Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:5]=[C:6]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][OH:10])[CH:7]=1.[CH:25](=O)[CH3:26]>>[CH2:11]([C:8]1([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([S:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[CH:5]=2)[CH2:9][O:10][CH:25]([CH3:26])[O:13]1)[CH3:12]
Reactant: CCC(O)(CO)c1cc(F)cc(Sc2ccc3ccccc3c2)c1
Reactant: CC=O
Product: CCC1(c2cc(F)cc(Sc3ccc4ccccc4c3)c2)COC(C)O1
Yield: 86 %

Procedure:
Using a similar procedure to that described in Example 4, (+)-2-[5-fluoro-3-(naphth-2-ylthio)phenyl]butane-1,2-diol was reacted with acetaldehyde. There was thus obtained as a 2:1 mixture of diastereoisomers (+)-4-ethyl-4-[5-fluoro-3-(naphth-2-ylthio)phenyl]-2-methyl-1,3-dioxolane in 86% yield as an oil.
Reaction SMILES: [C:1]([C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:16]([O:18][C:19]([C:21]1([NH2:30])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:30][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1C(=O)C(C)C
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
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C(=O)C(C)C)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 2-isobutyryl-3-methyl-benzoic acid (227) (200 mg, 0.97 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (220 mg, 1.07 mmol), HATU (441 mg, 1.16 mmol) in anhydrous DMF (10 mL) is added DIPEA (192 μL, 1.16 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in DCM (50 mL) and washed with water (1×5 mL) and brine (1×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (228) as a pale yellow solid (340 mg, 89%).
Reaction SMILES: [CH3:1][N:2]([CH3:46])[CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:39])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[S:34][C:33]([C:35]([O:37]C)=[O:36])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7].[OH-].[Na+]>O1CCOCC1>[CH3:46][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:39])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[S:34][C:33]([C:35]([OH:37])=[O:36])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)s6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)s6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 70 °C

Procedure:
A mixture of methyl 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)thiophene-2-carboxylate (60 mg, 0.092 mmol) and sodium hydroxide (0.028 mL, 0.277 mmol) in dioxane (2 mL) was heated up at 70° C. for 3 hours. LCMS indicated the formation of desired product. The reaction mixture was filtered and purified by prep HPLC to give the title compound as a white solid (6.4 mg, 10%). LCMS: m/e 635.35 (M+H)+, 2.18 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.49 (t, J=5.65 Hz, 1H), 7.37 (br. s., 1H), 6.86 (d, J=3.66 Hz, 1H), 5.72 (d, J=4.88 Hz, 1H), 4.67 (d, J=2.44 Hz, 1H), 4.55 (s, 1H), 3.21 (td, J=13.20, 6.56 Hz, 1H), 3.08-2.98 (m, 2H), 2.61-2.53 (m, 1H), 2.26 (td, J=6.79, 2.29 Hz, 2H), 2.15 (s, 6H), 2.15-2.06 (m, 2H), 1.64 (s, 3H), 1.82-1.04 (m, 19H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:2]1([CH2:1][N:8]2[CH2:9][C@@H:10]([S:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:11]([OH:13])[CH2:12]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1ccccc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Sc1ccccc1

Procedure:
A mixture of 8.8 g. (0.05 mole) of 1-benzyl-3,4-epoxypyrrolidine, 6.0 g. (0.055 mole) of thiophenol, and 3 drops of water was heated on a steam bath overnight. Upon cooling the mixture, a solid crystallized. The solid was dissolved in methylene chloride and the methylene chloride solution was washed with two 50-ml portions of 5% sodium hydroxide. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give a yellow oil which solidified on standing. The solid was recrystallized from cyclohexane to give 8.6 g. (60%) of a tan solid, m.p. 97°-99°.
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:25]([OH:27])=[O:26])[C:23]=2[CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.O.[CH2:30](O)[CH3:31]>>[CH2:1]([C:16]1[NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH2:30][CH3:31])=[O:26])[C:23]=2[CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCO
Reactant: CCCCCCCCCCCCCCCc1cc2c(C(=O)O)cccc2[nH]1
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCCCCCc1cc2c(C(=O)OCC)cccc2[nH]1

