Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](Cl)=[CH:14][NH:15]2)(C)(C)C.[OH-:29].[Na+]>COC(O)C>[CH2:21]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][C:14](=[O:29])[NH:15]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N(CCOc1cccc2[nH]cc(Cl)c12)Cc1ccccc1
Reactant: [OH-]
Agent: COC(C)O
Agent: [Na+]
Product: O=C1Cc2c(cccc2OCCNCc2ccccc2)N1
Temperature: 100 °C
Yield: 86.1 %

Procedure:
A mixture of N-benzyl-N-[2-(3-chloro-1H-indol-4-yloxy)-ethyl]-carbamic acid tert-butyl ester (5.4 g, 13.5 mmol) in methoxyethanol (25 mL) containing 85% phosphoic acid (10 mL) was heated to 100° C. for 1 hour. The reaction was allowed to cool and then basified with 2N sodium hydroxide and extracted with methylene chloride (2×150 mL). The organic layer dried over anhydrous magnesium sulfate, filtered and chromatographed (5% methanol-methylene chloride) to afford 3.28 g of a grayish-white solid (86.1%): mp 145°-146° C. The fumarate salt was prepared in isopropanol: mp 220°-221° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10]2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[C:21]([F:36])=[CH:22][C:23]([CH:33]2[CH2:35][CH2:34]2)=[C:24]([N:26]2[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]2)[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[F:18][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:19][C:20]2[C:21]([F:36])=[CH:22][C:23]([CH:33]3[CH2:35][CH2:34]3)=[C:24]([N:26]3[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]3)[CH:25]=2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1NC1CCN2CCCC2C1
Reactant: Cn1nnn(-c2cc(N)c(F)cc2C2CC2)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(NC4CCN5CCCC5C4)n3)c(F)cc2C2CC2)c1=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
A mixture of N-(2-chloro-5-fluoropyrimidin-4-yl)octahydroindolizin-7-amine (54 mg, 0.2 mmol), 1-(5-amino-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5-one (52 mg, 0.21 mmol; prepared according to US20110130415 pages 43-48, which is hereby incorporated by reference in its entirety) and para-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) in isopropyl alcohol (3 ml) were combined in a sealed vial, heated to 70° C. and stirred for 2 days. After cooling, the mixture was concentrated under vacuum to leave a crude residue. The residue was purified by preparative high-performance liquid chromatography to give a solid. The solid was partitioned between EtOAc (20 ml) and 1N NaOH (20 ml). The aqueous layer was extracted with EtOAc (2×20 ml) and the combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave the product (46 mg, 47%) as a solid after freeze-drying from MeCN/H2O.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][CH:10]([CH3:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:12].O>C(Cl)Cl>[CH3:9][CH:10]([CH3:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[N:12]=[CH:7]/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: CC(C)C(N)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(C)C(/N=C/c1ccccn1)c1ccccc1

Procedure:
In air, 2-pyridinecarboxaldehyde (0.185 g, 0.164 mL, 1.72 mmol, 1.00 equiv) was added to a solution of 2-methyl-1-phenylpropan-1-amine (0.257 g, 1.72 mmol, 1.00 equiv) in CH2Cl2 (8 mL). After heating at reflux for 2 h with azeotropic removal of water using a Dean-Stark trap, the reaction mixture was concentrated under reduced pressure and dried under high vacuum to give ligand (L-1), (E)-2-Methyl-1-phenyl-N-(pyridin-2-ylmethylene)propan-1-amine, as a yellow oil (0.379 g, 92% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[N:9]1([C:14]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC1CCCCO1
Solvent: ClCCl
Product: O=C(OCC1CCCCO1)n1ccnc1

Procedure:
A solution of (tetrahydro-2H-pyran-2-yl)methanol (1 g, 8.60 mmol) and di(1H-imidazol-1-yl)methanone (2.8 g, 17.2 mmol) in 17 mL CH2Cl2 was heated overnight at 50° C. The reaction was quenched with water, extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](N(OC)C)=[O:15])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:33])(=[O:32])[N:27]=CN(C)C)=[CH:22][CH:21]=3)[C:9]=2[CH3:34])=[CH:4][CH:3]=1.[CH2:35]1COC[CH2:36]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](=[O:15])[CH2:35][CH3:36])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:27])(=[O:32])=[O:33])=[CH:22][CH:21]=3)[C:9]=2[CH3:34])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1c(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Product: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 0 °C
Yield: 21.08 %

