Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:17][C:18]1[C:23]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])(=[O:27])=[O:26])=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][N:19]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:17][C:18]1[C:23]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])(=[O:27])=[O:26])=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:16][CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:20][N:19]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: Clc1ccc2ncnc(NC3CCC3)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine (Intermediate 19) (0.050 g, 0.213 mmol), N-(2-chloro-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.110 g, 0.256 mmol), PdCl2(dppf)-CH2Cl2 Adduct (1.74 mg, 2.13 μmol) and 1 N aq. sodium bicarbonate (0.426 ml, 0.426 mmol) in dioxane (1.00 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(cyclobutylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.087 g, 81%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.84-1.95 (2H, m), 2.10-2.20 (2H, m), 2.54-2.62 (2H, m), 4.77-4.87 (1H, m), 6.94-7.02 (2H, m), 7.34 (1H, d, J=8.0 Hz), 7.86-7.92 (1H, m), 8.07 (1H, d, J=8.8 Hz), 8.21 (1H, d, J=8.8 Hz), 8.65 (1H, s), 8.73 (1H, d, J=2.4 Hz), 8.84 (1H, d, J=2.4 Hz). m/z=503.2 [M+1]+.
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[CH:25]1([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26]1.[Cl:37][C:38]1[CH:39]=[C:40]([CH2:45][CH2:46][NH2:47])[CH:41]=[CH:42][C:43]=1[Cl:44].[BH4-].[Na+]>>[CH:25]1([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][NH:47][CH2:46][CH2:45][C:40]3[CH:41]=[CH:42][C:43]([Cl:44])=[C:38]([Cl:37])[CH:39]=3)=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=Cc1ccc(C2CCC2)cc1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ccc(CCNCc2ccc(C3CCC3)cc2)cc1Cl

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 200 mg of 4-cyclobutyl-benzaldehyde (1.25 mmol), 237 mg of 2-(3,4-dichloro-phenyl)-ethylamine (1.25 mmol) and 71 mg of sodium borohydride (1.87 mmol). The isolated yellow oil (416 mg, 100%) was used in the following step without further purification. 1H NMR (CDCl3, 300 MHz): δ 1.84 (m, 1H), 1.95-2.21 (m, 3H), 2.33 (m, 2H), 2.76 (m, 2H), 2.87 (m, 2H), 3.53 (quint, J=9 Hz, 1H), 3.76 (s, 2H), 7.03 (dd, J=8 and 2 Hz, 1H), 7.19 (m, 4H), 7.29 (d, J=2 Hz, 1H), 7.34 (d, J=8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[CH2:42]([Li])CCC.CI.CO>O1CCCC1.CCCCCC>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([CH3:42])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3cc(C)sc3c12)c1ccccc1
Temperature: -20 °C
Yield: 35 %

Procedure:
500 mg (0.89 mmol) of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide in 50 ml of tetrahydrofuran were lithiated at -70° C. with 1.1 ml of 1.6N n-butyllithium solution in hexane. After stirring at -70° C. for 1 hour 0.17 ml (2.68 mmol) of methyl iodide was added thereto and the mixture was left to warm to -20° C. during 5 hours. Then, 20 ml of methanol were added thereto, the mixture was left to warm to room temperature, treated with 40 ml of aqueous buffer solution pH 4 and extracted with dichloromethane. Drying with sodium sulphate, evaporation of the solvent and chromatography over silica gel with ethyl acetate/hexane 1:1 gave 0.18 g (35%) of 8-(4-benzyloxy-phenyl)-2-methyl-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide as a yellow foam.
Reaction SMILES: ClC([O-])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[CH2:8]1[CH2:9][CH2:10][N:5]2[C:10](=[N:5][CH2:6][CH2:7][CH2:8]2)[CH2:6][CH2:7]1
Reactant: c1ccncc1
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Product: C1CCC2=NCCCN2CC1

