethyl acetate to yield the titled compound (2.56 g, 73%).
Reaction SMILES: BrCCC1C([Cl:10])=CC=[CH:6][C:5]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1CCBr.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[ClH:10].[Cl:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:5][CH2:6][NH:25][CH:22]([CH3:24])[CH3:23]
Reactant: Clc1cccc(Oc2cccc(Cl)c2CCBr)c1CCBr
Reactant: CC(C)N
Product: CC(C)NCCOc1cccc(Cl)c1
Product: Cl

Procedure:
Following the procedure of Preparation 11, 2-bromoethyl-3-chlorophenyl ether and isopropyl amine in excess were reacted and the reaction mixture processed to yield an oil, the free base of the title compound. A portion of the oil converted to the hydrochloride salt (77.8%), m.p. 153.5°-155.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27]1.CCN=C=NCCCN(C)C>>[O:26]1[CH2:30][CH2:29][CH:28]([C:31]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:32])[CH2:27]1
Reactant: O=C(O)C1CCOC1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)C4CCOC4)c3)c2c1
Yield: 15.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with tetrahydro-3-furoic acid (0.10 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 40 mg (15% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.7 (t, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4 (s, 1H), 3.9 (m, 1H), 3.82–3.68 (m, 2H), 3.3–3.1 (m, 2H), 2.2–2.0 (m, 2H); ES-MS (m/z) 351 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)=[CH2:6])[CH3:2].[F:17][C:18]([F:22])=[C:19]([F:21])[F:20]>CC1C2C(C)(C)C(C2)CC=1.C1C=CC=CC=1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:6][C:18]([F:22])([F:17])[C:19]2([F:21])[F:20])=[CH:8][CH:9]=1)[CH3:15]
Reactant: C=C(C(=O)OCC)c1ccc(OCC)cc1
Reactant: FC(F)=C(F)F
Agent: CC1=CCC2CC1C2(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C1(c2ccc(OCC)cc2)CC(F)(F)C1(F)F
Reaction time: 17 h
Yield: 75 %

Procedure:
2-(4-ethoxyphenyl)propenoic acid ethyl ester (13.2 g) was mixed with benzene (7.5 ml), α-pinene (2 drops) N-ethyldiisopropyl amine (2 drops) and tetrafluoroethylene (15.5 ml) and heated to 150°-155° for 24 hours then 155°-60° C. for 17 hours. After evaporation of volatile materials the residue (16.6 g) was dissolved in dichloromethane and chromatographed on a column of silica gel to give the ester as a colourless oil 14.5 g (75%). Analysis: C 56.47%, H 5.24%, F 23.4%, C15H16F4O3 requires C 56.25%, H 5.04%, F. 23.7%.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:8](=[S:10])=[S:9].O=O>C(O)(C)C>[CH2:1]([N:4]([CH2:5][CH2:6][CH3:7])[C:8](=[S:10])[S:9][S:9][C:8](=[S:10])[N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH2:2][CH3:3]
Reactant: S=C=S
Reactant: CCCNCCC
Agent: O=O
Solvent: CC(C)O
Product: CCCN(CCC)C(=S)SSC(=S)N(CCC)CCC
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 99.2 %

