Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([NH:17][C:18](=[O:33])[CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:13](=[O:34])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[O:34]=[C:13]1[CH2:12][NH:11][CH2:16][CH2:15][N:14]1[NH:17][C:18](=[O:33])[CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)NN2CCNCC2=O)CC1

Procedure:
A solution of N-(4-benzyloxycarbonyl-2-oxo-1-piperazinyl)-2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetamide (840 mg) and 10% Pd/C (500 mg) in methanol (35 ml) was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off and the reaction mixture was concentrated to obtain N-(2-oxo-1-piperazinyl)-2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetamide as a colorless syrup. A solution of the resultant 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]-N-(2-oxo-1-piperazinyl)acetamide in ethyl acetate (40 ml) and a 10% aqueous solution of sodium carbonate (40 ml) was combined at 0° C. with 6-chloronaphthalene-2-sulfonyl chloride (470 mg) and stirred at room temperature for 30 minutes. The organic phase was separated, washed with brine, dried and concentrated to obtain a residue, which was purified by a column chromatography on a silica gel (ethyl acetate) and crystallized from ethyl acetate to obtain the title compound (420 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[OH-].[K+].[CH3:22]I>C(O)C>[CH3:1][C:2]1[N:3]([CH3:22])[C:4](=[O:19])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1
Reactant: Cc1nc2c(c(C)c(C)n2-c2ccccc2)c(=O)[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C)n(-c2ccccc2)c2nc(C)n(C)c(=O)c12
Yield: 78.5 %

Procedure:
A mixture of 2,5,6-trimethyl-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidin-4-one (1.46 g, 5.8 mM) (N S Girgis et atl, Synthesis, 1985, p101-104). A mixture of potassium hydroxide flake (327 mg, 5.8 mM) and methyl iodide (0.54 ml, 8.7 mM) in ethanol (37 ml) was heated under reflux for 15 hours. A mixture of methyl iodide (0.5 ml) and potassium hydroxide flake (0.3 g) was added and the reaction mixture heated under reflux for a further 3 hours. The solvent was evaporated and the residual solid suspended in water. The solid was collected by filtration and washed with water to give 2,3,5,6-tetramethyl-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidin-4-one (1.21 g, 78.5% yield) as a light foam solid, m p 215°-217° C.; NMR: DMSO-d6 2.0-2.1(3H, s, CH3), 2.3(3H, s, pyrrole CH3), 2.4(3 H, s, pyrrole- CH3), 3.4-3.5(3H, s, N--CH3), 7.3-7.6(5H, complex, aromatic).
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:31]([F:34])([F:33])[F:32])=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][NH:29][CH3:30])=[CH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16]COC)=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[ClH:1].[C:2]1([C:8]([C:31]([F:32])([F:33])[F:34])=[C:9]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][NH:29][CH3:30])=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCOc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCOC)cc2)cc1
Agent: Cl
Solvent: CO
Product: CNCCOc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(O)cc2)cc1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
1.5 ml of a 9% methanolic hydrochloric acid are added to a solution of 1.50 g (3.28 mmoles) of 2-phenyl-3,3,3-trifluoro-1-[4-(2-methylaminoethoxy)-phenyl]-1-(4-methoxymethoxy-phenyl)-propene in 15 ml of methanol, and the mixture is boiled for one hour. The solution is evaporated to dryness, and the residue is crystallized from isopropanol. 1.06 g (71.6%) of the aimed compound are obtained; m.p.: 213°-218° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6](Cl)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.[H][H].O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Nc1nc(-c2ccc(F)cc2)nc(Cl)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2ccc(F)cc2)nc1N
Yield: 61.5 %