Procedure:
Compounds of Formula (I) wherein R1 is --SO2NHCO2R23 may be prepared by reacting an appropriate chloroformate with the sulfonamide (28) in pyridine or in the presence of DBU in THF to afford the desired compound (30), as outlined in Scheme 10. ##STR83##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:13][N:14]=[C:15]=[S:16]>ClCCl>[CH3:13][NH:14][C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:16]
Reactant: Nc1ccccc1N1CCCC1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)Nc1ccccc1N1CCCC1

Procedure:
Reaction of 1-(2-aminophenyl)pyrrolidine (10 g) with methyl isothiocyanate (6.3 g) in dichloromethane (45 ml) at room temperature for 4 days gave 1-methyl-3-[2-(1-pyrrolidinyl)phenyl]thiourea (m.p. 125°-126° C.).
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CS(C)=O>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:14][C:11]5[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=5)[CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CN(Cc2ccccc2)c2nccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3)n2)cc1
Reaction time: 5 h
Yield: 81 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol) and sodium hydroxide (38 mg, 0.96 mmol) were added in dimethylsulfoxide (1 mL), and mixed at 100° C. for 30 minutes. This solution was added with a solution of benzyl bromide (63.1 μL, 0.53 mmol) in dimethylsulfoxide (1 mL) at 100° C. for 30 minutes, followed by stirring for 5 hours. This solution was cooled and added with water (100 mL) and a saturated saline solution, and then allowed to stand for 24 hours. The precipitated crystalline material was purified by column chromatogram (silica gel, hexane: EtOAc=8:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]1[CH2:16][CH:15]([CH2:17][CH3:18])[NH:14][C:13]2[N:19]([CH3:23])[N:20]=[C:21]([CH3:22])[C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O>[CH2:40]([O:39][C:37]([N:14]1[CH:15]([CH2:17][CH3:18])[CH2:16][CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:24])[C:12]2[C:21]([CH3:22])=[N:20][N:19]([CH3:23])[C:13]1=2)=[O:38])[CH3:41]
Reactant: CCOC(=O)Cl
Reactant: CCC1CC(NC(=O)OCc2ccccc2)c2c(C)nn(C)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1c2c(c(C)nn2C)C(NC(=O)OCc2ccccc2)CC1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
(6-Ethyl-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-4-yl)-carbamic acid benzyl ester (0.35 g, 1.08 mmol) obtained in step (ii), dry THF (5 mL) and potassium carbonate (0.45 g, 3.2 mmol) were charged to a flask under a nitrogen atomsphere. This mixture was stirred at room temperature for about 0.5 h, after which time ethyl chloroformate (0.47 g, 3.2 mmol) was added drop-wise. This reaction mixture was then stirred for about 4 h, water was added to the mixture, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×20 mL), dried over sodium sulphate, and concentrated under vacuum to afford the title compound (0.375 g, 88%).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]=[C:6]([NH:13][CH:14]([CH2:16][CH3:17])[CH3:15])[CH:5]=1.[OH-].[Li+].Cl>CO.C1COCC1>[C@@H:14]([NH:13][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]=1)[C:3]([OH:18])=[O:2])([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(C(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(C(F)F)n1