Procedure:
A solution of 2-(n-pentadecyl)indole-4-carboxylic acid (15 g) in ethanol (100 ml) containing a solution of hydrogen chloride gas in ethanol (100 ml, of strength 35% w/v) was refluxed for 6 hours. After cooling, the solution was poured into water and the solid was collected and was recrystallised from methanol to give ethyl 2-(n-pentadecyl)indole-4-carboxylate (12.4 g), in the form of a pale yellow solid, m.p. 42°-45° C.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:16]1[O:15][C:12]2[CH:13]=[CH:14][C:9]([C:2]([C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6])=[O:1])=[CH:10][C:11]=2[O:17]1
Reactant: COC(=O)C#CC(O)c1ccc2c(c1)OCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C#CC(=O)c1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
A solution cf 7.3 g (31 mmol) of methyl 4-hydroxy-4[3,4-(methylenedioxy)phenyl]-2-butynoate in 80 ml of methylene chloride was added dropwise at 0° to a suspension of 77 g (0.89 mol) of manganese dioxide in 150 ml of methylene chloride. The reaction mixture was stirred at 0° for 30 minutes, filtered over magnesium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded methyl 3-[3,4-(methylenedioxy) benzoyl)-propiolate of melting point 95°-97°.
Reaction SMILES: [OH:1][CH:2]([CH:7]([CH3:9])[CH3:8])[C:3](=[CH2:6])[C:4]#[N:5].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17].Cl>O.C(Cl)Cl>[C:4]([C:3](=[CH2:6])[CH:2]([O:1][C:16](=[O:18])[CH3:17])[CH:7]([CH3:9])[CH3:8])#[N:5]
Reactant: CC(=O)Cl
Reactant: C=C(C#N)C(O)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C#N)C(OC(C)=O)C(C)C
Yield: 98.7 %

Procedure:
A nitrogen-purged 5 L, three-necked, round-bottom flask with overhead stirring is charged with 50 g (0.4 mol) of 3-hydroxy-4-methyl-2-methylenepentanenitrile, 0.4 L of methylene chloride, and 80 mL (1 mol) of pyridine. The solution is cooled at 10° C. to 15° C. in an ice bath. Using a 500 mL graduated addition funnel, a mixture of 100 mL of methylene chloride and 43 mL (0.6 mol) of acetyl chloride is added slowly while maintaining the reaction temperature at 25° C.±5° C. The reaction is stirred at 22° C.±3° C. for about one additional hour. The reaction solution is poured into a 4 L separators funnel containing 85 mL (1.0 mol) of hydrochloric acid and 750 mL of water. The lower organic layer is washed again with a solution of 20 mL (0.2 mol) of HCl and 250 mL of water. The organic layer is dried over anhydrous magnesium sulfate (20 g), filtered, and concentrated by rotary evaporation to provide 66 g of acetic acid 2-cyano-1-isopropyl-allyl ester as a yellow oil which may be used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[Mg].II.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C:24]([CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH:27]=[O:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C:24]([CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH:27]([C:2]2[C:6]3[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)[OH:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)CCC1(C=O)CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc2scc(Br)c2c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)CCC1(C(O)c2csc3ccc(F)cc23)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 21.6 %

