Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:22])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[CH2:3]C1.Br[C:24]1[CH:39]=[CH:38][C:27]2[C:28]([CH2:31][C:32]([NH:34][CH2:35][CH2:36][OH:37])=[O:33])=[N:29][O:30][C:26]=2[CH:25]=1.[C:40](=O)([O-])[O-].[Na+].[Na+]>C(O)(C)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>[CH:4]1([NH:5][C:6](=[O:22])[C:7]2[CH:12]=[CH:11][C:10]([CH3:40])=[C:9]([C:24]3[CH:39]=[CH:38][C:27]4[C:28]([CH2:31][C:32]([NH:34][CH2:35][CH2:36][OH:37])=[O:33])=[N:29][O:30][C:26]=4[CH:25]=3)[CH:8]=2)[CH2:1][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cc1noc2cc(Br)ccc12)NCCO
Reactant: CC1(C)OB(c2cccc(C(=O)NCC3CC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(CC(=O)NCCO)noc2c1

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5) (0.04 g) 2-(6-bromo-1,2-benzisoxazol-3-yl)-N-(2-hydroxyethyl)acetamide (Intermediate 35) (0.04 g) 2M aqueous sodium carbonate (1.5 ml) and tetrakis(triphenylphosphine)palladium(0) (1 mg) in isopropanol (3 ml) was stirred at reflux under nitrogen for 18 h. The mixture was absorbed onto silica (Merck 7734) and applied to a Varian Bond-Elut SPE cartridge (silica, 5 g) and eluted with a toluene:ethanol gradient (100:0 to 0:100) to give the title compound as a white solid (0.03 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:9][CH:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15].C(O)(=O)C.B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(CC(C)C)C2
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc2cc(CC(C)C)sc2c(Cl)c1Cl
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A mixture of 18 g of 6,7-dichloro-2,3-dihydro-2-isobutyl-5-methoxybenzo[b]thiophene, 90 ml of glacial acetic acid and 25 ml of boron trifluoride etherate is heated on a steam bath until dissolution occurs and for an additional 30 mins, with stirring. The reaction mixture is poured onto ice and the mixture is basified with 25% sodium hydroxide solution and extracted with ether. The ether extracts are washed with water, sodium bicarbonate solution, water, dried and filtered. Evaporation of the filtrate affords an oil which crystallies on cooling in a dry ice-acetone bath. Chromatography of the crystalline material on alumina using dichloromethane as the eluent affords 14.5 g of 6,7-dichloro-5-methoxy-2-isobutylbenzo[b]thiophene, mp 40°-41°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11](OCC)=[O:12].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(OCC)(=O)C.Cl>O>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:11](=[O:12])[C:10]([F:16])([F:17])[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A mixture of 100 mg of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate and 370 mg of 4-chloroaniline was subjected to reaction at 150°-160° C. for 5 hours. The reaction mixture was cooled to room temperature. Thereto were added 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 30 mg of N-(4-chlorophenyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][CH:21]([C:30]([O:32]CC)=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]1=[O:35])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:37](CCC1C=CC=CC=1)C(OC(C)(C)C)=O>>[CH2:1]([O:8][C:9]([CH:11]([N:13]1[CH2:37][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][CH:21]([C:30]([OH:32])=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]1=[O:35])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(=O)CCc1ccccc1
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCCCN(C(C)C(=O)OCc2ccccc2)C1=O
Product: CC(C(=O)OCc1ccccc1)N1CCCCCC(NC(CCc2ccccc2)C(=O)O)C1=O

