Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]#[N:7])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]([F:30])([F:29])[C:16]1[CH:17]=[C:18]([N:26]=[C:27]=[S:28])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.[CH3:31]I>CC(C)=O>[F:23][C:22]([F:24])([F:25])[C:20]1[CH:19]=[C:18]([NH:26][C:27]([S:28][CH3:31])=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]#[N:7])[CH:17]=[C:16]([C:15]([F:29])([F:14])[F:30])[CH:21]=1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: CI
Reactant: CS(=O)(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
To a solution of methanesulfonylacetonitrile (0.55 g, 4.6 mmol) in dry acetone (10 ml) first dry potassium carbonate (1.28 g, 9.3 mmol) and then 3,5-bis(trifluoromethyl)phenyl isothiocyanate (1,32 g, 4.7 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 4 h, and then filtered. To the filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried (sodium sulfate) and concentrated. The residue was recrystallised from ethyl acetate/heptane 1:2 to give the title compound (1.55 g, 83%). Mp 129-131° C. 1H NMR (200 MHz, CDCl3): δ=2.35 (s, 3H), 3.25 (s, 3H), 7.77 (s, 2H), 7.80 (s, 1H)H), 9.90 (br s, 1H); EI SP/MS: 404 (M+).
Reaction SMILES: [C:1]([S:4][C@@H:5]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6]CC(O)=O)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[S].[C:41](OC(=O)C)(=[O:43])[CH3:42]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:41]([O:3][CH:1]1[S:4][C@@H:5]([CH2:11][O:12][Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:2]1)(=[O:43])[CH3:42]
Reactant: CC(=O)S[C@H](CCC(=O)O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [S]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1

Procedure:
D-glutamic acid (1) was treated with sodium nitrite in hydrochloric acid to produce (R)-1,4-butyrolactone-4-carboxylic acid (2). Compound 2 was then reduced by borane-dimethyl sulfide complex in THF to give the corresponding (R)-4-(hydroxymethyl)-4-butyrolactone (4), which was subsequently treated with tert-butyldiphenylsilyl chloride in methylene chloride using imidazole as a catalyst to afford (R)-5-O-tert-butyldiphenylsilyl-4-hydroxymethyl-1,4-butyrolactone (53). The protected lactone 53 was opened with sodium hydroxide in ethanol and then converted to the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(R)-hydroxypentanoic acid (54) by reaction with dimethyl sulfate in dimethyl sulfoxide. Compound 54 was transformed into the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(S)-iodopentanoic acid (55) by treatment with triphenylphosphine, imidazole and iodine. Displacement of the iodo group in compound 55 by thioacetate in toluene occurred readily to give the methyl ester of 4-(R)-(acetylthio)-5-[(tert-butyldiphenylsilyl)oxy]pentanoic acid (56). Compound 56 was then treated with 2 equivalents of diisobutylaluminum hydride (DIBAL) in toluene to reductively deprotect the sulfur and reduce the methyl ester to an aldehyde, thereby producing the thiolactol via spontaneous cyclization. The thiolactol was acetylated with acetic anhydride in pyridine to give 1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-4-thio-L-ribofuranose (57): 1HNMR (CDCl3) delta 7.67 (m, 4H, ArH), 7.40 (m, 6H, ArH), 6.10 (m, 1H, 1-H), 3.70 (m, 1H, 4-H), 3.52 (m, 2H, 5-H), 2.20 (m, 2H, CH2), 2.00 (2 s, 3H, CH3CO-), 1.92 (m, 2H, CH2), 1.08 (s, 9H, tert-butyl).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[CH3:27])=O)(=O)OC.O.[NH2:33][NH2:34]>>[C:28]([N:25]1[C:26]([CH3:27])=[C:22]([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:34][N:33]=2)[CH:23]=[N:24]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)c1cnn(C(C)(C)C)c1C)OC
Reactant: NN
Solvent: O
Product: Cc1c(-c2cc3c(nn2)[C@@]2(C)CC[C@@H]3C2(C)C)cnn1C(C)(C)C

