Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([OH:25])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccncc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(Cc1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of 27.8 g (0.30 mole) of 4-picoline in 400 ml of tetrahydrofuran and under an atmosphere of nitrogen was cooled to -30° C. in a dry-ice acetone bath. A solution of 2.5 moles n-butyllithium in hexane (119 ml, 0.3 mole) was added over 1 hr and the mixture was stirred for an additional 30 min at -30° C. The reaction mixture was allowed to warm to room temperature over 1.5 hr, and 66.7 g (0.30 mole) of 4,4'-difluorobenzophenone in 100 ml of tetrahydrofuran was added. The mixture was stirred for 2 hr and then was poured into an icy solution of ammonium chloride. A white solid was collected. The aqueous mixture was extracted with several portions of methylene chloride and the methylene chloride then removed in vacuo to give additional solid. The solid fractions were combined and recrystallized from a mixture of ether-hexane to give 63.14 g (68% yield) of title compound as a white, crystalline solid, mp 158°-159.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:22])(=[O:21])[NH:19][CH3:20])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=2[CH:27]=1.B([O-])([O-])O[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:40]([O:39][CH2:38][CH2:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([C:12]4[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:22])[NH:19][CH3:20])=[CH:14][CH:13]=4)[CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=3[CH:27]=2)=[CH:35][CH:34]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CNS(=O)(=O)c1ccc(N2CCC(C(=O)OC)=Cc3cc(Br)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(=O)(=O)NC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A mixture of methyl 7-bromo-1-(N-methyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1 g), 4-(2-butoxyethoxy)phenyl borate (0.69 g), 1M potassium carbonate solution (8 ml), ethanol (8 ml) and toluene (100 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.13 g), and the mixture was refluxed under argon atmosphere for 2.5 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N-methyl4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[H-].[Na+].Cl[CH2:26][S:27][CH3:28]>CN(C)C=O>[CH3:26][S:27][CH2:28][N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22]
Reactant: CSCCl
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To a solution of 100 mg (0.35 mmol) of 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one in 0.5 ml of dimethylformamide were added 17 mg (0.42 mmol, 1.2 equiv.) of a 60% sodium hydride suspension in mineral oil. After stirring for 1 h at room temperature, 40 uL (50 mg, 0.52 mmol, 1.5 equiv.) of chloromethyl methylsulfide were added and the suspension was stirred for another 16 h at room temperature. After workup with methylene chloride/water, the crude material was purified by flash chromatography (SiO2, gradient ethyl acetate to ethyl acetate:methanol 90:10 v/v) to yield 32 mg of the title compound as a light yellow solid, MS: 350.2 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][NH2:24]>>[CH3:22][O:23][NH:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: CON
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Product: CONCc1ccc(-c2nc3cccc(C(=O)OC)c3o2)cc1
Yield: 65 %

Procedure:
Following the experimental procedure as described in Example 144 C, and replacing methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate with methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate and substituting dimethylamine with methoxyamine, methyl 2-(4-((methoxyamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (Yield: 65%. LC-MS (ESI) m/z: 313 (M+1)+) was made.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[Na].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[N:9]=1>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: OC1CCC1
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cccc(OC2CCC2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To cyclobutanol (1 mL), was added sodium (36 mg, 1.56 mmol). When the sodium was consumed, the mixture was diluted with 1 mL THF and 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 3 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 106 mg of 158.1 as a colorless oil. LCMS (2 min gradient) RT=1.87 min, 228.17 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[C:7]2[CH:8]=[N:9][CH:10]=[N:11][C:12]=2[CH2:13][CH2:14][CH:15]=1.C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:2]2[C:6]3([CH2:5][O:4][C:3]=2[CH:16]=1)[CH2:15][CH2:14][CH2:13][C:12]1[N:11]=[CH:10][N:9]=[CH:8][C:7]3=1
Reactant: COc1ccc(Br)c(OCC2=CCCc3ncncc32)c1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: COc1ccc2c(c1)OCC21CCCc2ncncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1 mmol of 5-(2-bromo-5-methoxyphenoxymethyl)-7,8-dihydroquinazoline, 0.5 mmol of azoisobutyronitrile (AIBN) and 1.5 mmol of tributyltin hydride in 50 ml of benzene is heated at reflux for 1-2 hours. The reaction solution is concentrated and the residue is taken up in diethyl ether. The solution is admixed with 1M NaOH and stirred vigorously at room temperature for 1 hour. The phases are separated and the organic phase is washed with 1M sodium hydroxide solution and brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:26][CH3:27].[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>CN(C)C=O.C(OCC)(=O)C>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH:21]=[CH:20]5)=[N:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:26][CH3:27])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
A mixture of 7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (200 mg, 0.47 mmol), (WO 00/47212 A1, Example 314), and 1-acetylpiperazine (180 mg, 1.40 mmol) in N,N-dimethylformamide (4 ml) was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate and washed with brine (×2), dried (MgSO4) and concentrated under reduced pressure. Column chromatography of the residue (5% methanol/dichloromethane) gave 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (109 mg, 49%) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([C:26]([NH:39][C:40]2[CH:41]=[C:42](/[CH:46]=[CH:47]/[CH2:48]O)[CH:43]=[CH:44][CH:45]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:51]>O1CCCC1>[C:20]1([C:26]([NH:39][C:40]2[CH:41]=[C:42](/[CH:46]=[CH:47]/[CH2:48][Br:51])[CH:43]=[CH:44][CH:45]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: OC/C=C/c1cccc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrC/C=C/c1cccc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h