Procedure:
Dissolve 2-sec-butylamino-6-difluoromethyl-isonicotinic acid methyl ester (140 mg, 0.54 mmol) in methanol (2 mL and THF (10 mL). Slowly add 1 N aqueous lithium hydroxide (0.7 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute with ethyl acetate (20 mL) and wash the organic layer with saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.O.Cl.Cl.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>ClC(Cl)Cl>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]([CH:28]([CH3:30])[CH3:29])[C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)N(C(=O)c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
4-fluorobenzoic acid chloride (3.7 cc) is added to a solution of 1-benzyl-4-isopropylaminopiperidine dihydrochloride hydrate (3.83 g) and triethylamine (15 cc) in trichloromethane (50 cc). After 6 hours' stirring at 20° C., water (50 cc) is poured in and the mixture is left to stand for 16 hours. Settling is allowed to take place and the aqueous phase is extracted with trichloromethane (50 cc). The organic phases are washed with water (50 cc), then dried over magnesium sulphate and concentrated to dryness under reduced pressure (5.2 kPa). The oil obtained is chromatographed on a column 4 cm in diameter containing silica gel (200 g), eluting first with a dichloromethane/ethanol mixture (95:5 by volume) (1400 cc) and collecting 60-cc fractions. The fractions between 480 and 1980 cc are concentrated to dryness to give an ocher solid which is recrystallized in a diisopropylether/ethanol mixture (95:5 by volume) to obtain N-(1-benzyl-4-piperidyl)-N-isopropyl-4-fluorobenzamide (1.2 g) in the form of a white solid, m.p. 98° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](Cl)=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:36]=2[F:40])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH2:20]([O:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[C:33]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])=[CH:9][C:10]=3[O:15][CH:16]([CH3:18])[CH3:17])[CH:34]=[CH:35][C:36]=2[F:40])[CH2:31]1)=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)Oc1cc(CC(=O)OC(C)(C)C)ccc1Cl
Reactant: CC1(C)OB(c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Oc1cc(CC(=O)OC(C)(C)C)ccc1-c1ccc(F)c2c1CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C

Procedure:
A mixture under N2 of (4-chloro-3-isopropoxy-phenyl)-acetic acid tert-butyl ester (142 mg, 0.50 mmol, 1.00 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (232 mg, 0.50 mmol, 1.00 eq.), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (18 mg, 0.03 mmol, 0.05 eq.) and potassium carbonate (138 mg, 1.00 mmol, 2.00 eq.) in toluene (2.5 mL) and water (0.25 mL) was stirred at 110° C. for 2 days. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt) to yield the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][C@H:40]([C:48]([OH:50])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:48]([OH:50])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 39.3 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (1 g) prepared by the method described in Preparation 2 and L-phenylalanine (1 g), N-(3-hexadecanoyloxyoctadecanoyl)-L-phenylalanine (500 mg) was obtained as powders according to a similar manner to that of Example 6.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(O)C.N1C=CC=CC=1.Cl.[NH2:23][OH:24]>CCOCC.O>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:23][OH:24])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NO
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CC(C)Cc1ccc(C=NO)cc1
Yield: 84 %