Procedure:
yellow crystalline solid. MS (ESI): 325.2 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo [2.2.1]heptane-2,3-dione, [2-(1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][C:16](=[O:20])[NH:17]2)=[C:13]([Cl:21])[N:12]=1.CO.[CH3:24]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O>[Cl:21][C:13]1[N:12]=[C:11]([N:10]2[C:3]3[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=3[N:1]=[CH:24]2)[N:19]=[C:18]2[C:14]=1[NH:15][C:16](=[O:20])[NH:17]2
Reactant: N#Cc1ccc(N)c(Nc2nc(Cl)c3[nH]c(=O)[nH]c3n2)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CS(C)=O
Product: N#Cc1ccc2ncn(-c3nc(Cl)c4[nH]c(=O)[nH]c4n3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
To a solution of crude 4-amino-3-(6-chloro-8-oxo-8,9-dihydro-7H-purin-2-ylamino)benzonitrile (1.23 mmol) in anhydrous DMSO (10 mL) was added methanol (150 mL), followed by anhydrous trimethylorthoformate (5 mL) and p-toluene sulfonic acid (100 mg) and the reaction mixture was stirred under Ar at room temperature for 3 h (LC-MS monitoring). The solvent was removed in vacuo and the residue redissolved in 7 mL of DMSO, then 40 mL of water were added. The pink solid formed was filtered under vacuo using a fine porosity Buchner filter funnel, washed with water, then dried in the vacuum oven at 60° C. to give 0.26 g of the desired product (67% yield on 2 steps). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.24 (s, 1H), 9.00 (s, 1H), 7.91 (d, 1H), 7.69 (d, 1H); MS (EI) m/z 312.2 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:23]=[C:22]([CH3:24])[C:21]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[C:16]2[S:17][C:18]=1[S:19][CH3:20].ClC1C=CC=C(C(OO)=[O:40])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH2:9][O:10][CH3:11])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:14]1[N:15]2[N:23]=[C:22]([CH3:24])[C:21]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[C:16]2[S:17][C:18]=1[S:19]([CH3:20])=[O:40]
Reactant: CCCN(CCC)c1c(C)nn2c(-c3c(OC)cc(COC)cc3OC)c(SC)sc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(CCC)c1c(C)nn2c(-c3c(OC)cc(COC)cc3OC)c(S(C)=O)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
To a dichloromethane (670 μl) solution of 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methyl-2-(methylthio)-N,N-dipropylpyrazolo[5,1-b][1,3]thiazole-7-amine (31.5 mg, 0.068 mmol) was added 3-chloroperbenzoic acid (23.4 mg, 0.136 mmol), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, a saturated aqueous solution of sodium carbonate was added, the mixture was extracted with dichloromethane, and then, the organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered to yield a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform:methanol=12:1) to obtain 7.3 mg (0.0152 mmol) of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]1[N:20]=[CH:19][O:18][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[O:18]1[CH:19]=[N:20][C:16]([CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[N:17]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1ncon1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ncon2)CC1
Temperature: 50 °C
Reaction time: 22 h
Yield: 67.4 %

Procedure:
To a solution of Boc-piperazine (571 mg, 3.07 mmol) and 3-(chloromethyl)-1,2,4-oxadiazole (400 mg, 3.37 mmol) in CH2Cl2 (30 mL) was added triethylamine (1.70 mL, 12.3 mmol). The reaction was stirred for 22 h at 50° C. before concentrated in vacuo to give a crude oily white solid. Purification was accomplished by flash chromatography on silica gel (4×12) eluting with MeOH/CH2Cl2 (5%) to yield the title compound (555 mg, 67%) as a white solid. 1H-NMR (500 MHz, CDCl3) 1.43 (s, 9H, C(CH3)3), 2.52 (app t, J=4.9 Hz, 4H, CH2), 3.45 (app t, J=4.9 Hz, 4H, CH2), 3.78 (s, 2H, CH2C—), 8.71 (s, 1H, CHar); LC-MS (ESI, m/z): Rt=1.67 min-213 (M-tBu)+, 169 (M-Boc)+.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.Cl.[CH3:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17].[C@H:25]1([NH:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([NH2:45])[CH:41]=3)[N:36]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>>[CH3:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:1]([NH:45][C:40]2[CH:41]=[C:42]3[C:37](=[CH:38][CH:39]=2)[N:36]=[C:35]([NH:34][C@H:25]2[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26]2)[CH:44]=[CH:43]3)=[O:12])[CH2:20][CH2:19]1)=[O:17]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)N1CCC(N)CC1
Agent: Cl
Product: COC(=O)N1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 4-amino-piperidine-1-carboxylic acid methyl ester hydrochloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=460.8 (M+H−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28]>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH3:20])=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: COc1ccccc1S
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Product: COc1ccccc1Sc1nc(C(=O)NCC(=O)O)c(O)c2ccccc12

