Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5](OC)=[C:6](OC)[C:7]([OH:9])=[O:8].C1OC1CO.S(=O)(=O)(O)O.OCC(CO)O>CS(C)=O>[C:7]([OH:9])(=[O:8])[CH:6]=[CH:5][C:4]1[CH:3]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(C(=O)O)=C(OC)c1ccccc1OC
Agent: O=S(=O)(O)O
Agent: OCC1CO1
Solvent: CS(C)=O
Solvent: OCC(O)CO
Product: O=C(O)C=Cc1ccccc1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
4.35 g of trimethoxy cinnamic acid and 10 g of glycidol were dissolved in 5 ml of DMSO. The mixture was stirred and heated to 90° C. Catalystic amount of sulfuric acid was added, heating and agitation were carried out for 3.5 hours, and then the adduct of cinnamic acid and glycerin was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:29])[C@H:16]([NH:21]C(=O)OC(C)(C)C)[C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][C@H:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:13]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](N)C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl 1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (crude from above) in dichloromethane (5 mL) was added TFA (5 mL). Upon completion of addition, the resulting solution was allowed to stir at rt. for 2 h. After this time, the solvent was removed by rotary evaporation to provide an oil which was partitioned between dichloromethane and 1 N NaOH. The dichloromethane extract was washed with water, dried over MgSO4 and evaporated to provide (R)-2-amino-1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3,3-dimethylbutan-1-one as an oil (1.09 g).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=2[N+:16]([O-])=O)[CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[NH2:16][C:7]1[CH:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: CC(=O)Nc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NCC2CC2)c(N)c1
Yield: 89.6 %

Procedure:
Following general procedure 2C: N-{4-[(cyclopropylmethyl)amino]-3-nitrophenyl}acetamide (7.0 g, 28 mmol) was hydrogenated in ethyl acetate (300 mL) with 10% Pd/C (0.8 g) at 25 psi H2 in Parr shaker. After work up, isolated the desired product (5.5 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[I:12]Cl.O>C(O)(=O)C>[NH2:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]([CH3:8])=[CH:6][C:7]=1[I:12]
Reactant: ClI
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Yield: 25.6 %

Procedure:
A solution of 4-amino-3-nitrotoluene (30.4 g) in acetic acid (250 ml) was refluxed with iodine monochloride (65.0 g) for 7 h with stirring, then was cooled and added to excess water. The precipitate was filtered off, washed with aqueous sodium sulfite and after column chromatography yielded 4-amino-3-iodo-5-nitrotoluene (14.2 g). δ (360 MHz, DMSO-d6) 2.19 (3H, s, CH3), 6.88 (2H, bs, NH2), 7.88 (1H, d, 2-H) and 7.94 (1H, d, 6-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][C:3]=1[F:22].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][C:3]=1[F:22]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(Cl)c(F)c1
Yield: 91.9 %

Procedure:
Dimethyl 2-(4-chloro-3-fluorophenyl)piperidine-1,4-dicarboxylate (1.625 g, 4.93 mmol) was dissolved in acetonitrile (20 mL) and water (0.400 mL). lithium bromide (3.42 g, 39.42 mmol) was added. Triethylamine (2.73 mL, 19.71 mmol) was then added and the reaction heated under reflux for 1.5 h. Water (200 mL) and MTBE (150 mL) were added, shaken and the phases separated. The organic phase was extracted with water (2×200 mL). The combined aqueous phases were acidified with 3 M HCl to pH 1 and then extracted with MTBE (2×500 mL). The combined organic phases were dried with Na2SO4, filtered and evaporated in vacuo yielding 2-(4-chloro-3-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.430 g, 92%). MS m/z 314 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]#[C:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]#[C:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:33][CH:34]([CH3:39])[CH3:35])=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1C#Cc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(C#Cc2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a solution of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylethynyl]-nicotinic acid (69 mg, 0.21 mmol) and TBTU (76 mg, 0.24 mmol) in DMF (1.0 mL) was added DIPEA (183 μL, 1.07 mmol). Then isopropylamine (20 μL, 0.24 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (39 mg, 50%) as a light yellow solid after recrystallisation from ethyl acetate/heptane. MS: m/e=364.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>C(O)(C)C>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CC(C)O
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 71 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isoporpyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 121° C (from ethanol).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C.CO>[CH2:1]([N:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:9])[C:18]=2[N:17]=[C:16]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(Br)cccc2[nH]1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloride (1.527 mL) was added to a solution of 4-bromo-2-methyl-1H-benzimidazole (1.40 g) and sodium hydride (0.531 g) in DMF (10 ml) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (1.88 g) as tan oil. The mixture of 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (496 mg), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (700 mg), Pd(Ph3P)4 (87 mg), sodium carbonate (476 mg) and THF (18 mL)-water (0.90 mL) was heated at 100° C. for 1 h under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give 3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (450 mg) as white crystals.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:17]2=[N:18][C:19]=1[Cl:20])[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:37]I.O>CN(C=O)C>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:28]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[C:16]2[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:17]2=[N:18][C:19]=1[Cl:20])[C:8]1[N:9]=[N:10][N:11]([CH3:37])[N:12]=1
Reactant: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 121.4 %

