Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)#[N:2].[ClH:14].[H][H]>CO.[Pd]>[ClH:14].[CH3:13][O:12][C:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1)=[O:11]
Reactant: COC(=O)Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccc(CN)cc1

Procedure:
A solution of 8.8 g (0.05 Mol) of methyl 4-cyanobenzene acetate in 200 ml of methanol was hydrogenated, after the addition of 50 ml of 1 N aqueous hydrochloric acid and 3 g of palladium on activated charcoal (10%), at ambient temperature under a hydrogen pressure of 3 bar until the uptake of hydrogen had ended. The solution freed from catalyst was evaporated down, the residue was combined with two batches of 50 ml of toluene and evaporated down again. 10.7 g (99% of theory) of a crude crystalline material was obtained which was used without further purification in the next step.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:22]3[CH2:26][C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])=[CH:24][C:23]3=[O:35])[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9]2)[CH2:4][O:3]1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:22]2[CH2:26][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])=[CH:24][C:23]2=[O:35])[CH2:16][CH2:17][C:18]([F:20])([F:19])[F:21])=[N:9]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CCC(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(CCC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
In a round bottom flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (210 mg, 0.39 mmol), methanol (5 mL) and p-toluenesulfonic acid hydrate (17 mg). This mixture was stirred at 25° C. for 16 h and then diluted with dichloromethane and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire, 40 g column, 100% ethyl acetate to 5% methanol/ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (140 mg, 71%) as a white foam: HR-ES-MS m/z calculated for C21H21N4O5ClF3 [M+H]+ 503.1304, observed 503.1300; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.88-2.46 (m, 4H), 3.20-3.33 (m, 2H), 3.68-3.82 (m, 1H), 3.86 (dd, J=13.4, 7.2 Hz, 1H), 4.09 (dd, J=13.4, 3.9 Hz, 1H), 4.32 (d, J=18.1 Hz, 1H), 4.53 (m, J=18.1 Hz, 1H), 4.72 (t, J=5.4 Hz, 1H), 4.78 (dd, J=9.1, 5.1 Hz, 1H), 4.83 (s, 1H), 4.94 (d, J=5.1 Hz, 1H), 6.42 (d, J=2.1 Hz, 1H), 7.33-7.40 (m, 1H), 7.42-7.57 (m, 3H), 7.66 (d, J=8.2 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[CH:8][C:7]=1[N+:23]([O-])=O)[CH3:2]>C(O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:8][C:7]=1[NH2:23])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(C(=O)c2cccc(N)c2)cc1N
Reaction time: 1 h

Procedure:
A 2 L metal reactor was charged with [2-Nitro-4-(3-nitro-benzoyl)-phenyl]-acetic acid ethyl ester (65 g, 181.4 mmol) in ethanol (1.3 L) was added Pt(IV)O2 (6.5 g). The reactor was evacuated, purged with N2(g) then filled with H2(g) (15 psi). The temperature of the reaction was controlled with a H2O coiled condenser and the maximum allowable temperature was 26° C. After 1 h and 15 min, the reaction was determined to be complete by thin layer chromatographic analysis (TLC) (Hexanes/EtOAc 1:1). The TLC was viewed with short wavelength UV and I2 stain. At the end of the reaction, the reactor was evacuated and purged with N2(g). The reaction was filtered through celite and the celite was washed with THF (1 L). The filtrates were concentrated and the solids were dried in a vacuum oven under 28 mmHg at 45° C. to afford [2-Amino-4-(3-amino-benzoyl)-phenyl]-acetic acid ethyl ester in quantitative yield (54 g, 181.0 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.289g. of valeric acid chloride as in Example 1. The 0.590 g. of brownish colored turbid oil obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.518 g. of a colorless, turbid oil which crystallizes upon trituration. It is recrytallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl valerate obtained melts at 36.5°-36.9° and has a clearing point of 61.7°. UV (EtOH): ε 271 = 25800.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([O:32][CH3:33])=[O:31]>C1COCC1.CCOC(C)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[CH3:33][O:32][C:30]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]=[C:5]2[N:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14])=[O:31]
Reactant: COc1ccc(N(C)c2nc(C)nc3ccc(N)cc23)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc2nc(C)nc(N(C)c3ccc(OC)cc3)c2c1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 71.8 %