Procedure:
The diastereomers of this compound may be prepared from 3-amino-1-(1-benzyloxycarbonylethyl)perhydroazocin-2-one (Example 8) and t-butyl 2-oxo-4-phenylbutyrate following the procudure in Example 7.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH2:26])=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.C(N(CC)CC)C.[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1.CCOC(OC(OCC)=O)=O>O1CCCC1.O>[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:40]=[CH:41][C:42]([C:43]([NH:26][C@@H:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[C:18]([N:17]2[C@@H:13]3[C@@H:14]([C@H:5]([CH2:4][O:3][CH3:2])[NH:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=43)[CH2:15][CH2:16]2)=[O:19])=[O:44])=[CH:46][CH:47]=1
Reactant: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Reactant: O=C(O)c1ccc(-c2ncc[nH]2)cc1
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc(-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of (1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine hydrochloride (200 mg, 0.480 mmol) in tetrahydrofuran (5 ml) were added triethylamine (0.199 ml, 1.44 mmol), 4-(1H-imidazol-2-yl)benzoic acid (99.0 mg, 0.529 mmol) and DEPC (0.079 ml, 0.529 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel and eluted with ethyl acetate-methanol (1:0-4:1) to give the title compound (150 mg, 61%) as an amorphous form.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]#[N:14])([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(N(C)C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:13]#[N:14])=[N:8]1
Reactant: N#Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: Cn1nc(C#N)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
5-nitro-1H-indazole-3-carbonitrile (150 mg, 0.797 mmol) was taken up in DMA (4 mL) and K2CO3 (331 mg, 2.392 mmol) was added, followed by drop wise addition of MeI (0.060 mL, 0.957 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was quenched with a saturated solution of NaHCO3 and Na2S2O3, and then diluted with EtOAc. The organic layer was washed with saturated NaHCO3, then brine, and dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography eluting with 0%-50% EtOAc/Hex. 1-methyl-5-nitro-1H-indazole-3-carbonitrile (134 mg) was obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH3:20][CH:21]([NH2:23])[CH3:22]>O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:23][CH:21]([CH3:22])[CH3:20])=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)N
Solvent: O
Product: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Yield: 97.2 %

Procedure:
A solution of 14 parts of (4-chloro-3-nitrophenyl)(4-fluorophenyl)methanone in 69 parts of 2-propanamine was stirred overnight at reflux temperature. The reaction mixture was poured into water. The precipitate was filtered off and washed with water, dried, filtered and evaporated, yielding 14.7 parts (97.2%) of (4-fluorophenyl) [4-[(1-methylethyl)amino]-3-nitrophenyl]methanone as a residue (int. 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:24][CH:23]([C:25](O)=[O:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[CH3:38][NH2:39]>C(Cl)Cl>[CH3:38][NH:39][C:25]([CH:23]1[CH2:24][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH2:11][C:10]([C:4]4[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=4)([C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:20][CH:19]=2)[CH2:22]1)=[O:26]
Reactant: CN
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a stirred solution of 1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 12, 0.1 g, 0.203 mmol) in DCM (4 mL) was added oxalyl chloride (0.030 g, 0.0.243 mmol) at 0° C. and stirred for 1 hour under nitrogen atmosphere at room temperature. After 1 hour, saturated solution of methyl amine (4 mL) was added. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh). Compound was eluted using 0.7% methanol in DCM to afford pale yellow solid (0.055 g, 54%). 1H-NMR (400 MHz, CDCl3) δ: 2.86-2.90 (d, 3H, J=4.84 Hz), 3.36-3.39 (m, 1H), 3.61 (d, 1H, J=17 Hz), 4.01-4.09 (m, 5H), 5.62-5.63 (m, 1H), 6.40-6.42 (m, 2H), 7.46-7.50 (m, 2H), 7.63 (s, 2H); LC-MS (m/z): [M−H] 503.80. HPLC purity: 96.77%.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Br:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[Br:13][C:12]1[C:11]([F:14])=[CH:10][CH:9]=[C:3]2[C:2]=1[NH:1][C:16](=[O:18])[N:6]([CH2:7][CH3:8])[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNC(=O)c1ccc(F)c(Br)c1N
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1c(=O)[nH]c2c(Br)c(F)ccc2c1=O
Temperature: 25 °C
Yield: 291 %