Procedure:
4-amino-6-chloro-2-(4-fluorophenyl)-5-nitropyrimidine (15.3 g, 57 mmol) was dissolved in a mixture of methanol (200 mL) and ethyl acetate (100 mL), and after adding thereto 10% palladium on carbon (2.88 g) and triethylamine (12 mL), the mixture was stirred in a hydrogen stream for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, to which was added water. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then concentrated in vacuo. The residue was purified by silica gel column chromatography (C-300, chloroform:methanol=20:1) to give the title compound as a brown solid (7.16 g, 68%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.C(OC=O)=O.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>C(Cl)Cl.C(OCC)(=O)C.C(O)C.C(O)(=O)C>[C:31]1([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][NH:16][CH:5]=[O:7])=[CH:23][CH:22]=3)[CH2:30][CH2:29]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=COC=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O=CO
Product: O=CNCc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of acetic anhydride (0.36 ml) and formic acid (0.15 ml) was stirred at 50-60° C. for 2 hr, and to the obtained acetic acid and formic acid anhydride was added a solution of 4-((4-(aminomethyl)phenyl)methyl)-1-phenylpiperazine (0.5 g) in methylene chloride (10 ml) under ice-cooling. This reaction mixture was stirred at 5-10° C. for 2.5 hr and left standing at room temperature for 14 hr. To this reaction mixture were added ethanol (20 ml) and ethyl acetate (150 ml) and the mixture was washed with saturated sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (0.56 g). The obtained solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give a pale-brown solid (0.55 g). The obtained solid was crystallized from ethyl acetate-hexane (2:1) to give the title compound (0.41 g) as pale-yellow white crystals, m.p.=108-109° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=2)[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)[N:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[C:23]([O:22][C:21](=[O:27])[NH:20][CH:17]1[CH2:18][CH2:19][CH:14]([CH2:13][N:4]2[C:5]3=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=[C:10]3[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:3]2)[CH2:15][CH2:16]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: OB(O)c1ccccc1
Reactant: CSc1ncc2c(Br)nn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc2c(-c3ccccc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 150 °C
Yield: 88.2 %

Procedure:
A microwave tube was charged with tert-butyl trans-4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.046 g, 0.1 mmol), phenylboronic acid (0.037 g, 0.3 mmol), potassium phosphonate (0.063 g, 0.3 mmol), tetrakis(triphenylphosphine)palladium (0.012 g, 0.01 mmol), dioxane (2 mL) and water (0.5 mL). The mixture was heated in microwave at 150° C. for 10 min. The reaction mixture was poured into water. The aqueous layer was extracted with Et2O (3×). The combined organic layers were dried (Na2SO4), concentrated, and purified by Isco to give tert-Butyl-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.040 g, 88%) as a white solid. MS m/z 454.3 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1C=CC=CC=1>[C:19]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C(OCCO)c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)OCCOC(=O)c1ccccc1

Procedure:
To sixteen grams (0.1 mole) of ethylene glycol monobenzoate containing 20 gms (0.25 mole) of pyridine was added 22 gms (0.1 mole) of lauroyl chloride with stirring. With the final addition of lauroyl chloride approximately 50 ml of benzene was added and the mixture stirred for 1 hour. The pyridine hydrochloride was filtered off and the product water washed to remove residual pyridine. The benzene solution was dried over anhydrous sodium sulfate and percolated through a column filled with activated alumina to removal residual free acid. The solvent was removed at reduced pressure. The product, 2-benzoyloxyethyl laurate, was characterized on the basis of the chemical shifts in the NMR spectrum and the absence of OH-stretching and other bands associated with reaction byproducts or impurities.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N[CH2:13][CH:14]([OH:41])[CH2:15][NH:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][CH2:29]1)=[CH:22]2)=[O:18])CC>>[CH:1]1([CH2:7][NH:8][CH2:13][CH:14]([OH:41])[CH2:15][NH:16][C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([N:28]2[CH2:29][CH2:30][CH:31]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:32][CH2:33]2)=[CH:22]3)=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: CCCNCC(O)CNC(=O)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Product: O=C(NCC(O)CNCC1CCCCC1)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1