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 2-methoxybenzenethiol under conditions analogous to Example D-110. The final product was crystallized from dichloromethane; MS (−) m/z 383.08 (M−1)
Reaction SMILES: [CH:1]1([CH:6]([F:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]#N)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:19].[Na+].C(O)C[OH:23]>O>[CH:1]1([CH:6]([F:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([OH:23])=[O:19])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(C(F)C3CCCC3)cc2)CC1
Reactant: [OH-]
Reactant: OCCO
Agent: [Na+]
Solvent: O
Product: O=C(O)C1(c2ccc(C(F)C3CCCC3)cc2)CC1
Temperature: 100 °C

Procedure:
To a mixture of 1-{4-[cyclopentyl(fluoro)methyl]phenyl}cyclopropanecarbonitrile (600.0 mg, 0.002466 mol) and 19.4 M of sodium hydroxide in water (0.51 mL) was added 1,2-ethanediol (5 mL, 0.09 mol), and the mixture was refluxed at 100° C. overnight. After cooling down to rt, the reaction mixture was poured into water and extracted with ether. The aqueous phase then was acidified with HCl and extract with ether. Then the organic phase was washed with brine, dried over MgSO4, and concentrated to afford the desired product.
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1(C)[O:12]C(=O)C[C:9](=O)[O:8]1.N1C=CC=CC=1>C(Cl)Cl>[F:1][CH2:2][C:3](=[O:4])[CH2:6][C:7]([O:8][CH3:9])=[O:12]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)CF
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC(=O)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
Fluoroacetyl chloride (7.1 g, 73 mmoles) was added dropwise to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (10.65 g, 74 mmoles) and pyridine (16.85 ml, 210 mmoles) in methylene chloride (75 ml) keeping the temperature below 10°. After stirring for 16 hours at room temperature the solution was diluted with methylene chloride (100 ml and then washed with 1N hydrochloric acid (200 ml) and water (100 ml). The organic extract was dried (Na2SO4) and the solvent removed in vacuo. The residue was dissolved in methanol (150 ml) and the solution heated at reflux for 2.5 hours. Removal of the solvent followed by distillation at 60°-80° (bath temp)/14 mm Hg gave methyl 4-fluoro-3-oxobutanoate (6.4 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17](O)[CH3:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.CCOC(C)=O>[N:34]([CH:17]([CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)[CH3:18])=[N+:35]=[N-:36]
Reactant: CC(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(N=[N+]=[N-])C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3-(1-hydroxyethyl)piperidine (510 mg, 1.94 mmol) in methylene chloride (5 mL) at 0° C. was added diisopropylethylamine (507 μL, 2.91 mmol) followed by methanesulfonyl chloride (180 μL, 2.33 mmol). After stirring 10 min at 0° C., the ice bath was removed and the mixture stirred at room temperature for 30 min The reaction mixture was diluted with EtOAc then was washed with saturated aqueous NaHCO3, 1N HCl, saturated aqueous NaHCO3 and brine, respectively. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was dissolved in DMF (5 mL), and to this was added sodium azide (190 mg, 2.91 mmol). The mixture was heated at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with H2O (3×20 mL) followed by brine. The organic layer was dried over Na2SO4. The crude material was purified by flash chromatography using 1:15 EtOAc:hexane system to obtain 442 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 7.34 (m, 5H); 5.12 (br s, 2H); 3.38 (m, 1H); 1.3 (br s, 3H). Mass spectrum 289.4 (ESI, M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]2)=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-:23].[Na+].[Na+]>O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2([OH:23])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3=[N:2][CH2:3][CH2:4][CH2:5][N:6]23)=[CH:20][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: NCCCn1cc2ccccc2c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: OC1(c2ccc(Cl)cc2)c2ccccc2C2=NCCCN21