Procedure:
A solution of 2-amino-3-bromo-N-ethyl-4-fluorobenzamide (512a, 2.00 g, 7.66 mmol) and triphosgene (Aldrich; 0.796 g, 2.68 mmol) in toluene (80 mL) was heated at 110° C. for 18 h (water-cooled reflux condenser attached to flask). The reaction mixture was then cooled to RT and concentrated in vacuo to give 8-bromo-3-ethyl-7-fluoroquinazoline-2,4(1H,3H)-dione (2.238 g, 7.80 mmol) as a light-yellow solid: m/z (ESI, +ve) 286.9/288.8 (M+H)+. This material was used directly in the subsequent transformation.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[N:13](C(OC(C)(C)C)=O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([OH:21])=[CH:16][CH:15]=3)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:30][CH2:31][N:32]([CH2:34][CH2:35][O:36][CH3:37])[CH3:33].C(=O)([O-])[O-:39].[Cs+].[Cs+]>CN(C)C=O.O.C(O)(=O)C>[CH3:37][O:36][CH2:35][CH2:34][N:32]([CH3:33])[CH2:31][CH2:30][O:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:11]1[C:2](=[O:39])[NH:3][C:4]3[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:20]2
Reactant: COCCN(C)CCCl
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O)ccc21
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(C)CCOc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Temperature: 70 °C

Procedure:
A mixture of tert-butyl 2-(2-chloro-3-quinolinyl)-5-hydroxy-1H-indole-1-carboxylate (1-8, 1.50 g, 3.80 mmol, 1 equiv), 2-chloro-N-(2-methoxyethyl)-N-methylethanamine (720 mg, 4.75 mmol, 1.25 equiv), and cesium carbonate (3.09 g, 9.50 mmol, 2.50 equiv) in N,N-dimethylformamide (20 mL) was heated at 70° C. for 5 hours. The reaction mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water then brine, dried over magnesium sulfate, and concentrated to give a brown gum. The gum was dissolved in a 1:1 mixture of water and acetic acid (60 mL), and the resulting solution was heated at 100° C. for 18 hours. The reaction mixture was concentrated, and the residue was partitioned between aqueous saturated sodium bicarbonate solution and ethyl acetate. The organic layer was washed with water then brine, dried over magnesium sulfate, and concentrated to give a yellow solid. Purification by flash column chromatography (5% ethanol saturated with ammonia/CH2Cl2, grading to 10% ethanol saturated with ammonia/CH2Cl2) provided 3-(5-{2-[(2-methoxyethyl) (methyl)amino]ethoxy}-1H-indol-2-yl)quinolin-2(1H)-one (1-9) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.10 (s, 1H), 9.72 (s, 1H), 8.32 (s, 1H), 7.68 (br d, 1H, J=7.8 Hz), 7.53 (br t, 1H, J=7.6 Hz), 7.35 (d, 1H, J=8.8 Hz), 7.29 (br t, 1H, J=7.8 Hz), 7.24 (br d, 1H, J=8.2 Hz), 7.09 (d, 1H, J=2.2 Hz), 6.97 (d, 1H, J=1.4 Hz), 6.89 (dd, 1H, J=8.6, 2.2 Hz), 4.16 (t, 2H, J=5.9 Hz), 3.54 (t, 2H, J=2.67 (t, 3H, J=5.7 Hz), 3.38 (s, 3H), 2.92 (t, 3H, J=6.0 Hz), 2.73 (t, 3H, J=5.8 Hz), 2.44 (s, 3H).
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].[O-:6][C:7]#[N:8].[K+].Cl[CH2:11][C:12]([O-:14])=[O:13].[Na+]>O>[NH:5]([CH2:4][CH2:3][S:2][CH2:11][C:12]([OH:14])=[O:13])[C:7]([NH2:8])=[O:6]
Reactant: NCCS
Reactant: N#C[O-]
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NC(=O)NCCSCC(=O)O
Temperature: 50 °C
Yield: 78.7 %