Procedure:
Grignard reagent (ethyl magnesium bromide, 0.531 g, 3.98 ml, 1M soln. In THF, 3.98 mmol) was added dropwise under a nitrogen atmosphere to a stirred solution of 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N, 1,4-trimethyl-1H-pyrrole-2-carboxamide (compound 49ω, 0.400 g, 0.79 mmol) in anhydrous THF (15 ml) at 25° C., and the reaction mixture was then heated to about 70 to about 75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the cooled reaction mixture was quenched by addition of saturated solution of ammonium chloride (10 ml). The mixture so formed was extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent from the dried organic solution was evaporated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC to obtain the title compound (0.070 g, 21.08%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[S:37]1[CH2:41][CH2:40][N:39]2[CH:42]=[C:43]([CH:45]=O)[N:44]=[C:38]12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].P([O-])([O-])([O-])=O>ClCCl>[S:37]1[CH2:41][CH2:40][N:39]2[CH:42]=[C:43]([CH2:45][NH:1][C:2]3[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][C@@H:22]([C:24]5[CH:35]=[CH:34][C:27]6[O:28][C:29]([CH3:32])([CH3:33])[O:30][CH2:31][C:26]=6[CH:25]=5)[O:21][C:20]4=[O:36])[CH:5]=[CH:6][CH:7]=3)[N:44]=[C:38]12
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: O=Cc1cn2c(n1)SCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NCc5cn6c(n5)SCC6)c4)C(=O)O3)ccc2O1
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (200 mg) and 2,3-dihydroimidazo[2,1-b][1,3]thiazole-6-carboxaldehyde (62 mg) (WO94/10178) in dichloromethane (10 ml) was treated under nitrogen with sodium triacetoxy borohydride (340 mg) and stirred at 20° for 1.5 h. The mixture was cooled to 0°, phosphate buffer solution (pH6.5, 20 ml) was added and the mixture was extracted with EtOAc (3×30 ml). The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by SPE. Elution with dichloromethane, dichloromethane-EtOH-ammonia (400:8:1) then (225:8:1) gave the title compound (172 mg). LCMS RT=3.16 min, ES +ve 637 (MH)+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH:14]1([N:20]=[N:21][C:22]2(Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>CO>[CH:22]1([N:21]=[N:20][C:14]2([S:13][C:10]3[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:12][CH:11]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: ClC1(N=NC2CCCCC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(SC2(N=NC3CCCCC3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4.96 grams (.062 moles) of 50% sodium hydroxide in 100 ml of methanol in a 250 ml erlenmeyer flask was added 10.45 grams (.063 moles) of para-(t-butyl)thiophenol and the solution stirred for 15 minutes at room temperature. The solution was cooled to 5° C. and 13.7 grams (.06 moles) of 1-cyclohexylazo-1-chlorocyclohexane (from Example 3-11) was added dropwise over 20 minutes while holding the reaction temperature at 5° to 10° C. with a cold water bath. After the addition was complete the bath was removed and the reaction stirred for an additional 60 minutes at room temperature. A 1.0 gram portion of 50% sodium hydroxide was then added to react with any excess thiophenol, the reaction mixture poured into 300 ml water and the product extracted into 100 ml of pentane. The pentane solution was separated and successively washed with 50 ml portions of water, 10% HCl, water, 5% sodium hydroxide and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid that weighed 14.0 grams (63% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-cyclohexylazo-1-[para-(t-butyl)-thiophenoxy] cyclohexane.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=1[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.C1CN2C(=NCCC2)C1>C(#N)C>[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:8][C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[C:4]([O:3][CH3:2])=[O:5])=[CH:36][CH:35]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: [Br-]
Solvent: CC#N
Product: COC(=O)c1ccccc1C=Cc1ccc(OC)cc1