Procedure:
substituting propylamine for cyclohexylmethylamine, N-{3-n-propylamino-2-hydroxypropyl}-4-benzylpiperidinyl indole-5-carboxamide:
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH2:3][C:4]1[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:39]=[CH:38][C:22]([C:23]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:24])=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1CCCCC1>[N:25]1([C:23]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=4[CH2:3][C:2]([NH2:1])=[O:44])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=3)=[CH:39][CH:38]=2)=[O:24])[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C(=O)N3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate (A26) (0.182 g, 0.297 mmol) in DCM (4 mL) was added TFA (1 mL) and the resulting mixture was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (10 mL) and 2 M aqueous NaOH (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then the combined organic fractions were washed with water (10 mL), brine (10 mL) and dried over MgSO4. The volatiles were removed in vacuo to give a yellow solid, which was suspended in cyclohexane and then filtered to give the title compound 6 as a white solid (0.132 g, 87%); 1H NMR (400 MHz, d4-MeOH) δ 8.62 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 7.27 (d, J=6.3 Hz, 1H), 7.23-7.15 (m, 3H), 3.68 (s, 2H), 3.82-3.46 (m, 4H), 3.23-3.15 (m, 2H), 3.12 (dd, J=9.8, 5.4 Hz, 2H), 3.02-2.71 (m, 4H). LCMS-A: rt 4.676 min; m/z 513.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Mg]Br)[CH3:19]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@H:14]([OH:15])[CH2:18][CH3:19])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CC[C@@H](O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (15.5 g; CAS 147959-19-1) in dry diethyl ether (100 ml) under an argon atmosphere at room temperature was added dropwise a solution of ethylmagnesium bromide in diethyl ether (42.6 ml, 3 M solution) and stirring continued for 1 hour. The reaction mixture was then quenched by careful addition of water (10 ml) and the mixture was then filtered through decalite. The filtrate was washed sequentially with water and with saturated brine and then the organic phase was separated, dried over sodium sulphate, filtered and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→50:50) to give (S)-4-((R)-2-hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (7.30 g) from fractions eluting first and (S)-4-((S)-2-hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (6.44 g) from fractions eluting later, both compounds as colourless oils. (S)-4-((R)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.52 (1H, br. D, J=3.3 Hz), 4.23 (1H, m), 4.00 (1H, dd, J=8.7 & 5.4 Hz), 3.66 (1H, d, J=8.7 Hz), 3.40 (1H, m), 1.79 (1H, td, J=11.4 & 2.1 Hz), 1.60-1.44 (16H, m), 0.95 (3H, t, J=7.5 Hz). (S)-4-((S)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.12 (1H, m), 3.98 (1H, dd, J=9.0 & 5.7 Hz), 3.82 (1H, m), 3.55 (1H, m), 2.88 (1H, br. s), 1.79 (1H, m), 1.70-1.40 (16H, m), 0.95 (3H, t, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:36])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19](=[O:35])[C:20]4[C:25]([F:26])=[CH:24][CH:23]=[C:22]([NH:27][S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[C:21]=4[F:34])[CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19](=[O:35])[C:20]4[C:25]([F:26])=[CH:24][CH:23]=[C:22]([NH:27][S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[C:21]=4[F:34])[CH:16]=3)[NH:11][CH:10]=2)=[O:36])=[CH:6][CH:7]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(O)c4ccc(Cl)cc4)c3c2)c1F
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)c4ccc(Cl)cc4)c3c2)c1F
Temperature: 25 °C
Reaction time: 60 h
Yield: 25 %

Procedure:
MnO2 (0.016 g, 0.19 mmol) was added to N-(3-((4-chlorophenyl)(hydroxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.004 g, 0.0075 mmol) in CHCl3 (0.2 mL). The reaction mixture was stirred at room temperature for 60 hours. The contents were filtered through a plug of silica to afford N-(3-(4-chlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (1 mg, 25%) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.94-8.94 (m, 1H), 8.68-8.60 (m, 1H), 8.04 (s, 1H), 7.83-7.86 (m, 2H), 7.63-7.69 (m, 1H), 7.56-7.58 (m, 2H), 7.11-7.17 (m, 1H), 3.10-3.14 (m, 2H), 1.85-1.90 (m, 2H), 1.04-1.08 (m, 3H); m/z (APCI-neg) M−1=531.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([S:23][CH3:24])=[CH:18][CH:19]=2)[N:14]=1.CC(O)C>O>[CH3:24][S:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CSc1ccc2ccc(N)nc2n1
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(SC)nc3n2)cc1
Temperature: 4 °C
Yield: 83.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (11.8 g), N,N'-carbonyldiimidazole (12.6 g) and 2-amino-7-methylthio-1,8-naphthyridine (9.6 g). The product produced by precipitation in water (15.8 g; m.p. 100° C.) is dissolved in boiling 2-propanol (180 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with 2-propanol (10 cc) and then isopropyl ether (2×10 cc), and dried at 40° C. under reduced pressure (0.067 kPa . N-(7-methylthio-1,8-naphthyridin-2-yl)-4-methoxybenzamide (13.6 g) is produced, m.p. 130° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1>>[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(CCl)cc1
Reactant: Fc1cccc(N2CCNCC2)n1
Product: CC(=O)N[C@@H](C)c1ccc(CN2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using (S)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine, the title compound was obtained as a pale-yellow oil.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:24].N([O-])=O.[Na+]>O>[O:24]=[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][NH:3]1
Reactant: O=S(=O)(O)O
Reactant: Nc1ncc(-c2c(-c3ccccc3)nn3ccccc23)cn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1ncc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]1
Reaction time: 2 h

