Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si]1(OC(C)C)N(C)[C@@H](C)[C@H](C2C=CC=CC=2)O1)[CH:2]=[CH2:3].[CH:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CCOC(C)=O>C1(C)C=CC=CC=1>[C:24]1([CH2:23][CH2:22][C@@H:21]([OH:30])[CH2:3][CH:2]=[CH2:1])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=CCCc1ccccc1
Reactant: C=CC[Si]1(OC(C)C)O[C@@H](c2ccccc2)[C@H](C)N1C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CC[C@H](O)CCc1ccccc1
Temperature: 21 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
Enantioselective allylation of dihydrocinnamaldehyde to give (3R)-1-phenyl-hex-5-en-3-ol: To a solution of (4S,5S)-2-Allyl-2-isopropoxy-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (0.437 g, 1.5 mmol) in toluene (2.5 mL) was added dihydrocinnamaldehyde (0.132 mL, 1.0 mmol). The mixture was allowed to stir at ambient temperature (˜21° C.) for 18 hours. To this solution was added 1N HCl (4 mL) and EtOAc (4 mL) and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organics were dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (5% EtOAc/hexanes) to afford 0.119 g (69%) of (3R)-1-phenyl-hex-5-en-3-ol in 94% enantiomeric excess (ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[O:28][CH3:27])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccccc1C=O
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccccc3OC)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 2-methoxybenzaldehyde to provide 21 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]([C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH3:16])=[C:11]([Cl:17])[CH:10]=1)=O)[C:3](O)=[O:4].Cl.[NH2:19][NH2:20]>C(O)C.O>[Cl:17][C:11]1[CH:10]=[C:9]([C:7]2[CH:6]=[CH:2][C:3](=[O:4])[NH:19][N:20]=2)[CH:14]=[C:13]([Cl:15])[C:12]=1[CH3:16]
Reactant: Cc1c(Cl)cc(C(=O)CC(Cl)C(=O)O)cc1Cl
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 66.6 %

Procedure:
1.48 g (0.005 mole) of 2-chloro-4-(3,5-dichloro-4-methylphenyl)-4-oxobutyric acid, prepared as described in step (a) above, were dissolved in a solution of 0.68 g (0.01 mole) of hydrazine hydrochloride in 15 ml of ethanol and 2 ml of water; the solution was then heated under reflux for 3 hours, after which it was cooled. The solvent was then distilled off and 20 ml of water were added to the residue. The mixture was stirred and the resulting crystals were collected by filtration, washed successively with water and with a small amount of diethyl ether and then dried, giving 0.85 g (yield 66.7%) of the desired 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone, having the same properties as the product obtained in the preceding Examples.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=O)[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])=[N:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1Cl
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2Cl)n(-c2cccc(Cl)c2)n1
Yield: 22 %

Procedure:
Starting from 1 g (3.46 mmol) of 4-(2,4-dichlorophenyl)-2,4-dioxobutanoic acid ethyl ester from example 11A and 842.25 mg (4.7 mmol) of 3-chlorophenylhydrazine hydrochloride, 297.5 mg (0.75 mmol, 22% yield of theory) of product are obtained according to the method described in example 4A and after purification by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)CC(OC(C)=O)C(Cl)(Cl)Cl
Yield: 91 %