Procedure:
11.54 g of triphenylphosphine was added to a solution of 7.83 g of (E)-3-(3-triphenylmethylaminophenyl)allyl alcohol and 14.59 g of carbon tetrabromide dissolved in 60 ml of tetrahydrofuran, with ice-cooling. The mixture was stirred for 1 hour at the same temperature to obtain a tetrahydrofuran solution of (E)-(3-triphenylmethylaminophenyl)allyl bromide. To this solution were added 4.45 g of triethylamine and 6.47 g of 3-nitro-5-(piperazin-1-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, with ice-cooling. The mixture was stirred for 5 hours at room temperature. To the reaction mixture was added 200 ml of water and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/acetone=3/1) to obtain 7.8 g of light yellow oily 3-nitro-5-[4-{(E)-3-(3-triphenylmethylaminophenyl)allyl}piperazin-1-yl]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[N:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[CH:16][CH:17]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCc1ccncc1
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCc1ccncc1

Procedure:
The product was made from D-glucose and 4-aminomethyl-pyridine comparable as in Example A. A resin-like, yellow product was obtained.
Reaction SMILES: O.[OH-].[K+].[C:4]1([CH:10]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][C@H:17]3[C@H:20]4[C@H:30]([CH2:31][CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH:24]=[C:25]([C:33]([O:35]C)=[O:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([CH:10]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][C@H:17]3[C@H:20]4[C@H:30]([CH2:31][CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH:24]=[C:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1=CC2=CC[C@H]3[C@@H]4CC[C@H](C(=O)NC(c5ccccc5)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1

Procedure:
10 ml of water and 1 g of potassium hydroxide were added to a solution of 25 ml of methanol containing 214 mg of methyl 17β-(N-diphenylmethylcarbamoyl)-androsta-3,5-diene-3-carboxylate (prepared as described in Example 27). The reaction mixture was then heated under reflux for 4 hours. At the end of this time, methanol from the reaction mixture was removed by distillation under reduced pressure. The mixture was then made acidic by the addition of 1N aqueous hydrochloric acid and extracted with methylene chloride three times. The combined organic extracts were washed with water and with a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 20 g of silica gel and using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 2:98 to 50:50 by volume as the eluent, to give 110 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:49]>C(Cl)Cl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N+:37]([O-:49])([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)cc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Cn1nc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CC[N+](C)([O-])C3)c1=O
Reaction time: 18 h
Yield: 30.8 %

Procedure:
To a solution of 6-tert-butyl-8-fluoro-2-(3-(hydroxymethyl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)phthalazin-1(2H)-one (500 mg, 854 μmol, 1 equiv.) in DCM (10 ml) was added 3-chlorobenzoperoxoic acid (191 mg, 854 μmol, 1 equiv.). The reaction mixture was stirred for 18 h. The reaction mixture was diluted with methylene chloride and washed with 1.0 N NaOH (aq). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford a liquid that gradually hardened to a low melting, yellow solid under vacuum, overnight. The solid was dissolved in a minimum of methanol, diluted with methylene chloride and loaded onto a column. The crude material was purified by flash chromatography (silica gel, 40 g, 50% 60:10:1 DCM:MeOH:NH4 OH in DCM) to give 2-(6-(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H) -yl)-3-(hydroxymethyl)pyridin-4-yl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 5-oxide (158.5 mg, 263 μmol, 30.9% yield) as a yellow solid. (M+H)+=602 m/e. 1H NMR (300 MHz, METHANOL-d4) d ppm 1.47 (s, 9 H) 3.45 (s, 3 H) 3.74 (dt, J=12.46, 2.46 Hz, 1 H) 3.89 (s, 3 H) 4.07 (td, J=11.80, 4.72 Hz, 1 H) 4.25-4.43 (m, 1 H) 4.45-4.62 (m, 2 H) 4.61-4.85 (m, 3 H) 6.13 (s, 1 H) 7.54-7.79 (m, 2 H) 7.87 (d, J=1.51 Hz, 1 H) 8.07 (s, 1 H) 8.50 (d, J=2.64 Hz, 1 H) 8.66 (d, J=5.29 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>CN(C=O)C>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:16]=[CH2:17])[CH:10]=2)[C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nn(C)c2cc(Br)ccc12
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(C(=O)OC)nn(C)c2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 109.3 %

