Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1.[ClH:19].[C:20](OCC)(=O)C>CN(C)C=O.O1CCOCC1.IC>[ClH:19].[ClH:19].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH3:20])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccnc(-c2cccc(NC(N)=S)c2)c1
Agent: Cl
Solvent: CI
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccnc(-c2cccc(NC(=N)SC)c2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of N-(3-(4-methoxypyridin-2-yl)phenyl)thiourea (122 mg) in N,N-dimethylformamide (2.5 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.25 ml) and iodomethane (0.156 ml), and the mixture was stirred at ambient temperature for 5 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration. The precipitate was dissolved in water, and to the solution was added a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(3-(4-methoxypyridin-2-yl)phenyl)-S-methylisothiourea dihydrochloride (153 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:38]1[CH2:47][C@H:46]([OH:48])[CH2:45][C@H:39]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:28]1[CH:33]=[C:32]([CH:34]=O)[CH:31]=[CH:30][C:29]=1[O:36][CH3:37].[NH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:24])[F:25])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:38]1[CH2:47][C@H:46]([OH:48])[CH2:45][C@H:39]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:28]1[CH:33]=[C:32]([CH2:34][N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[CH:31]=[CH:30][C:29]=1[O:36][CH3:37]
Reactant: C1CCNCC1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CN4CCCCC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg of the compound obtained in Step 198-3 in CHCl3 (3.5 ml) was added piperidine (0.14 ml) and acetic acid (0.24 ml), and the reaction mixture was stirred for 30 minutes. To the solution was added 327 mg of sodium triacetoxy borohydride, and the reaction mixture was further stirred for 15 hours. After the end of the reaction, water was added to the solution and the resulting mixture was extracted with CHCl3. The organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: MeOH/CHCl3=1/99; v/v) to obtain respectively 94 mg (Isomer A: colorless amorphous) and 217 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[NH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[NH:17][C:16]=2[Br:25])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncnc2[nH]cc(-c3cccc(OCc4ccccc4)c3)c12
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]c(Br)c(-c3cccc(OCc4ccccc4)c3)c12
Reaction time: 8 h

Procedure:
To a solution of 20 g (63.2 mmol) 5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (see WO 97/28161) in 1 l dry N,N-dimethylformamide, 12.4 g (69.5 mmol) N-bromosuccinimide are added at ca. 10° C. Stirring was continued at ca. 10° C. for 30 min and overnight at RT. The precipitate formed is filtered off and washed thoroughly with N,N-dimethylformamide and hexane. After drying for 24 h at 30-35° C. under vacuum, the title compound is used in the next step without further purification. Additional material can be obtained from the mother liquor through chromatography on silicagel. Analytical HPLC: tR=10.07 min (Grad 1); ES-MS: m/eo=394.9 and 396.9; NMR (DMSO-d6): 12.55/s (NH); 8.06/s (1H), 7.25-7.5/several m's (6H), 7.07/“d” (1H); 7.03/s (1H); 6.98/“d” (1H); 5.5-6.0/b (NH2); 5.12/s (2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9]2.[C:23](=O)([OH:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].O1CCCC1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[N:11]([C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc([N+](=O)[O-])c2[nH]1
Reactant: CC(C)(C)OC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OCCOC)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a mixture of ethyl 5-(2-methoxyethoxy)-7-nitro-1H-indole-2-carboxylate (3.08 g), t-butyl bicarbonate (4.37 g) and tetrahydrofuran (100 mL) was added N,N-dimethyl-4-aminopyridine (122 mg), and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was washed successively with 10% aqueous citric acid solution, aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography to give the title compound (3.93 g, yield 96%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[O:7])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH2:21].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH:21][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: O=C1CCCCC1C(=O)c1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: COc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To a mixture of 2-(4-fluorobenzoyl)cyclohexanone (99.0 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (75.6 g, 48.1%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[N:26][C:27]=3[NH2:29])[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:21]=2)=[CH:16][C:15]=1[O:43][CH3:44]>N1C=CC=CC=1>[NH2:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:10]([C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:11])=[C:15]([O:43][CH3:44])[CH:16]=3)[C:28]=12
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Reaction time: 5 h
Yield: 60.2 %