Procedure:
To a solution of 34.1 g of β-mercaptoethylamine hydrochloride in 200 cc of water there are added a solution of 24.3 g of potassium cyanate in 80 cc of water, then 36 g of sodium monochloroacetate in 200 cc of water. The solution is heated at 50° C. for 2 hours while maintaining the pH at 6 by the addition of 2 N soda. The mixture is then acidified, concentrated to dryness and washed with a mixture of water and ethanol. After filtration, there are produced 42 g of the product which melts at 135° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[CH:17][CH:16]=2.I[CH3:24]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:24])[C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[CH:17][CH:16]=2
Reactant: O=c1[nH]c2ccncc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2cnccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 3-(2,6-dichloro-3-nitro-phenyl)-1H-[1,6]naphthyridin-2-one (2.0 g, 5.95 mmol) in DMF (50 mL) is added HNa (286 mg, 60%, 7.14 mmol) and IMe (0.5 mL, 8.03 mmol) at 0° C. The mixture is stirred for two hours at 0° C., diluted with EtOAc (300 ml) and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column elute with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3)(98.5/1.5) to give the titled intermediate as a solid (1.67 g, 80.3%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.Cl.[S-:10][C:11]#[N:12].[NH4+]>ClC1C=CC=CC=1C>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11]([NH2:12])=[S:10]
Reactant: N#C[S-]
Reactant: Cc1ccccc1N
Agent: Cl
Agent: [NH4+]
Solvent: Cc1ccccc1Cl
Product: Cc1ccccc1NC(N)=S
Temperature: 75 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
In a reactor, 107.2 g of o-toluidine and 250 ml of o-chlorotoluene were charged and 106 g of 36% hydrochloric acid was charged with stirring. The mixture was heated to 75° C. and 87.5 g of ammonium thiocyanate was admixed with the mixture and the reaction was performed at 75° to 85° C. for 20 hours. The resulting crystal was separated by a filtration and washed with water and dried to obtain 163.5 g of o-tolylthiourea having a melting point of 154° C. The product was analyzed by high speed liquid chromatography to find a purity of 98.0% and an yield of 96.4% as a pure product.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:29]1([P:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC#N>[Cl-:1].[CH3:28][C:5]1[NH:4][C:3]([CH2:2][P+:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:6]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Solvent: CC#N
Product: CCOC(=O)C1=C(C)NC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Product: [Cl-]
Yield: 66 %

Procedure:
A mixture of 2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (6 g) and triphenylphosphine (4 g) in CH3CN (60 ml) is heated to reflux temperature for six hours, then it is evaporated in vacuum and the residue crystallized from EtOH to give 6.5 g of [6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl]methyltriphenylphosphonium chloride, m.p. 225°-227° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.Cl.[C:15](=[O:18])([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[CH3:4][C:5]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]2[C:15](=[O:18])[C:6]=1[CH2:7][CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Cl)cn1
Agent: Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1c(C)nc2ccc(Cl)cn2c1=O
Yield: 91 %

Procedure:
12.8 g. of 2-amino-5-chloropyridine are reacted with 15.8 g. of ethyl-2-ethylacetacetate in a mixture of 46 g. of phosphorus oxychloride and 7 g. of polyphosphoric acid at 120° to 130° C. for 3 hours. The initially violent hydrogen chloride gas evolution gradually ceases. The reaction mixture is treated with 100 ml. of water at 70° to 80° C. Upon cooling the pH-value of the mixture is adjusted to neutral with sodium carbonate. The aqueous reaction mixture is shaken with four 100-ml. portions of chloroform. The combined chloroform solutions, dried on sodium sulphate, are evaporated and ethyl acetate is distilled through the residue. 20.2 g. (91%) of 2-methyl-3-ethyl-7-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine are obtained, melting at 114° to 116° C. after recrystallization from a mixture of ethanol and ether.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.B(O)(O)[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[S:35][CH:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[S:35]1[CH:34]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=3)[NH:4][N:3]=2)[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]1=2
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)c1csc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3csc4ccccc34)c2c1
Yield: 35.8 %