Procedure:
20.2 g (0.2 mol) of di-n-propylamine, 24.4 mg (0.1×10-3 mol) of Mn(CH3COO)2.4H2O and 100 g of isopropanol were charged to the reaction equipment described in Example 1. 16.0 g (0.21 mol) of carbon disulfide were added thereto, and the resulting solution was heated to 50° C., treated with oxygen at a pressure of 1.7 bar, and stirred vigorously. An immediate absorption of oxygen was observed and the reaction ceased after 75 minutes. 35.1 g of a white, crystalline product were obtained by concentrating and cooling the reaction solution. Upon analysis, the product was found to correspond to tetra-n-propyl thiuram disulfide (yield=99.2% of theoretical, FP=60° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]#N)=[CH:7][CH2:6][CH2:5]2.[OH2:14].[CH3:15][OH:16]>S(=O)(=O)(O)O>[C:12]([C:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH:7]=1)([O:16][CH3:15])=[O:14]
Reactant: N#CC1=CCCc2cc(Cl)ccc21
Reactant: O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1=CCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
6-Chloro-1-cyano-3,4-dihydronaphthalene (5 g, 263 mmol), lit ref, was dissolved in 77% sulfuric acid in methanol and the resulting solution was heated at 95°-100° C. for 2.5 h. The reaction mixture was allowed to cool to ambient temperature and 45 mL was added, followed by 5 mL of water. The reaction mixture was stirred at ambient temperature for 2 days and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 20% ethyl acetate in hexane to give 1.53 g (26% yield) of the title compound; MS DCI-NH3M/Z: 240 (M+H)+ ; 1H NMR (CDCl3) δ2.37-2.45 (2H, m), 2.75 (2H, t, J=7.5 Hz), 3.85 (3H, s), 7.15 (1H, d, J=1.5 Hz), 7.15 (1H, d, 9 Hz), 7.2 (1H, d, J=7.5 Hz), 7.77 (1H, d, J=7.5).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[F:14][C:15]([F:29])([C:20]1[CH:24]=[CH:23][NH:22][C:21]=1[C:25]([O:27][CH3:28])=[O:26])[C:16]([F:19])([F:18])[F:17].[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.N1C=CC=CC=1>ClCCl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:1])([F:12])[F:13])=[C:4]2[C:8]([O:10][CH3:11])=[O:9])=[CH:33][CH:32]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:22]2[CH:23]=[CH:24][C:20]([C:15]([F:14])([F:29])[C:16]([F:19])([F:18])[F:17])=[C:21]2[C:25]([O:27][CH3:28])=[O:26])=[CH:33][CH:32]=1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: COC(=O)c1[nH]ccc1C(F)(F)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(C(F)(F)C(F)(F)F)ccn1-c1ccc(Cl)cc1
Product: COC(=O)c1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate and methyl 3-(perfluoroethyl)-1H-pyrrole-2-carboxylate (300 mg, 1.55 mmol, 1.00 equiv), (4-chlorophenyl)boronic acid (727 mg, 4.65 mmol, 3.00 equiv), Cu(AcO)2 (562 mg, 2.00 equiv), pyridine (491 mg, 6.21 mmol, 4.00 equiv) and dichloromethane (20 mL). The resulting solution was stirred for 2d at 20° C. The solids were filtered out. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15) to yield methyl 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate and methyl 1-(4-chlorophenyl)-3-(perfluoroethyl)-1H-pyrrole-2-carboxylate as yellow oil.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][Cl:6].[I].[Na].[CH3:20][N:21]([CH3:24])[CH:22]=O.Cl>CC(C)=O.CO>[ClH:6].[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:13]1[CH2:14][CH2:22][N:21]([C:24]2[CH:16]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:20][CH2:12]1
Reactant: CN(C)C=O
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Agent: Cl
Agent: [I]
Agent: [Na]
Solvent: CC(C)=O
Solvent: CO
Product: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccccc4)CC3)ccc2N1
Reaction time: 5 h