Procedure:
To the solution of methyl 6-bromo-1-methyl-1H-indazole-3-carboxylate (60 mg, 0.22 mmol) in DMF (10 mL), tributyl(vinyl)tin (99 μL, 0.34 mmol), Pd(Ph3)4 (11 mg, 9 μmol) was added. After the addition was completed, the mixture was stirred at 90° C. for 4 h under Ar. Then the solvent was removed under reduced pressure. Purification by CC afforded compound 9a (52 mg, 88%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:10][CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[CH:5][C:4]=1[C:22]([F:25])([F:24])[F:23])#[N:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:10][CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[C:22]([F:23])([F:25])[F:24])#[N:2]
Reactant: COC(=O)C(C)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Temperature: 75 °C
Yield: 92.9 %

Procedure:
A solution of methyl 3-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]-2-methylpropanoate (0.056 g, 0.152 mmol) in 1:1 THF/MeOH (6 mL) was treated with NaOH (1N, 1 mL, 1.0 mmol) and heated at 75° C. for 30 min. Upon cooling, the mixture was partitioned between EtOAc and 0.1N HCl. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (0.050 g, 94% yield): 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.8 Hz, 1H), 7.06 (d, J=2.6 Hz, 1H), 6.92 (dd, J=8.8, 2.6 Hz, 1H), 4.20-4.02 (m, 2H), 3.87 (dd, J=15.6, 9.0 Hz, 1H), 3.56 (dd, J=15.6, 5.0 Hz, 1H), 3.0-2.9 (m, 1H), 1.29 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:42]=[CH:43][N:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CC(C)C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CC(C)C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-isobutylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (600 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (326 mg) in dichloromethane (15 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, and stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-isobutylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (415 mg) (Compound 350) as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[C:15]([OH:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([F:18])=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:19])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27]Cl>C1COCC1>[F:1][C:2]1[C:15]([O:16][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([F:18])=[C:9]([O:17][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:10]=3)[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(F)c(O)cc2oc2cc(O)c(F)cc12
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1cc2oc3cc(OCOCCOC)c(F)cc3c(=O)c2cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A cloudy solution of 8 (2.4 g, 9.1 mmol) in dry THF (50 mL) was treated with sodium hydride (1.1 g, 45.8 mmol) at 0° C. under an Ar atmosphere. The mixture was stirred at 0° C. for 30 min and then 2-methoxyethoxymethyl chloride (5.2 mL, 45.8 mmol) was added. The mixture was stirred at 0° C. for an additional 30 min and then warmed to room temperature overnight. The reaction mixture was cooled to 0° C., quenched with 1M citric acid (50 mL), and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with CH2Cl2/hexane/EtOAc=1:1:0.4 to yield 2.6 g (65%) of 9 as a white solid. Rf=0.47 (in CH2Cl2/hexane/EtOAc=1:1:0.4); 1H NMR (300 MHz, CDCl3) δ7.91 (d, 2H, J=10.6 Hz), 7.28 (d, 2H, J=6.5 Hz), 5.46 (s, 4H), 3.91 (m, 4H), 3.60 (m, 4H), 3.39 (s, 6H); 13C NMR (75 MHz, CDCl3) 6174.4, 153.3, 153.2, 151.4, 151.0, 150.9, 148.2, 115.2, 115.1, 111.8, 111.6, 104.8, 94.2, 71.3, 68.6, 59.0; 19F NMR (282 MHz, CDCl3) δ −137.0 (dd, 2 F); mass spectrum, calculated for C21H22F2O8 (MH+) 441.1, Found 441.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C:16]#[N:17])[C:10]2[CH:33]=[C:34]([CH2:41][CH3:42])[C:35]([C:37]([F:40])([F:39])[F:38])=[CH:36][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:43]([Sn](CCCC)(CCCC)CCCC)=[N+:44]=[N-:45]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:18][C:19]2[CH:20]=[C:21]([C:29]([F:31])([F:32])[F:30])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=2)[C:16]2[N:43]=[N:44][NH:45][N:17]=2)[C:10]2[CH:33]=[C:34]([CH2:41][CH3:42])[C:35]([C:37]([F:40])([F:38])[F:39])=[CH:36][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Yield: 79.1 %

Procedure:
Heat a mixture of (S)-5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid tert-butyl ester (0.510 g, 0.837 mmol), azidotributyltin (0.344 mL, 1.26 mmol) in anhydrous toluene (20 mL) at 100° C. under nitrogen for 16 h. Dilute the cooled mixture with ethyl acetate (50 mL) and wash with aqueous NaF (50 mL) and brine (50 mL). Dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-60%), to provide the title compound (0.432 g, 79%), MS (ES+): 653 (M+H).