Procedure:
In 50 ml of acetonitrile were dissolved 4.91 g (10 mmol) of 2-methoxycarbonylbenzyltriphenylphosphonium bromide and 1.77 g (13 mmol) of 4-methoxybenzaldehyde, and 2.48 g (20 mmol) of 1,5-diazabicyclo[4.3.0]-5-nonene was added to the solution and the mixture was refluxed for 5 hours.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5]
Reactant: CCCCCC(O)CC(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-hydroxyoctanoic acid (1.90 g) and triethylamine (1.65 ml) in DMF (20 ml) was added benzyl bromide (1.41 ml) and the mixture was stirred at room temperature for 3 days. After the solvent was removed in vacuo, ethyl acetate and water were added to the residue. The separated ethyl acetate layer was washed twice with water and then dried over anhydrous sodium sulfate. After concentration, the residue was purified by a silica gel column chromatography (silica gel 15 g, chloroform: methanol=100:0-8) to afford 1.71 g of benzyl 3-hydroxyoctanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C:22]1[C:23](=[O:35])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:21][C:22]3[C:23](=[O:35])[N:24]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:25]=[CH:26][CH:27]=3)=[O:18])=[CH:19][CH:20]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Reactant: Nc1cccn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Nc1cccn(-c2ccc(F)cc2)c1=O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a 2 dram vial was added 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoic acid (0.050 g, 0.17 mmol, prepared as described in Example XIV, step 1b), 3-amino-1-(4-fluorophenyl)pyridin-2(1H)-one (0.053 g, 0.26) from 1a-1 and 1a-2 described below, EDCI (0.050 g, 0.26 mmol), HOBt (0.035 g, 0.26 mmol), TEA (0.07 ml, 0.51 mmol), DMF (0.8 ml) and CH3CN (0.8 ml). the reaction was allowed to stir at 50° C. for 12 hrs. Upon cooling, the solvent was removed in vacuo and diluted with methanol (2 ml). The solution was purified by HPLC (20-100% methanol gradient), which yielded 0.0.12 g of 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[NH2:19][N:20]1[C:25]([NH2:26])=[CH:24][C:23]([NH2:27])=[N:22][C:21]1=[S:28].CO.N>C(#N)C>[NH2:17][CH:16]1[C:15](=[O:18])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][S:28][C:21]3[N:22]=[C:23]([NH2:27])[CH:24]=[C:25]([NH2:26])[N+:20]=3[NH2:19])[CH2:7][S:8][C@H:9]12
Reactant: Nc1cc(N)n(N)c(=S)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: N
Solvent: CC#N
Solvent: CO
Product: Nc1cc(N)[n+](N)c(SCC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
Under an anhydrous condition, a solution containing 2.72 g of 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid and 1.50 g of 1,4,6-triamino-2(1H)-pyrimidinethione suspended in 20 ml of dry acetonitrile was cooled to 0° C.; and 4.8 ml of boron trifluoride diethylether was added. The temperature of the reaction solution was increased to 50° C; the solution was stirred for two hours; and then 10 ml of methyl alcohol was added. The resultant solution was stirred for 10 minutes and was added with 30 ml of ice water. The pH of the solution was adjusted to 7.1 by adding aqueous ammonia solution. After concentration under a reduced pressure, e.g., about 20 mmHg, the solution was adjusted to pH 3.7 with 2N-aqueous hydrochloric acid; and allowed to stand at a room temperature for 24 hrs. The precipitates resulted from the reaction solution were filtered, washed with 10 ml of distilled water and with 10 ml of methyl alcohol, and dried to give 2.55 g of the title compound as a solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[N:26]1([C:24]2[N:25]=[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:21]=[N:22][CH:23]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: Clc1cncc(N2CCc3ccccc32)n1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: c1ccc2c(c1)CCN2c1cncc(-c2cnc3[nH]ccc3c2)n1
Temperature: 90 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and 1-(6-chloropyrazin-2-yl)indoline (88) 423 mg, 0.185 mmol, 0.9 eq) in DME (7 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.410 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional 10 minutes was performed. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 5-(6-(indolin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 134 in 12 mg quantity. The compound 134 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 9.06 (s, 2H), 8.59 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.44 (m, 1H), 8.16 (s, 1H), 7.41 (m, 1H), 6.99 (m, 1H), 4.21 (m, J=8.53, 2H), 3.33 (m, J=341.82, 2H); MS m/z 313.9 (M+H)+.
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]([CH2:38][S:39][C:40]5[N:44]([CH3:45])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Mg+2]>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]([CH2:38][S:39]([C:40]5[N:44]([CH3:45])[CH:43]=[N:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4nncn4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Mg+2]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4nncn4C)cc2)CCN3CC(C)C)cc1
Temperature: -12.5 °C
Reaction time: 1.5 h
Yield: 27.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylthiomethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.26 g) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.26 g) in dichloromethane (10 ml) at −78° C. and the mixture was stirred at −10 to −15° C. for 1.5 hours. To the reaction solution was added magnesium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:4) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylsulfinylmethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 118) (73.8 mg) as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:34])=[O:33]
Reactant: COC(=O)c1cc(N(CCO)CCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A stirred solution of methyl 5-[bis(2-hydroxyethyl)amino]-2,4-dinitrobenzoate [Palmer et al., J. Med. Chem 1994, 37, 2175] (5.50 g, 16.7 mmol) and Et3N (5.82 mL, 41.8 mmol) in dry CH2Cl2 (50 mL) was treated dropwise at 0° C. with MsCl (3.14 mL, 40.0 mmol). After 30 min, 10% aqueous KHCO3 (100 mL) was added, and the mixture was stirred for a further 30 min at 0° C. and then diluted with pet. ether (500 mL). The precipitated product was collected and washed with water and iPr2O to give methyl 5-(bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,4-dinitrobenzoate (7) (7.44 g, 92%):
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH2:14][C:15]3[NH:16][CH:17]=[CH:18][N:19]=3)[CH:12]=[CH:13][C:7]=2[C:6]=1[CH3:20])=[O:4].[OH-].[K+].O>CO>[NH:19]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6]([CH3:20])=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1sc2cc(Cc3ncc[nH]3)ccc2c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)sc2cc(Cc3ncc[nH]3)ccc12
Yield: 84.1 %