Procedure:
A solution of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene (65 g) in pyridine (100 ml) was heated with acetic anhydride (65 ml) at 100° C. for 3 hours. The reaction mixture was poured into water (600 ml) and the resulting solution extracted with ether (3×200 ml). The combined other phases were dried over MgSO4 and the ether was evaporated. Distillation and re-distillation yielded 71.4 g (91%) of 1,1,1-trichloro-2-acetoxy-4-methyl-4-pentene. B.p. 92°-96° C./11 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][CH:23]2O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:23]2[C:24]3[C:20](=[C:19]([O:18][CH3:17])[CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CCO[C@@H](CC(=O)OC)c1ccc(O)cc1
Reactant: COc1cccc2c1CCC2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCO[C@@H](CC(=O)OC)c1ccc(OC2CCc3c(OC)cccc32)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.446 mmol) produced in Example 41 (41C) and 4-methoxy-1-indanol (110 mg, 0.669 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (87 mg, yield: 53%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:31])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([S:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:18])[C:11]([N+:28]([O-])=O)=[CH:10][N:9]=1)(=[O:3])[CH3:2].[Cl-].[NH4+].C(O)C>O>[C:1]([NH:4][C@@H:5]([CH3:31])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([S:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:18])[C:11]([NH2:28])=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(C)=O)ncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(C)=O)ncc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of 2-ethylhexyl 3-((2-(((2S)-2-acetamidopropyl)oxy)-5-nitropyridin-4-yl)sulfanyl)propanoate (3.38 g), reduced iron (2.07 g), ammonium chloride (0.397 g), ethanol (40 mL) and water (10 mL) was stirred overnight at 80° C. The precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.83 g).
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][CH:22]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:23]([O-:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>Cl>[C:14]([O:18][C:19]([NH:21][CH:22]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C(=O)[O-])C1CCCC1
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1CCCC1

Procedure:
tert-Butoxycarbonylamino-cyclopentyl-acetate dicyclohexylammonium salt (2.85 g, 6.6 mmol; commercially available from Bachem) was dissolved in 1M HCl. Immediate EtOAc extractions were washed with brine and dried over anhydrous Na2SO4. Following concentration in vacuo, tert-Butoxycarbonylamino-cyclopentyl-acetic acid was isolated as a white foamy solid (1.6 g, quant) and was used without further purification. LCMS found 241.9
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1)[CH2:5][NH:6][C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:10][CH:9]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl.C(OCC)(=O)C>[C:40]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][C:4]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[C:2]([F:1])[CH:3]=3)=[O:20])=[CH:9][N:10]=2)[CH2:15][CH2:16]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2ccc(CNC(=O)c3ccc(N4CCNCC4)nc3)cc2F)ccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(C(=O)NCc3ccc(-c4ccnc(C)c4)c(F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude N-(3-fluoro-4-(2-methylpyridin-4-yl)benzyl)-6-(piperazin-1-yl)nicotinamide 20-3 (10 mg, 0.025 mmol) and DIEA (21.8 μL, 0.125 mmol) in dichloromethane (1.0 mL) was added acetyl chloride (3.6 μL, 0.05 mmol), and the solution was stirred 30 minutes at room temperature. The solution was diluted with ethyl acetate (30 mL) and washed with 10% Na2CO3 aqueous solution and water. After the organic phase was dried over Na2SO4, the solvent was evaporated under reduced pressure and the residue subjected to preparative reverse phase HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(3-fluoro-4-(2-methylpyridin-4-yl)benzyl)nicotinamide 20 as a solid. MS m/z 448.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.63 (d, 1H), 8.54 (d, 1H), 7.98 (dd, 1H), 7.42 (dd, 1H), 7.33 (bs, 1H), 7.29-7.25 (m, 1H), 7.22 (dd, 1H), 7.16 (dd, 1H), 6.64 (d, 1H), 6.61 (t, 1H), 4.67 (d, 2H), 3.78-3.70 (m, 4H), 3.65-3.54 (m, 4H), 2.61 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1.Cl[CH2:12]I.C([Zn]CC)C>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C=COc1ccc(Br)cc1
Reactant: ClCI
Agent: CC[Zn]CC
Solvent: ClCCCl
Product: Brc1ccc(OC2CC2)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a 0° C. solution of 1-bromo-4-vinyloxy-benzene (31.75 g, 159.51 mmol) and chloroiodomethane (101.3 g, 574.2 mmol) in 1,2-dichloroethane (410 mL), slowly add diethylzinc (1 M in heptane, 380 mL) over 1 hr while maintaining the temperature below 5° C. Stir the white mixture at 0-5° C. for 2 hours. Quench the reaction slowly at 5° C. with aqueous saturated ammonium chloride (400 mL, exothermic) and separate the layers. Extract the aqueous layer with diethyl ether (2×200 mL). Combine the organic layers, wash with saturated ammonium chloride (400 ml), dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound (33 g, 97%) as an oil: GCMS: 212.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[N:2]1.[CH3:10][O:11][C:12](=[O:30])[C:13]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH2:14]>CO>[CH3:10][O:11][C:12](=[O:30])[CH:13]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:14][N:6]1[CH2:7][CH2:8][C:9]2[NH:1][N:2]=[CH:3][C:4]=2[CH2:5]1
Reactant: c1n[nH]c2c1CNCC2
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)C(CN1CCc2[nH]ncc2C1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (160 mg) in 2.5 mL methanol was added 2-(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (400 mg). The reaction was concentrated to approximately 1.5 mL by application of a gentle stream of nitrogen. The solution was stirred at room temperature overnight. The reaction was concentrated, dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was pure enough to use without purification. 1H-NMR (CDCl3, 500 MHz) δ 1.44 (s, 9H), 2.73 (m, 3H), 2.91 (m, 1H), 3.06 (dd, J=13.4, 8.6, 1H), 3.22 (dd, J=13.4, 8.2, 1H), 3.54 (d, J=13.4, 1H), 3.63 (d, J=13.4, 1H), 3.71 (s, 3H), 5.11 (dd, J=8.5, 5.2, 1H), 7.25 (s, 1H). Mass spec.: 425.23 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][SiH:14](Cl)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][Si@H:14]([CH2:6][CH2:7][CH2:2][CH2:3][CH3:4])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(OCC2CC[SiH](Cl)CC2)cc1F
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](COc2ccc(F)c(F)c2)CC1