Procedure:
5.0 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydrocarbostyril and 3.5 g of sodium iodine were mixed in 100 ml of acetone and the mixture was stirred at 40°-50° C. for 5 hours. Then 80 ml of dimethylformamide was added to the mixture and acetone was removed from the mixture by distillation under reduced pressure. To this reaction mixture, 5.0 g of 4-phenylpiperazine and 5 g of triethylamine were added and stirred at 70°-80° C. for 6 hours. The reaction mixture was concentrated under a reduced pressure and 50 ml of 5%-sodium hydrogencarbonate solution was stirred to effect crystallization. Crude crystals thus formed were collected by filtration and washed with water and dried. Then the dried crude crystals were dispersed in 80 ml of chloroform and stirred at a room temperature for 1 hour. Insoluble matters in the chloroform solution were removed from the solution and chloroform was removed by distillation to obtain the residue. To the residue thus obtained was added 50 ml of methanol and 10 ml of concentrated hydrochloric acid and mixture was concentrated under a reduced pressure to dryness. To the residue thus obtained was added 50 ml of acetone and stirred to obtain crude crystals. The crude crystals were collected by filtration and washed with acetone and recrystallized from ethanol-water to obtain 5.7 g of 6-[1-oxo-4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydrocarbostyril monohydrochloride in yellowish powdery crystals.
Reaction SMILES: C(=O)(O)O.C(OC(C1CC[N:13](C(N)=O)[CH2:12]C1)=O)C.N([C:23]1[CH:49]=[CH:48][C:26]([C:27]([NH:29][CH:30]([C:45]([OH:47])=[O:46])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=2)=[O:28])=[CH:25][CH:24]=1)C(N)=N.[ClH:50].O1CCO[CH2:53][CH2:52]1>CCCCCC>[ClH:50].[CH2:52]([O:47][C:45](=[O:46])[CH:30]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:33]=1)[NH:29][C:27]([C@H:26]1[CH2:48][CH2:49][C@H:23]([CH2:12][NH2:13])[CH2:24][CH2:25]1)=[O:28])[CH3:53]
Reactant: N=C(N)Nc1ccc(C(=O)NC(Cc2cccc(Oc3ccccc3)c2)C(=O)O)cc1
Reactant: C1COCCO1
Reactant: CCOC(=O)C1CCN(C(N)=O)CC1
Agent: Cl
Agent: O=C(O)O
Solvent: CCCCCC
Product: CCOC(=O)C(Cc1cccc(Oc2ccccc2)c1)NC(=O)[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the compound (III) (0.60 g), a 4N-hydrogen chloride/1,4-dioxane solution (5 ml) was added, followed by stirring at room temperature for one hour. Hexane (50 ml) was then added and the upper layer was removed by decantation. This procedure was repeated twice and the residue was solidified with ethyl acetate. Thus, N-(trans-4-aminomethylcyclohexylcarbonyl)-3-phenoxy-DL-phenylalanine ethyl ester hydrochloride (0.44 g) was obtained in the form of a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:28])[C:5]([C:8](=[N:23][O:24][CH:25]([CH3:27])[CH3:26])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32].O>C(N(CC)CC)C.[Cu]I>[Cl:28][C:4]1[C:5]([C:8](=[N:23][O:24][CH:25]([CH3:27])[CH3:26])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=[C:2]([C:32]#[C:31][C:30]([CH3:34])([CH3:33])[CH3:29])[CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C#CC(C)(C)C)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a solution of 0.15 g of N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(isopropoxyimino)ethyl]-2-(trifluoromethyl)benzamide and 0.05 g of 3,3-dimethyl-1-butyne in 3 ml of triethylamine, 0.04 g of copper(I) iodide and 0.02 g of dichlorobistriphenylphosphine palladium(II) were added, and the mixture was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 10 ml of water and extracted with ethyl acetate (20 ml×1). The resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:5 to 2:4) as the eluent to obtain 0.15 g of the desired product as a yellow resinous substance.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a solution of (R)-(tetrahydrofuran-2-yl)methanol (1.0 g, 9.8 mmol) in CH2Cl2 (3 mL) and pyridine (3 mL) at ambient temperature was added 4-methylbenzene-1-sulfonyl chloride (2.0 g, 10.3 mmol) portionwise over 5 min. The mixture was stirred for 16 hours at ambient temperature then quenched by the addition of 5% aqueous HCl (10 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purifined by column chromatography (SiO2, 75% hexanes in EtOAc) to afford the title compound (1.7 g, 6.8 mmol, 69% yield). MS (DCI/NH3) m/z 257 (M+H)+ and 274 (M+NH4)+.
Reaction SMILES: [H-].[Na+].CI.[Br:5][C:6]1[CH:11]=[N:10][C:9]2[N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:8]=2C=1N.[CH3:26][N:27]([CH3:30])[CH:28]=O>>[Br:5][C:6]1[CH:11]=[N:10][C:9]2[N:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:8]=2[C:28]=1[N:27]([CH3:30])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(Br)cnc32)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C)c(Br)cnc32)cc1
Reaction time: 2 h