Procedure:
A mixture of 6-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.25 g.) potassium hydroxide (0.10 g.), water (2.5 ml.) and methanol (2.5 ml.) was heated under reflux for 1 hour and then evaporated to small bulk. The solution was acidified with acetic acid and the solid was filtered off and dissolved in a slight excess of diluted potassium hydroxide solution. The solution was filtered and the filtrate was acidified. The solid was filtered off, washed with water and dried to give 6-(1-imidazolylmethyl)-3-methylbenzo[b]-thiophene-2-carboxylic acid (0.20 g.), m.p. 277°-278° C.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:12][S:13]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2)(=[O:15])=[O:14].O[CH:27]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[CH:28]1[CH2:30][CH:29]1[C:31]#[N:32]>ClCCl>[CH3:39][C:36]1[CH:37]=[CH:38][C:33]([CH:27]([C:22]2[C:21]3[C:25](=[C:17]([CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[CH:18]=[CH:19][CH:20]=3)[NH:24][CH:23]=2)[CH:28]2[CH2:30][CH:29]2[C:31]#[N:32])=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: Cc1ccc(C(O)C2CC2C#N)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cccc23)C2CC2C#N)cc1

Procedure:
195 mg (0.88 mmol) of indium(III) chloride and 0.11 ml (1.44 mmol) of trifluoroacetic acid were added to 168 mg (0.80 mmol) of the compound from Example 86A and 150 mg (0.80 mmol) of the compound from Example 158A under argon in 9 ml of dichloromethane, and the mixture was heated under reflux for 1 h. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 100 mg (33% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1[CH:40]=[CH:39][C:33](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:32][CH:31]=1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:36](=[O:37])/[CH:35]=[CH:34]/[C:33]4[CH:39]=[CH:40][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J (0.50 mmol), and trans-4-fluorocinnamic acid, by the method of Example 1, step K, giving the title compound as a white solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H35FN4O2: 503 (M+H). Found: 503