Procedure:
A mixture of (3,5-bis-trifluoromethyl-benzyl)-(6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethyl)-(2H-tetrazol-5-yl)-amine (8.5 g, 10 mmol) and sodium hydride (0.81 g, 30 mmol) in DMF (150 mL) was stirred at 0° C. for 20 minutes. Thereafter, methyl iodide (3.5 g, 20 mmol) was added and the resulting mixture was stirred at 0-10° C. for 30 minutes. Water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography over 230-400 mesh silica gel. Elution of the column with 10% acetone in hexanes gave the pure product as a colorless solid (6.3 g), yield: 75%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:30][C:31]([F:34])([F:33])[F:32])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:30][C:31]([F:32])([F:34])[F:33])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][N:23]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A mixture of ethyl {2-[7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (780 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at 50° C. for 30 min. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (490 mg, yield 64%) as brown crystals. The crystals were recrystallized from ethyl acetate-hexane to give brown prism crystals. melting point 247-248° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37](Cl)=[O:38]>ClCCl>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH:23][C:37](=[O:38])[O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCOC(=O)Cl
Reactant: Cn1ccnc1C(=NOCc1nccc(N)n1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)Nc1ccnc(CON=C(c2ccccc2)c2nccn2C)n1
Yield: 12 %

Procedure:
A solution of 2-[({[(1-methyl-1H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine (200 mg, 0.64 mmol), triethylamine (0.18 mL, 1.29 mmol), chloroformic acid n-amyl ester (0.19 mL, 1.29 mmol) in dichloromethane (10 mL) was stirred 4 h20 at room temperature. After dilution with water (50 mL), the layers were separated and the aqueous layer further extracted with dichloromethane (30 mL). The combined organic layers were dried over MgSO4 and the solvents removed in vacuo. Purification on silica gel afforded pentyl {2-[({[(1-methyl-1H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-yl}carbamate as an oil [34 mg, yield 12%; HPLC/MS: m/z=423 (M+H); log P(HCOOH)=2.28].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27]([C:29]1[CH:34]=[C:33]([C:35](OC)=[O:36])[CH:32]=[C:31]([C:39]([O:41][CH3:42])=[O:40])[CH:30]=1)=[O:28]>O1CCCC1>[CH3:42][O:41][C:39]([C:31]1[CH:32]=[C:33]([CH:34]=[C:29]([C:27]([O:26][CH3:25])=[O:28])[CH:30]=1)[C:35]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1)=[O:36])=[O:40]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cc(C(=O)OC)cc(C(=O)OC)c2)n1
Yield: 14.2 %