Procedure:
The 2-(3-aminopropyl)-1-(4-chlorophenyl)isoindole, hydrochloride (2 gms.) is dissolved in water and neutralized with a sodium carbonate solution. The regenerated base is extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 250 ml. of ethanol and air is bubbled through the solution for 48 hours. The precipitated white crystalline solid is separated by filtration and upon recrystallization from dimethylformamide there is obtained 6-(4-chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol, m.p. 274°-6°C. dec., which is insoluble in water and soluble in dimethylacetamide.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:24]4[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>C1COCC1.CO>[CH3:34][C:25]1[C:24]([NH:23][C:20]2[N:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:35])=[O:2])[CH2:6][CH2:7]4)=[CH:12][CH:13]=3)=[CH:22][CH:21]=2)=[CH:29][CH:28]=[C:27]([C:30]([F:32])([F:31])[F:33])[N:26]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4C)nc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1Nc1ccc(-c2ccc(C3CCC(CC(=O)O)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-{4-[6-(2-Methyl-6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (332 g, 0.69 mmol) was dissolved in THF/MeOH (3:1, 4 mL) and to it was added aqueous LiOH (4M, 1 mL). The mixture was stirred at room temperature for 18 hours, then the organic solvent was removed via rotary evaporation. The remaining crude was diluted with water and the pH was adjusted to 2 with 1M HCl. The resulting precipitate was collected by filtration and dried under vacuum to obtain the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 0.95-1.04 (m, 2 H) 1.44 (dd, J=12.51, 2.91Hz, 2 H) 1.67 (br. s., 1 H) 1.74-1.87 (m, 6 H) 2.47 (m, 1 H) 2.60 (s, 3 H) 7.25 (d, J=8.59 Hz, 1 H) 7.30 (d, J=8.34 Hz, 2 H) 7.56 (d, J=8.34 Hz, 2 H) 7.66 (d, J=8.34 Hz, 1 H) 7.97 (dd, J=8.72, 2.65 Hz, 1 H) 8.48 (d, J=2.27 Hz, 1 H) 8.67 (d, J=8.34 Hz, 1 H) 8.80 (s, 1 H); MS (M+H)+ 470.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCC1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under hydrogen gas at 60 psi at 25° C. for 18 h. The catalyst was then filtered off through a pad of celite, which was washed well with ethyl acetate. The resulting filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (3.52 mg, 53.3%) as a yellow oil: EI-HRMS m/e calcd for C16H23NO2 (M+) 261.1729 found 261.1727.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([OH:42])=O)[C:35]3[C:30](=[CH:31][C:32]([CH3:43])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[CH:62]1([NH:66][C:67]([C@@H:69]2[CH2:73][CH2:72][CH2:71][NH:70]2)=[O:68])[CH2:65][CH2:64][CH2:63]1>C(Cl)Cl.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:44])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([N:70]3[CH2:71][CH2:72][CH2:73][C@H:69]3[C:67](=[O:68])[NH:66][CH:62]3[CH2:63][CH2:64][CH2:65]3)=[O:42])[C:35]3[C:30](=[CH:31][C:32]([CH3:43])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)c3ccc(C)cc3c2)CC1
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3c2)CC1
Reaction time: 2 h

Procedure:
To a solution of 670 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 10 ml of DCM, 418 mg of EDC, 402 mg of pentafluorophenol was added and the reaction mixture was stirred for 2 h. Then, 329 mg of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide hydrochloride and 251 mg of NEM in 1.5 ml of DCM was added. After 16 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.5 g
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:24])=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(CC(=O)Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyloxy-3-methoxyphenylacetic acid (5.0 g, 18 mmol), from Step 2, in THF (40 mL) was added oxalyl chloride (2.54 g, 20 mmol, 1.1 equivalent) followed by a catalytic amount of DMF (~0.2 mL). The resulting mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure to give the title compound which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:45])[C:30]([C:43]#[N:44])=[CH:31][C:32]([NH:35]C(=O)OC(C)(C)C)([CH3:34])[CH3:33])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[ClH:46].C(OCC)C>CO.O1CCOCC1>[ClH:46].[NH2:35][C:32]([CH3:33])([CH3:34])[CH:31]=[C:30]([C:43]#[N:44])[C:29]([NH:28][C@H:26]([CH3:27])[CH2:25][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:12]=2[F:24])=[N:9]1)=[O:45]
Reactant: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)C(C#N)=CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)C(C#N)=CC(C)(C)N
Reaction time: 96 h
Yield: 95 %

Procedure:
To a solution of tert-butyl N-[4-[[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]amino]-3-cyano-1,1-dimethyl-4-oxo-but-2-enyl]carbamate (71 mg, 0.12 mmol) in methanol (1 mL) was added 4N HCl in Dioxane (2 mL). The solution was stirred for 4 days and then it was added dropwise to stirring ethyl ether (70 mL). The suspension was stirred for 30 minutes and then filtered and rinse with ethyl ether (10 mL) to obtain 57 mg (95%) of the title compound as an HCl salt.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:31]=2[N:32]=1.Cl.C(OCC)(=O)C>C(O)=O>[ClH:27].[Cl:37][C:35]1[CH:34]=[CH:33][C:31]2[N:32]=[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=3)[S:29][C:30]=2[CH:36]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1nc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2,6-dichloro-1,3-benzothiazole as starting materials and by an operation similar to that of Example 303-3 was treated with formic acid and 4 mol/L hydrochloric acid-ethyl acetate, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure to give the title compound.