Procedure:
To a solution of 4-isobutylbenzaldehyde (5.0 g, 31 mmol) in a mixed solvent of ethanol (25 ml) and pyridine (25 ml) was added hydroxylamine hydrochloride (2.4 g, 34 mmol) with stirring, and the resulting mixture was stirred at room temperature for 18 hours. After evaporating the reaction mixture in vacuo, the residue thus obtained was diluted with ether, poured into water (150 ml) and extracted with ether. The extract was washed successively with 1N hydrochloric acid and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:19 to 1:9) as the eluent to afford the title compound (4.6 g) in a yield of 84% as a colourless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7](OC)[N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].[CH2:20]([Si](C)(C)C)[CH:21]=[CH2:22].B(F)(F)F.CCOCC.O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:22][CH:21]=[CH2:20])[N:6]1[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:4]
Reactant: C=CC[Si](C)(C)C
Reactant: COC(=O)C1CCCC(OC)N1C(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCC1CCCC(C(=O)OC)N1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 6-methoxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 37, (5.0 g, 18.3 mmol) and allyltrimethylsilane (5.8 mL, 36.6 mmol) in CH2Cl2 (125 mL) at −78° C. is added dropwise boron trifluoride etherate (2.5 mL, 19.7 mmol). After 1 h, the solution is poured into water and extracted with EtOAc. The extracts are washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue is used in the next step without purification.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].NO.[K].[CH3:9][C:10]1[C:14]2[CH2:15][N:16]([C:19]([C:21]3[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:17][CH2:18][C:13]=2[S:12][C:11]=1[C:27]([O:29]CC)=O.C(O)=O>CO.CS(C)=O>[OH:3][NH:2][C:27]([C:11]1[S:12][C:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:15][C:14]=2[C:10]=1[CH3:9])=[O:29]
Reactant: CCOC(=O)c1sc2c(c1C)CN(C(=O)c1cccn1C)CC2
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [K]
Solvent: CS(C)=O
Solvent: CO
Solvent: O=CO
Product: Cc1c(C(=O)NO)sc2c1CN(C(=O)c1cccn1C)CC2
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A mixture of hydroxylamine hydrochloride (2 g, 29 mmol) in methanol (10 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogenous. To the heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). The formation of a white precipitate was observed. After heating at 90° C. for 30 minutes, the mixture was cooled to room temperature and the solids allowed to settle. The resulting solution was assumed to have a 1.7 M concentration of hydroxylamine•potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (1 mL, 1.7 mmol) was added to a solution of ethyl 3-methyl-5-(1-methyl-1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate obtained in the previous step dissolved in methanol (1 mL). After stirring for 30 minutes at room temperature, the reaction was quenched with the addition of formic acid (0.1 mL, 3 mmol). The reaction mixture was concentrated to dryness and the residue obtained redissolved in DMSO (1 mL) and purified by reverse phase Gilson prep-HPLC to afford the title compound as a white solid (7.2 mg, 22.5% over two steps). LCMS (FA) ES+ 320; 1H NMR (400 MHz, DMSO) δ 6.93-6.92 (m, 1H), 6.44 (dd, J=3.8, 1.6 Hz, 1H), 6.06 (dd, J=3.7, 2.6 Hz, 1H), 4.55 (s, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.67 (s, 3H), 2.88 (d, J=2.8 Hz, 2H), 2.22 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:6]1.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([NH:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:14]=1)[NH:11][C:10]([C:7]1[S:8][CH2:9][C@@H:5]([CH2:4][C:3]([OH:26])=[O:2])[N:6]=1)=[CH:18]2
Reactant: COC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 905.1 %

Procedure:
The compound (1.5 g, 3.83 mmol) prepared in Example 26 was dissolved in tetrahydrofuran (100 ml) and methanol (50 ml). Lithium hydroxide monohydrate (640 mg, 15.3 mmol) was dissolved in water (50 ml) and added to the reaction solution, which was then stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran and methanol. 1N hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure and separated by column chromatography to give the title compound (13.1 g, Yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:20][C:21]([OH:23])=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl.Cl.[N:40]1([C:46]2[N:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:20][C:21](=[O:23])[N:43]1[CH2:44][CH2:45][N:40]([C:46]2[N:47]=[CH:48][CH:49]=[CH:50][N:51]=2)[CH2:41][CH2:42]1
Reactant: COc1ccccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1C1(CC(=O)N2CCN(c3ncccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 800 mg of [5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid, which is the compound described in Preparation 1.1 of the brochure WO03/008407 and 488 mg of HOBt/H2O in DMF (8 ml) was added 554 mg of EDC/HCl under ice cooling, then, the reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. The solution was cooled with ice again, 433 mg of 2-piperazin-1-yl pyrimidine was added to the reaction solution, and after warming to room temperature, the reaction mixture was stirred at room temperature for 14 hours. To the reaction solution was added EtOAc, a saturated aqueous solution of K2CO3 and water, and the mixture was stirred for 30 minutes. Liquid separation was performed, the obtained aqueous layer was extracted with EtOAc, the combined organic layer was washed with water and saturated brine, then, was dried over MgSO4, the drying agent was separated by filtration, then the solvent was evaporated under reduced pressure. The obtained residue was subjected to column chromatography (silicagel 60; mobile phase: CHCl3/MeOH/OH=10/1/0.1; v/v/v) to obtain 1.09 g of the title compound (colorless solid).