Procedure:
N-(3-Benzo[b]thiophen-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 300 mg thianaphthene-3-boronic acid, 20 ml of dimethylformamide, 1.9 ml of saturated aqueous solution of sodium hydrogencarbonate and 25 mg of tetrakis(triphenylphosphine)palladium[0]. 150 mg of N-(3-benzo[b]thiophen-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 235° C. (analysis C22H17N3O4S3% calculated C, 54.64; H, 3.54; N, 8.69; O, 13.23; S, 19.89. % found C, 54.35; H, 3.68; N, 8.68; S, 20.12).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9](Cl)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[N:15][CH:14]=1.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1>>[CH3:28][C:26]1[N:27]=[C:23]([NH:22][C:9]2[N:10]=[CH:11][C:2]([C:17]3[CH:18]=[N:13][CH:14]=[N:15][CH:16]=3)=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)[S:24][CH:25]=1
Reactant: OB(O)c1cncnc1
Reactant: Clc1ncc(Br)c2cccnc12
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3cncnc3)c3cccnc23)n1

Procedure:
The title compound, MS: m/e=321.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 5-bromo-8-chloro-[1,7]naphthyridine (Example H), 5-pyrimidineboronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [OH:1][C:2]1[NH:3][NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[Cl:12][C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1>[ClH:12].[CH3:16][O:15][C:13]([N:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=[C:2]([O:1][C:13]([O:15][CH3:16])=[O:14])[NH:3]1)=[O:14]
Reactant: COC(=O)Cl
Reactant: OC1=Nc2ncccc2NN1
Solvent: C1COCCO1
Product: COC(=O)OC1=Nc2ncccc2N(C(=O)OC)N1
Product: Cl
Reaction time: 5 h
Yield: 78.9 %

Procedure:
A mixture of 2.5 g (0.015 moles) of 3-hydroxy-1,2-dihydro-pyrido[2,3-e]-as-triazine, 2.16 g (0.03 moles) of methyl chloroformate and 100 ml of dioxane is maintained at 5°-10° C. for 3 hours and then at 40°-50° C. for 5 hours. Thereafter the solvent is removed to obtain 3.58 g (79%) of the title compound; m.p.: 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3([CH2:25][NH:26]C(=O)OC(C)(C)C)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[C:4]([O:34]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[NH2:26][CH2:25][C:22]1([C:19]2[CH:18]=[CH:17][C:16]([C:5]3[C:6]4[C:7]5[CH:15]=[CH:14][S:13][C:8]=5[C:9](=[O:12])[NH:10][C:11]=4[C:2]([Cl:1])=[CH:3][C:4]=3[OH:34])=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CC2)cc1
Agent: BrB(Br)Br
Product: Cl
Product: NCC1(c2ccc(-c3c(O)cc(Cl)c4[nH]c(=O)c5sccc5c34)cc2)CC1
Yield: 97.4 %

Procedure:
Following General Procedure F, tert-butyl (1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)cyclopropyl)methylcarbamate (50 mg, 0.09 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 0.58 mL, 0.58 mmol) to afford the desired product (19 mg, 48%) as a white solid: 1H NMR; (500 MHz, MeOD) δ 7.66-7.58 (m, 3H), 7.38-7.27 (m, 3H), 6.14 (d, J=5.4 Hz, 1H), 3.26 (s, 2H), 1.19 (t, J=5.5 Hz, 2H), 1.11 (t, J=5.5 Hz, 2H); ESI MS m/z 397 [C21H17ClN2O2S+H]+; HPLC 98.4% (AUC), tR=9.24 min.