Procedure:
To a solution of (6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (150 mg, 0.51 mmol) in 5 ml of THF was added potassium carbonate (160 mg, 1.16 mmol), 2 mg of sodium sulfate. The reaction mixture was cooled to 0° C., and methyl chloroformate (0.4 ml, 5 mmol) was added. The reaction mixture was stirred at 0° C. for 10-15 min, then diluted with EtOAc (20 ml), washed with water, brine, dried over Na2SO4, filtered and concentrated by vacuum. The crude product was purified by chromatography on silica gel with acetate, hexane (1:3 to 1:1) as eluent, yielding 129 mg of title compound (72%) as yellow solids. 1H NMR (CDCl3): 7.70 (s, 2H), 7.12-7.07 (m, 2H), 6.94-6.89 (m, 3H), 6.32 (brs, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 3.57 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH:11]2[CH2:13][O:12]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[OH:14][CH2:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>CCO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:11]([OH:12])[CH2:13][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@H:16]2[CH2:15][OH:14])=[CH:10][C:3]=1[O:2][CH3:1])#[N:6]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: COc1cc(C2CO2)ccc1C#N
Solvent: CCO
Product: COc1cc(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc1C#N
Temperature: 25 °C

Procedure:
A Pyrex vessel was charged with magnetic stirring bar, (0.350 g, 2.00 mmol) of 2-methoxy-4-(oxiran-2-yl)benzonitrile, (0.457 g, 2.20 mmol) of tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate, and 6 mL of EtOH. Then it was introduced in the microwave reactor and irradiated at 150° C. for 3 h. Then the mixture was cooled to RT and the solvent was evaporated and the resulting residue was purified by column chromatography (silica gel, 1-20% dichloromethane/MeOH) which afforded the title compound as a mixture of two diastereomers (1:1). LC/MS: (IE, m/z) [(M+1)-t-Bu]+=336.1.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:21])([CH3:3])[CH3:2].CC1C=C(CCCCCCCCC)C=C(C=[N:27][OH:28])C=1O>>[CH:1]([C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[C:6]([CH:7]=[N:27][OH:28])[C:5]=1[OH:21])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCc1cc(C)c(O)c(C=NO)c1
Reactant: CCCCCCCCCc1cc(C=O)c(O)c(C(C)C)c1
Product: CCCCCCCCCc1cc(C=NO)c(O)c(C(C)C)c1
Yield: 96.1 %

Procedure:
Oximation and workup of 3-isopropyl-5-nonylsalicylaldehyde (3b) (57.6 g, 0.2 mol) as described for 1c gave 3-isopropyl-5-nonylsalicylaldoxime (58.21 g) in 96.1% yield.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]1)C1C=CC=CC=1>ClCCCl>[Cl:27][C:22]1[CH:21]=[C:20]([C@@H:18]2[CH2:19][NH:15][CH2:16][C@H:17]2[C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COC(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 98.3 %

Procedure:
1-Chloroethyl chloroformate (1.5 mL, 13.9 mmol) was added to a solution of (3S,4R)-methyl 1-benzyl-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (4.20 g, 11.5 mmol) in DCE (50 mL) at 0° C. The mixture was refluxed for 1 hour. After cooling, the solvent was removed under vacuum at 65° C. for 1 hour. MeOH (50 mL) was added to the residue and refluxed for 1 hour. The MeOH was removed. The solid was redissolved in CHCl3 and treated with saturated Na2CO3. The aqueous layer was separated and extracted with CHCl3 (2×30 mL). The organic phase was combined and dried. The solvent was removed to afford (3S,4R)-methyl 4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (3.1 g, 98%). (LCMS (APCI+) [M+H]+ 274.1; Rt: 2.25 min.).
Reaction SMILES: C(N(C1C=CC=CC=1)S(C1C=CC(N2C(=O)C3CN(C(OC(C)(C)C)=O)CCC=3N2)=NC=1)(=O)=O)C.[CH:36]1([N:41]([CH2:60][CH:61]2[CH2:65][O:64]C(C)(C)[O:62]2)[S:42]([C:45]2[CH:46]=[N:47][C:48]([N:51]3[C:55](=[O:56])[C:54]4[CH2:57][S:58][CH2:59][C:53]=4[NH:52]3)=[CH:49][CH:50]=2)(=[O:44])=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>CC(O)=O>[CH:36]1([N:41]([CH2:60][CH:61]([OH:62])[CH2:65][OH:64])[S:42]([C:45]2[CH:46]=[N:47][C:48]([N:51]3[C:55](=[O:56])[C:54]4[CH2:57][S:58][CH2:59][C:53]=4[NH:52]3)=[CH:49][CH:50]=2)(=[O:43])=[O:44])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC1(C)OCC(CN(C2CCCC2)S(=O)(=O)c2ccc(-n3[nH]c4c(c3=O)CSC4)nc2)O1
Agent: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]c3c(c2=O)CN(C(=O)OC(C)(C)C)CC3)nc1
Solvent: CC(=O)O
Product: O=c1c2c([nH]n1-c1ccc(S(=O)(=O)N(CC(O)CO)C3CCCC3)cn1)CSC2
Yield: 30 %