Procedure:
To a mixture of 3-(2-aminopyrimidin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.70 g) and 50% sulfuric acid (5.6 ml) was gradually added aqueous solution (5.6 ml) of sodium nitrite (1.68 g) at 5° to 10° C., and the resultant mixture was stirred for 3 hours at the same temperature and then for 2 hours at room temperature. To the reaction mixture was added water (14 ml). The precipitates were collected by filtration subjected to a column chromatography on silica gel (14 g) with a mixture of chloroform and methanol (10:1) as an eluent. The fractions containing the objective compound were combined and the solvent was evaporated in vacuo to give 3-(2-oxo-1,2-dihydropyrimidin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.44 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[F:27])[N:23]([CH3:28])[C:22](=[O:29])[CH2:21][CH2:20]3)[CH:16]=1)(C)(C)C.[ClH:31]>CO>[ClH:31].[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[F:27])[N:23]([CH3:28])[C:22](=[O:29])[CH2:21][CH2:20]3)[CH:14]=[N:13][CH:12]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)OC(C)(C)C)c3)c(F)cc21
Agent: Cl
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)c(F)cc21

Procedure:
In analogy to the procedure described for the preparation of example 42, reaction of {2-[5-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yloxy]-ethyl}-carbamic acid tert-butyl ester (example 232) with hydrogen chloride (in dixoane) in methanol gave the title compound as light yellow solid. MS: 316.5 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:19][O:20][P:21]([O-:24])[O:22][CH3:23]>C(OCC)(=O)C>[CH3:19][O:20][P:21]([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:24])[O:22][CH3:23]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COP([O-])OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77 %

Procedure:
3-Nitrobenzaldehyde (20 g, 0.132 mol) was dissolved in 100 mL of ethyl acetate. Triethylamine (22 mL, 0.158 mol, 1.2 eq) was added, followed by dimethylphosphite (15.7 mL, 0.171 mmol, 1.3 eq) and the mixture was stirred at room temperature. After 2 hours the mixture was diluted with 150 mL of ethyl acetate and washed with saturated aqueous ammonium chloride (2×50 mL) and water (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was treated with ethyl ether to obtain a beige solid, which was filtered and dried under vacuum at 40° C. for 1 h (26.7 g, 77% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]4[C@@H:25]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH2:24][N:23]([C@@:33]([CH:47]5[CH2:50][CH2:49][CH2:48]5)([CH3:46])[C:34]([O:36]CC5C=CC(OC)=CC=5)=[O:35])[CH2:22]4)[CH2:16][CH2:15]3)=[CH:12][N:13]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C@@H:21]4[C@@H:25]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH2:24][N:23]([C@@:33]([CH:47]5[CH2:48][CH2:49][CH2:50]5)([CH3:46])[C:34]([OH:36])=[O:35])[CH2:22]4)[CH2:18][CH2:19]3)=[CH:12][N:13]=[C:7]2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(COC(=O)[C@@](C)(C2CCC2)N2C[C@H](CN3CCC(c4cnc5cc(C(C)(C)C)ccn45)CC3)[C@@H](c3cccc(F)c3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(C)c1ccn2c(C3CCN(C[C@H]4CN([C@@](C)(C(=O)O)C5CCC5)C[C@@H]4c4cccc(F)c4)CC3)cnc2c1
Yield: 91.1 %

Procedure:
The title compound was prepared from 40 mg of α-(R)-(3-(S)-((4-(7-t-butyl-imidazo[1,2-a]pyridin-3-yl)-piperidine-1-yl)methyl)-4-(S)-(3-fluorophenyl) pyrrolidin-1-yl)-cyclobutylpropanoic acid, 4-methoxy-benzyl ester (from Step D), 2 mL of TFA and 0.4 mL of anisole, using a procedure analogous to that described in Example 235, Step D to provide 30 mg of the title compound as a foamy solid. ESI-MS 561 (M+H); HPLC A 1.92 min.