Procedure:
55% Sodium hydride (19 mg) and methyl iodide (0.027 ml) were added to a solution of the compound obtained in Step 2 of Example 130 (64 mg) in N,N-dimethylformamide (3.6 ml) in an ice bath, and the mixture was stirred in an ice bath for 2 hours. The reaction solution was separated by adding an aqueous ammonium chloride solution and ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (73 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:43]4[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:51])=[O:52])[CH:46]=[CH:47][CH:48]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 85.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (250 mg, 0.46 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (intermediate 3) (150 mg, 0.506 mol) in sodium carbonate (146 mg, 1.38 mol), bis(triphenyl phosphine)palladium(ii) dichloride (16 mg, 0.023 mmol) and toluene/ethanol/water (7/7/4 ml) to afford 250.0 mg (85.91% yield) of the pure product after column purification using 40% ethyl acetate in hexane as eluent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:31]=[CH:30][S:29][C:28]=1[CH:32]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].CC(O)=O.[BH3-]C#N.[Na+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:31]=[CH:30][S:29][C:28]=1[CH2:32][NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccsc3C=O)n(CC(=O)OC(C)(C)C)c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccsc3CNCCN(C)C)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-(2-formyl-3-thienyl)-1H-indole-6-carboxylate in THF (0.05 M) was treated with N,N-dimethylethane-1,2-diamine (10 eq) and the pH was adjusted to 6 with AcOH; after stirring for 1 h at RT solvent was removed and the residue dissolved in MeOH (0.05M), then NaCNBH3 (1.5 eq) was added and the mixture was stirred during the weekend. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated affording methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-1H-indole-6-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]Br.CN(C)C=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:9][CH:10]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ncc[nH]1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2ccnc2C)cc1
Yield: 41 %

Procedure:
A mixture of 16.4 parts of 2-methyl-1H-imidazole, 37.4 parts of 1-bromo-4-methoxybenzene, 1 part of copper-(I)bromide, 20 parts of potassium carbonate and 270 parts of N,N-dimethylformamide is stirred and refluxed for one week. The reaction mixture is cooled, poured onto water and the whole is extracted with 2,2'-oxybispropane. The extract is washed twice with a diluted hydrochloric acid solution. The acid aqueous phase is separated and alkalized with sodium hydroxide. The product is extracted twice with 2,2'-oxybispropane. The combined extracts are dried, filtered and evaporated, yielding 4 parts (41%) of 1-(4-methoxyphenyl)-2-methyl-1H-imidazole as a residue.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[CH:9]([NH:12][CH2:13]CO)([CH3:11])[CH3:10].C=O.[O:18]1CCO[CH2:20][CH2:19]1>>[OH:18][CH2:19][CH2:20][C:9]([NH:12][CH2:13][CH2:2][C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:3])([CH3:10])[CH3:11]
Reactant: CC(=O)c1ccsc1
Reactant: C1COCCO1
Reactant: CC(C)NCCO
Agent: C=O
Product: CC(C)(CCO)NCCC(=O)c1ccsc1

Procedure:
3-acetylthiophene (121 mg), isopropyl-2-hydroxyethyl amine (126 mg), and paraformaldehyde (36 mg) were reacted in dioxane (0.2 ml) at 130° C. for 2 hours.