Procedure:
A solution of 470 mg (0.54 mmol) of 6 N-cyclopentyl-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-sulfonamide in 1 mL of AcOH is heated at 80° C. for 4 hours. The medium is concentrated under reduced pressure and then purified by reverse-phase chromatography on a C18 column, eluting with a 10−3N HCl/CH3CN gradient of from 0 to 100% CH3CN. 48 mg of N-cyclopentyl-N-(2,3-dihydroxypropyl)-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-sulfonamide are obtained in the form of a white solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:13]([CH:18]([CH3:21])[CH2:19][OH:20])=[N:14][CH:15]=[CH:16][CH:17]=1>C(Cl)Cl>[Cl:11][C:12]1[C:13]([CH:18]([CH3:21])[CH:19]=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(CO)c1ncccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C=O)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
To a −78° C. solution of dimethylsulfoxide (4.04 g, 3.67 mL, 51.7 mmol) in methylene chloride (25 mL) was added a solution of oxalyl chloride (3.28 g, 2.26 mL, 25.9 mmol) in methylene chloride (5 mL) over two minutes. The reaction mixture was stirred for 15 minutes, and then a solution of the product of Example 38C (0.74 g, 4.31 mmol) in methylene chloride (25 mL) was added over 8 minutes. The reaction was allowed to warm to ambient temperature and quenched with water. The quenched reaction mixture was extracted with methylene chloride, and the organic layer washed with brine and concentrated. The residue was chromatographed on silica gel eluting with 25% ethyl acetate-hexane to give the title compound (0.71 g, 97%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 8.53 (dd, J=1.5, 4.7, 1H), 8.00 (dd, J=1.4, 8.1, 1H), 7.40 (dd, J=4.7, 8.1, 1H), 4.28 (q, J=7.0, 1H), 1.34 (d, J=7.0, 3H). MS (DCI) m/z 170 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12](/[C:11](/[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:14]\[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:20]=1)#[N:13]
Reactant: CCOC(=O)CCl
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 33.8 %

Procedure:
Compound 1 (281 mg) and ethyl chloroacetate (245 mg) were dissolved in acetone, and potassium carbonate was added to the resultant solution, followed by reflux for three hours. The resultant mixture was subjected to filtration, and insoluble matter was removed from the mixture. The resultant filtrate was concentrated to dryness under reduced pressure, followed by recrystallization, to thereby produce the target product (124 mg, yield: 34%).
Reaction SMILES: [Li].[CH3:2][O:3][C:4](=[O:13])[CH2:5][S:6][CH2:7][CH2:8][C:9](OC)=[O:10]>CO>[O:10]=[C:9]1[CH2:8][CH2:7][S:6][CH:5]1[C:4]([O:3][CH3:2])=[O:13]
Reactant: COC(=O)CCSCC(=O)OC
Agent: [Li]
Solvent: CO
Product: COC(=O)C1SCCC1=O
Reaction time: 8 h
Yield: 43.2 %

Procedure:
Lithium metal (2.70 g, 390.15 mmol) was added to 500 mL of methanol in an ice-bath. Then at rt methyl 3-(2-methoxy-2-oxoethylthio)propanoate (50.0 g, 260.10 mmol) was added dropwise to the solution. The reaction mixture was stirred overnight. The resulting reaction mixture was evaporated to remove the solvent. The mixture was neutralized to pH=7-8 with 3N HCl and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude residue obtained contained the target as the only isolable product. Purification by column chromatography on silica gel (eluent: PE/EA=20/1-5/1) provided methyl 3-oxo-tetrahydrothiophene-2-carboxylate as a colourless oil (18.0 g, 43%).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5](S(OCCC#C)(=O)=O)=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)C=C[CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:16]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23]1)[CH2:17][C:18]#[CH:19]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C#CCCN1CCN(c2ccccc2)CC1

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (1.72 g), N-phenyl piperazine (1.17 mL) and diisoproylethylamine (1.45 mL) in 1,2-dichloroethane (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with sat. aq. NaHCO3 (5 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (3% Et3N in EtOAc) afforded 1-(but-3-ynyl)-4-phenylpiperazine (0.76 g)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][CH:17]1Br)(=[O:14])[CH3:13]>[O-2].[Zn+2]>[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@H:17]1[S:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)Nc1ccc(S[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Yield: 25 %