Procedure:
3.0 g (20 mmols) of n-pentyl bromide was dropped in a mixture of 0.5 g of magnesium (21 mmols) and 50 ml of tetrahydrofuran (hereinafter referred to simply as THF) to obtain a Grignard reagent. Subsequently, the solution was dropped in 50 ml of a THF solution of 5.5 g (20 mmols) of 4-(3,4-difluorophenyloxymethyl)-1-chloro-1-silacyclohexane to obtain a crude product. This product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was after-treated by a usual manner and isolated through column chromatography to obtain 5.6 g (yield: 89%) of the intended trans isomer product The results of measurement of a phase transition temperature and the IR analysis are shown below.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-].[Na+].[O-:27]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>CO.O.OO>[CH3:24][C:8]1[C:9]([CH2:13][S+:14]([O-:27])[C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)=[N:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=S([O-])([O-])=S
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[nH]2)c1C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
2 g of 2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 1.93 g of45% NaOH in 14 ml water was added while stirring. 0.09 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.66 g H2O2 (50% aqueous solution), and further diluted with 10 ml of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes while stirring. 10 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Rabeprazole with a yield of about 88% (LC purity>95%).
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:41]1([C:44]2[C:45]([O:54][CH2:55][C:56]3([F:62])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)=[CH:46][C:47]([F:53])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[CH2:43][CH2:42]1>>[N:6]1([S:10]([NH:13][C:49](=[O:50])[C:48]2[CH:52]=[C:44]([CH:41]3[CH2:42][CH2:43]3)[C:45]([O:54][CH2:55][C:56]3([F:62])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]3)=[CH:46][C:47]=2[F:53])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(F)CCCCC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2(F)CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methane sulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-((1-fluorocyclohexyl)methoxy)benzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.037 g, 37%): 1H NMR (300 MHz, DMSO-d6) 11.64 (br s, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 4.16 (d, J=8.3 Hz, 2H), 4.05 (dd, J=8.3, 4H), 2.25-1.82 (m, 5H), 1.78-1.45 (m, 7H), 1.41-1.21 (m, 1H), 0.96-0.86 (m, 2H), 0.75-0.63 (m, 2H); MS (ES+) m/z 429.1 (M+1)
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH:13]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH:13]=[CH2:1]
Reactant: O=Cc1cnccc1Cl
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cnccc1Cl
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (4.45 g, 12.5 mmol) was suspended in THF (25 mL) under dry nitrogen and treated with butyllithium (2.5 M in hexanes, 5 mL). After stirring the suspension for 30 minutes, 4-chloropyridine-3-carboxaldehyde (1.47 g, 10.4 mmol) was added. After 2 hours at ambient temperature, the reaction was diluted with hexanes, filtered, and evaporated. The material thus obtained was used directly without further purification or characterization.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>O1CCOCC1>[NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:10](=[O:11])[C:9]3[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]2=[O:12])=[N:2]1
Reactant: Nc1cc[nH]n1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Temperature: 25 °C