Procedure:
trans-2-phenyl-1-cyclopropanecarbonyl chloride (42 mg, 0.231 mmol) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.229 mmol) in pyridine (1.0 mL). After 5 hours, the solvent was evaporated and the residue was purified by flash column chromatography to give N1-{4-[4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-trans-2-phenylcyclopropane-1-carboxamide (80 mg, 60%). 1H NMR (CDCl3) δ 1.42 (m, 1H), 1.77 (m, 2H), 1.85 (m, 2H), 2.06 (m, 3H), 2.36-2.45 (m, 8H), 2.62 (m, 1H), 3.00 (m, 2H), 3.10 (m, 2H), 3.96 (s, 3H), 4.75 (m, 1H), 5.54 (bs, 2H), 7.14-7.33 (m, 7H), 8.10 (s, 1H), 8.36 (s, 1H), 8.54 (d, J=8.50, 1H). LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+=581.4, Rt=1.77 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[N:16]=1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].N1(C(N2C=CN=C2)=O)C=CN=C1>ClCCl>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:34](=[O:35])[CH2:33][C:31]#[N:32])[CH2:26]3)[N:16]=[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][C:2]=3[F:1])[C:23]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2[C@@H]1CCCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.1 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-(2-fluoro-4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (190 mg, 0.47 mmol, 1.00 equiv) in dichloromethane (50 mL), 2-cyanoacetic acid (60 mg, 0.71 mmol, 1.50 equiv), and 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (114 mg, 0.70 mmol, 1.50 equiv). The resulting solution was stirred for 24 h at room temperature and then diluted with dichloromethane. The resulting mixture was washed with NH4Cl and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 100 mg (45%) of 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:17])[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:16][C:13]([C:11]1[N:12]=[C:8]([NH:7][C:6](=[O:5])[OH:17])[S:9][CH:10]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(C)(C)O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1csc(NC(=O)O)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 30.1 %

Procedure:
[4-(1-Hydroxy-1-methyl-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (250 mg, 0.92 mmol) was taken into dry dichloromethane and cooled in an ice bath. To this was added trifluoroacetic acid and the mixture stirred at 0° C. for 4 hours. The mixture was evaporated and the residue partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated out and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and evaporated. Chromatography of the residue over silica gel gradient eluted with 1:99 up to 3:97 methanol in dichloromethane gave [4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-carbamic acid (56 mg, 39%) as a white solid.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[CH2:8]([O:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O>[Cl:1][CH:2]([CH3:6])[C:3]([NH:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: CC(Cl)C(=O)Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(Cl)C(=O)NOCc1ccccc1
Yield: 48 %

Procedure:
Prepared in 48% yield (0.97 g, 3.9 mmol) from the reaction of 2-chloropropanoyl chloride (1.03 g, 8.2 mmol) with O-benzylhydroxylamine, hydrochloride (1.03 g, 8.2 mmol) via general procedure A. Rf=0.43 (3:1, hexanes:EtOAc); mp=70.1-72.8° C.; 1H-NMR (500 MHz, CDCl3): δ 9.09 (br s, 1H), 7.44-7.35 (m, 5H), 4.93 (s, 4H), 4.33 (q, J=7.1 Hz, 1H), and 1.69 (d, J=6.8 Hz, 3H); 13C-NMR (126 MHz, CDCl3): δ 167.1, 134.8, 129.5, 129.1, 128.8, 78.5, 53.2, and 22.3; FT-IR: (neat): 3112 (br), 2931, 1678 (s), 1494, 1454, 1364, 1222, 1204, 1074 cm-1. HRMS ESI-MS: calculated for C10H12ClNNaO2 (M+Na)+, 236.0449; found 236.0445.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=C)=[C:8]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1.[OH2:23]>C(Cl)(Cl)(Cl)Cl.CC#N.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:23])=[C:8]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1
Reactant: O
Reactant: C=Cc1ccc(CCC(=O)OC)cc1P(=O)(OCC)OCC
Solvent: CC#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)c1cc(CCC(=O)OC)ccc1C=O
Yield: 76 %

Procedure:
3-(3-Diethoxyphosphoryl-4-vinyl-phenyl)propionic acid methyl ester (200 mg, 0.61 mmol) was dissolved in 3.9 mL CCl4 and 3.9 mL of MeCN. NaIO4 (388 mg, 1.81 mmol) was dissolved in 6 mL H2O and was added. The mixture was stirred vigorously and RuCl3 (10 mg, 0.05 mmol) was then added and the mixture was stirred for 1 hr at rt The reaction was diluted with DCM, organic layer was separated, dried Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (4/1 EtOAc/hexane, Rf=0.37) to give pure product as an oil, 153 mg (yield 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:21])([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C(OCC)=O)=[O:5])[CH3:2].[OH-].[Na+].Cl>C(O)C>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([C:20](=[O:21])[CH2:19][CH:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: CCOC(=O)CCC(CC(=O)c1ccc([N+](=O)[O-])cc1)(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCC(CC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OCC
Yield: 71.9 %