Procedure:
Under the conditions of example 1B, 1 g of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl)-pyridine in 10 ml of tetrahydrofuran is mixed with 4.26 ml of n-butyllithium (1.6 molar in hexane) and 807 mg of 1,3,5-benzenetricarboxylic acid trimethylester in 6 ml of tetrahydrofuran, worked up and chromatographed on silica gel with hexane/ethyl acetate=95/5 to 75/25. 203 mg of oily crude product is obtained, which is subjected to complete purification of the high-pressure liquid chromatography on silanized silica gel (RP 18 material) with methanol/H2O=9:1. 74 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[CH2:30][CH2:31][N:32]([C:33](OC(C)(C)C)=O)[CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.CO.C=O>O.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[CH2:30][CH2:31][N:32]([CH3:33])[CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCN(C(=O)OC(C)(C)C)C2C1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCN(C)C2C1
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
To a solution of tert-butyl 6-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.20 g) in the mixture solvent of CH2Cl2 and MeOH was added 37% HCHO (0.10 mL), AcOH (0.15 mL) and NaB(O2CCH3)3H (0.26 g) in turn at room temperature. The mixture was stirred for 1.5 h, diluted with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated and redissolved in EA, to this, a solution of HCl in EtOAc (10 mL) was added under stirring. The mixture was filtered to give the title compound as a solid (0.13 g, 68.00%), HPLC: 98.22%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 500.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.45 (m, 2H), 1.68 (m, 3H), 1.80 (m, 2H), 2.10 (m, 1H), 2.22 (m, 5H), 2.25 (s, 3H), 2.42 (m, 3H), 4.03 (s, 3H), 4.10 (m, 2H), 6.76 (s, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.24 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 8.54 (s, 1H) ppm.
Reaction SMILES: BrC1C=CC(C(Cl)=O)=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([NH:43][C:44]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[C:12]([Cl:11])[CH:13]=2)=[S:45])=[O:42])=[CH:37][CH:36]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(N=C=S)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
4-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (80 mg, yield 83%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>ClCCl>[CH3:14][O:13][C:10]1[C:11]2[N:12]=[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:1][C:2]=2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1ccc(OC)c(N)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c2nc(-c3cccnc3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A solution of methyl 2,3-diamino-4-methoxybenzoate [0.73 g, Reference Example 8(a)] and triethylamine (0.94 g) in dry dichloromethane (20 ml), at 0° C., was treated with nicotinyl chloride (0.53 g). The reaction mixture was stirred at ambient temperature for 2 hours and then evaporated. The residue was dissolved in acetic acid (8 ml) and the solution heated at 80° C. for 2 hours. After cooling to room temperature the reaction mixture was treated with water. The insoluble material was subjected to flash chromatography on silica to give the title compound (0.46 g). NMR (CDCl3): δ 4.00(s,3H), 4.15(s,3H), 6.70(d,1H), 7.40(m,1H), 7.90(d,1H), 8.45(m,1H), 8.75(d,1H), 9.30(d,1H), 10.80(s,1H)].
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32](O)=[O:33])=[CH:4][N:3]=1.[CH3:35][O:36][CH:37]([O:40][CH3:41])[CH2:38][NH2:39].CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(O)(C)C>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:39][CH2:38][CH:37]([O:40][CH3:41])[O:36][CH3:35])=[O:33])=[CH:4][N:3]=1
Reactant: COC(CN)OC
Reactant: COc1cc(-c2csc3c(C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COc1cc(-c2csc3c(C(=O)NCC(OC)OC)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (1.0 g, 2.1 mmol) and 2,2-dimethoxy-1-ethanamine (252 uL, 2.3 mmol) were reacted according to General Procedure D. MP-carbonate resin (5 g) was added, and the mixture was shaken for 2 hours. The resin was filtered from the mixture and the filtrate was concentrated in vacuo to yield 1.5 g crude material. Isopropyl alcohol (35 mL) was added to and the crude product was triturated and filtered to yield the title compound (830 mg, 71% yield): 1H NMR (DMSO, 400 MHz) δ 9.48 (s, 1H), 8.56 (s, 2H), 7.98 (d, 1H), 7.69 (d, 1H), 7.56-7.58 (m, 2H), 7.31-7.33 (m, 2H), 7.04-7.17 (m, 3H), 4.54 (t, 1H), 4.02 (s, 3H), 3.89 (s, 3H), 3.37 (t, 2H), 3.31 (s, 6H), 2.51 (t, 2H); RP-HPLC (Conditions j) Rt 12.2 min. MS: 560.0 MH+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][N:7]=[C:8]([C:17]1[O:21][N:20]=[C:19]([CH3:22])[CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O>C1C=CC=CC=1>[CH3:5][O:6][N:7]=[C:8]([C:17]1[O:21][N:20]=[C:19]([CH3:22])[CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][Cl:3]
Reactant: CON=C(c1cc(C)no1)c1ccccc1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CON=C(c1cc(C)no1)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
Benzene (5 ml) and thionyl chloride (0.36 g, 3.0 mmol) were added to 2-hydroxymethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.62 g, 2.5 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-chloromethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.26 g, yield: 39.3%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].CN(C)C=O.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C>S(Cl)(Cl)=O.O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=2)=[O:10])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)Nc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution (20 mL) of 3-(acetyloxy)benzoic acid (18.0 g, 100 mmol) in thionyl chloride was added N,N-dimethylformamide (0.1 mL), and the mixture was stirred at room temperature for 1 hr. Excess reagents were evaporated under reduced pressure, and the obtained residue was dissolved in tetrahydrofuran (50 mL), and 4-(trifluoromethyl)aniline (24.2 g, 150 mmol) and N-ethyl-N-isopropylpropane-2-amine (19.4 g, 150 mmol) were successively added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=5:1), and triturated with diethyl ether to give the title compound (27.7 g, 86%) as a pale-yellow solid.