Procedure:
A mixture of 1H-pyrazol-3-amine (12 g, 144 mmol, Fluka Chemie AG) and phthalic anhydride (21.39 g, 144 mmol, Fluka Chemie AG) in 1,4-dioxane (200 ml) was heated at reflux for five days and allowed to cool to room temperature. The solid was filtered and washed with ether to give the title compound as an off white solid (22.44 g); LCMS: (System 3) MH+=214, tRET=0.67 min.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([CH2:38][NH:39][C:40]([NH:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:41])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:51][O:52]C(=O)C)(=O)C.N>CO>[NH3:14].[OH:10][C@@H:9]1[C@H:5]([OH:4])[C@@H:6]([CH2:51][OH:52])[O:7][C@H:8]1[N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([CH2:38][NH:39][C:40]([NH:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:41])=[N:18][C:19]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN4CCCCC4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 3 h
Yield: 109.8 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)tetrahydro-3-furanyl acetate (100 mg, 0.13 mmol) (Preparation 6) in methanol (50 ml) was saturated with ammonia gas and then left to stand for 3 hours. The solvent was removed under reduced pressure to give a residue that was purified by elution through a plug of silica gel with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume) to give the title compound as a foam (45 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=O.[CH:14]([NH2:16])=O.[OH-].[Na+]>CCOC(C)=O>[CH3:1][N:2]1[CH:3]=[C:4]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[N:16]=[CH:14]1
Reactant: CNCC(=O)c1ccc(C#N)cc1
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2ccc(C#N)cc2)c1

Procedure:
4-(N-Methylglycyl)benzonitrile (2.6 g) and 20 ml of formamide were heated in a microwave tube at 210° C. for 20 min. The reaction was diluted with EtOAc, made basic with 15% aq NaOH, washed with water (3×100 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was subject to silica column chromatography (70% EtOAc in hexanes to 100% EtOAc) to give 1.05 g of 4-(1-methyl-1H-imidazol-4-yl)benzonitrile. LCMS: M+1=184.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:13]C(OCC1C=CC=CC=1)=O)=[CH:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH2:13])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2
Reactant: [H][H]
Reactant: COC(=O)C(=CC1CC2CCC1C2)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)CC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
In a flask was placed 2-benzyloxycarbonylamino-3-bicyclo[2.2.1]hept-2-yl-acrylic acid methyl ester (491 mg, 1.49 mmol) and methanol (15 mL). To this mixture added 10% palladium on activated carbon (60 mg) and the flask was fitted with a balloon filled with hydrogen. The mixture was allowed to stir at 25° C. for 1 h and then filtered through celite and concentrated in vacuo to afford 2-amino-3-bicyclo[2.2.1]hept-2-yl-propionic acid methyl ester (206 mg, 70%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[CH2:13][O:14][C:15](=[O:16])[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>[Cl-].[Cl-].[Zn+2]>[CH:17]([NH:20][C:15]([C@H:10]1[C@@H:11]([CH2:13][OH:14])[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:16])([CH3:19])[CH3:18]
Reactant: O=C1OC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: CC(C)N
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)NC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CO

Procedure:
A suspension of (3aR*,6aS*)-5-benzyl-hexahydro-furo[3,4-c]pyrrol-1-one (1.50 g, 6.90 mmol) and ZnCl2 (0.94 g, 6.90 mmol) in iPrNH2 (20 mL) is refluxed overnight under a nitrogen atmosphere. The crude material is filtered over a pad of Celite and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH/NH4OH 70:25:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.38. MS (LC-MS): 277.2 [M+H]+.