Procedure:
A solution of diethyl 2-ethoxycarbonyl-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate (2.5 g, 5.9 mmol) in ethanol:1N NaOH (2:1, 105 ml) was stirred 20 hours at room temperature and then acidified to pH 1.5 with concentrated HCl and concentrated in vacuo. The residue was dissolved in diglyme (50 ml) and the solution stirred at reflux for 20 minutes and then concentrated in vacuo. The residue was then dissolved in ethanol (50 ml). HCl gas was bubbled into the solution for 30 seconds, and the solution was stirred at room temperature over the weekend and then concentrated in vacuo. The product was taken up in diethyl ether (100 ml), washed with saturated sodium bicarbonate solution (35 ml), dried (MgSO4), and concentrated in vacuo. Purification by chromatography on silica gel eluting with ethyl acetate:hexane (1:4) gave diethyl (RS)-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate (1.49 g) as an oil 1NMR (DMSO-d6, 200 MHz) δ: 1.13 (t, J=7 Hz, 3H, CH3), 1.19 (t, J=7 Hz, 3H, CH3), 1.74-1.93 (m, 2H, CH2), 2.35-2.45 (m, 2H, CH2CO2), 2.82-3.00 (m, 1H, CH), 3.24-3.67 (m, 2H, COCH2), 4.03 (q, J=7 Hz, 2H, ester CH2), 4.04 (q, J=7 Hz, 2H, ester CH2), 8.20 (d, J=9 Hz, 2H, Ar), 8.33 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C17H21NO7.1/4H2O: C, 57.38; H, 6.09; N, 3.94. Found: C, 57.35; H, 6.11; N, 3.89.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[C:27]1([CH:37]=O)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:37][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2cccc3ccccc23)CC1
Yield: 59.6 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.1 g) as starting compound and 1-naphthaldehyde (1.13 g) were reacted and treated in the same manner as in Example 121 to give 1.71 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(1-naphthylmethylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26]([OH:28])=O)=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:62][O:63][C@H:64]([CH2:67][N:68]1[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]1)[CH2:65][NH2:66].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26]([NH:66][CH2:65][C@H:64]([O:63][CH3:62])[CH2:67][N:68]4[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]4)=[O:28])=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Reactant: CO[C@@H](CN)CN1CCN(C)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@@H](CN4CCN(C)CC4)OC)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
7-[[(7R)-7-Ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (94 mg, 0.23 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (74 mg, 0.23 mmol) were dissolved in 20 mL of anhydrous dichloromethane followed by the addition of diisopropylethylamine (0.1 mL, 0.50 mmol) and (2S)-2-methoxy-3-(4-methylpiperazin-1-yl)propan-1-amine 38b (43 mg, 0.23 mmol) successively. The reaction solution was stirred for 2 hours. The resulting solution was added with 30 mL of saturated sodium carbonate solution and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2S)-2-methoxy-3-(4-methylpiperazin-1-yl)propyl]-2,3-dihydrobenzofuran-4-carboxamide 39 (35 mg, yield: 26.5%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([N:39]2[C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:31])[CH3:1])[CH:11]=[CH:10][CH:9]=4)[CH2:13][CH2:14]3)=[C:23]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: (M+H)+. 570.3.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][CH:27]([CH3:31])[CH2:28][NH:29]N.CCN(CC)CC>C(O)C.Cl>[CH3:26][CH:27]([CH3:31])[CH2:28][N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: CC(C)CNN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)Cn1nccc1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 53.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (500 mg, 1.5 mmol) in ethanol (10 mL) were added 2-methylpropylhydrazine hydrochloride (274 mg, 2.2 mmol) and Et3N (0.41 mL, 3.0 mmol). The mixture was stirred at 100° C. for 5 h. The mixture was diluted with 1N HCl aqueous solution, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=10/90 to 0/100) and recrystallized with AcOEt/i-Pr2O to yield the title compound as a pale yellow solid (289 mg, 54%).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)=O.[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)=[O:27])[CH3:24]>CN1C(=O)CCC1.O>[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:4]2[N:9]=[C:8]([C:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]4=[N:12][CH:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CS(=O)c1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(C(C)(C)O)cccn34)n2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
A mixture of 2-[3-(2-methylsulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (0.19 g), 4-amino-cyclohexanecarboxylic acid ethyl ester (0.31 g) in NMP (2 mL) was stirred at 100° C. for 3 h. The reaction mixture was cooled to RT, and diluted with water. The resulting solid was filtered and dried, then purified by ISCO using 100% DCM to 10% MeOH/DCM. Fractions were collected, concentrated, and titurated with EtOAc/hexane. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide 4-{4-[8-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (0.215 g).