Procedure:
If the procedure described in Preparation IV is followed starting from 4.5 g (27.10-3 mol) of N-(4-mercaptophenyl)acetamide, 11.43 g (32.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 2.16 g (27.10-3 mol) of zinc oxide (ZnO), 3 g (yield: 25%) of the expected product are obtained after recrystallization from a toluene/isopropyl ether mixture.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]([CH3:12])=[CH2:11])[CH:9]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:5]=[N+:6]([O-:23])[CH:7]=[C:8]([C:10]([CH3:12])=[CH2:11])[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)c1cncc(C(OC)OC)c1
Solvent: ClCCl
Product: C=C(C)c1cc(C(OC)OC)c[n+]([O-])c1
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To a stirred solution of 3-(dimethoxymethyl)-5-(prop-1-en-2-yl)pyridine (178 mg, 0.92 mmol) in CH2Cl2 (10 mL) was added m-CPBA (227 mg, 1.0 mmol). The reaction mixture was stirred for 2 h and quenched with saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine and dried over Na2SO4. The solvent was removed to provide 3-(dimethoxymethyl)-5-(prop-1-en-2-yl)pyridine 1-oxide (209 mg), which was converted to 3-formyl-5-(prop-1-en-2-yl)pyridine 1-oxide as described herein.
Reaction SMILES: C[N:2]([C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:31])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])([OH:22])[CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:10][CH:9]=1)[NH:3][C:4]([NH2:6])=[S:5].[CH3:33][O-].[Na+]>C(O)C>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C@:15]([OH:22])([C@H:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:6]([CH3:33])[C:4]([SH:5])=[N:3][N:2]=2)=[CH:13][CH:12]=1)[CH3:31])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: C[O-]
Reactant: CC(c1ccc(C(=O)N(C)NC(N)=S)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](c1ccc(-c2nnc(S)n2C)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of N-methyl-4-{2-[2,4-difluorophenyl]-2-hydroxy-1-[1,2,4-triazol-1-yl]but-3-yl}benzoylthiosemicarbazide (2.1 g, 4.5 mmol) in ethanol (50 ml) was heated under reflux and treated with sodium methoxide solution (30%, 5.5 mmol) in portions over 24 hours. The mixture was reduced in volume to 20 ml under reduced pressure and partitioned between ethyl acetate (100 ml) and water (50 ml). The aqueous layer was further extracted with ethyl acetate (3×50 ml) and the organic extracts combined, washed with brine (50 ml), dried (Na2SO4) and evaporated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C(CCc1ccc(O)c(Br)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br

Procedure:
Tert-butyl 2-(2-bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-acetate is prepared from 3-(3-bromo-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoacetate according to general procedure D.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:26][N:27]([CH:35]=[O:36])[O:28]C2CCCCO2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O>C(O)(=O)C>[CH:1]1([CH2:6][C@H:7]([CH2:26][N:27]([CH:35]=[O:36])[OH:28])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][N:23]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cnc(NC(=O)[C@@H]2CCNN2C(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)nc1
Solvent: CC(=O)O
Solvent: O
Product: COc1cnc(NC(=O)[C@@H]2CCNN2C(=O)[C@H](CC2CCCC2)CN(O)C=O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
A mixture of (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-N-[5-(methyloxy)-2-pyrimidinyl]-3-pyrazolidinecarboxamide (67 mg, 0.133 mmol) in acetic acid (7 ml)/water (1.8 ml) was stirred at ambient temperature for overnight. The solvent was removed to give a residue which was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-[5-(methyloxy)-2-pyrimidinyl]-3-pyrazolidinecarboxamide (27 mg, 0.061 mmol, 46% yield). MS (ES+) m/z 421.1 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>C(O)C>[CH3:7][C:2]([CH3:8])([N:1]1[C:12](=[O:13])[C:11]2[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]1=[O:14])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(N)CC(=O)O
Solvent: CCO
Product: CC(C)(CC(=O)O)N1C(=O)c2ccccc2C1=O
Temperature: 180 °C
Reaction time: 54 h
Yield: 33.2 %

Procedure:
An intimate mixture of of 3-amino-3-methyl butanoic acid (27.4 g, 0.234 mol) and phthalic anhydride (38.1 g, 0.257 mol) is heated at 180° C. for 1.5 hours. After cooling, the reaction mixture is dissolved in 40 ml of ethanol and kept in a refrigerator for 54 hours. The colorless crystalline precipitate thus obtained is collected by suction and dried at 50° C. for 3 hours in a vacuum oven to give 19.2 g of β,β-dimethyl-1,3-dioxo-2-isoindolinepropionic acid (58%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30]([OH:32])=O)=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:72][C@@H:73]1[CH2:77][CH2:76][C@H:75]([OH:78])[CH2:74]1>CN(C=O)C>[OH:78][C@@H:75]1[CH2:76][CH2:77][C@H:73]([NH:72][C:30]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[C:14]5[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=5)[N:17]([CH3:20])[N:16]=4)[N:22]=3)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:28]=2)=[O:32])[CH2:74]1
Reactant: N[C@@H]1CC[C@H](O)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](O)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
In a round-bottomed flask, cis-3-amino-cyclopentanol trifluoroacetate (crude from Step 2) was dissolved in DMF (1.2 ml) and N,N-diisopropylethylamine (0.40 ml, 2.3 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol) and HATU (114 mg, 0.30 mmol) were added. The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-4% MeOH) to afford 50 mg (35%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclopentyl)-amide as a light yellow solid.