Procedure:
A mixture of 3-bromo-5-fluoro-benzothiophene (0.4 g, 1.73 mmoles), magnesium (0.051 g, 2.1 mmoles) and a few particles of iodine in anhydrous tetrahydrofuran (10 mil) was refluxed for 7 hours, and then cooled in an ice bath. To the reaction mixture was slowly added a solution of 3-(3,3-dimethyl-butyl)-3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.39 g, 1.38 mmoles) in anhydrous tetrahydrofuran (9 mil). The reaction mixture was stirred at ice bath temperature for one hour and quenched with saturated aqueous ammonium chloride solution. The aqueous solution was extracted into ethylacetate which was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 20% ethyl acetate in hexane) to yield 3-(3,3-dimethyl-butyl)-3-[(5-fluoro-benzo[b]thiophen-3-yl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert butyl ester as yellow foam (0.13 g, 21%), MS=436 [M+H]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[CH:23]=[C:22]([C:33]([F:36])([F:35])[F:34])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[CH:23]=[C:22]([C:33]([F:34])([F:35])[F:36])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.25 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as a white solid (0.13 g, 26%). MS (ISN) 495.2 [(M−H)−]; mp 290° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[C:4]([F:18])[CH:3]=1.C(Cl)([Cl:21])=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([Cl:21])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2
Solvent: Clc1ccccc1
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ten parts of 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one and 50 parts of chlorobenzene were charged to a Hastalloy C-lined shaker tube. The vessel was closed, charged with 10 parts of phosgene from a pressurized cylinder, and heated to 130° with constant shaking for 4 hours. The vessel was cooled to 25° C, vented, opened and discharged. The product mixture was evaporated under reduced pressure to give 10.1 parts of 2-(4-chloro-2-fluorophenyl)-3-chloro,4,5,6,7-tetrahydro-2H-indazole, m.p. 82°-85°. (90.7% pure as determined by gas chromatography).
Reaction SMILES: C([S:4][CH2:5][C:6]([N:8]1[CH2:15][C:14]([OH:23])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.N>>[OH:23][C:14]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][N:8]([C:6](=[O:7])[CH2:5][SH:4])[C@H:9]([C:10]([OH:12])=[O:11])[CH2:13]1
Reactant: CC(=O)SCC(=O)N1CC(O)(Cc2ccccc2)C[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1CC(O)(Cc2ccccc2)CN1C(=O)CS

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 2 to yield 4-hydroxy-1-(2-mercapto-1-oxoethyl)-4-(phenylmethyl)-L-proline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(F)c1
Yield: 99.7 %

Procedure:
In 150 ml ethyl acetate was dissolved 5.74 grams methyl 3-fluoro-4-nitrobenzoate and the resulting solution was hydrogenated in the Parr apparatus (45 psi) over 600 mg 10% Pd-on-C for about 45 minutes, when the hydrogen uptake ceased. The catalyst was removed by filtration and the solvent was removed in vacuo to give 4.86 grams methyl 3-fluoro-4-aminobenzoate as an off-white solid, m.p. 107°-110° C.
Reaction SMILES: [C:1]([CH2:3]C(O)=O)#[N:2].[C:7]1([CH2:13][CH2:14][C:15](=O)[CH2:16][CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:16]([CH:15]([CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:1]#[N:2])[CH3:17]
Reactant: CCC(=O)CCc1ccccc1
Reactant: N#CCC(=O)O
Product: CCC(CC#N)CCc1ccccc1

Procedure:
The reaction was repeated utilizing an equimolar quantity of dimethyl malonate in place of the cyanoacetic acid to yield methyl 4-methyl-5-phenylpentanoate. Repeating the cyanoacetic acid condensation/reduction reaction utilizing 5phenylpentan-3-one as the starting material afforded 3-ethyl-5-phenylpentanenitrile.
Reaction SMILES: [C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:24])[CH3:23])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[NH:5]1)([OH:3])=O.[CH3:35]N(C)C=O.C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:24])[CH3:23])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[NH:5]1)(=[O:3])[CH3:35]
Reactant: CN(C)C=O
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
To a solution of 10 g of benzyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 120 ml of benzene are added 0.25 ml of N,N-dimethylformamide and 2.2 ml of oxalyl chloride, and the mixture stirred at room temperature for 45 minutes. The resulting solution of benzyl α-(3ξ-chlorocarbonyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is concentrated to about 1/2 volume, then dropwise added to a solution of diazomethane in 250 ml of ether (which has been prepared from 13 g of nitrosomethyl-urea) under ice-cooling, and stirred for 20 minutes. The resulting solution of benzyl α-(3ξ-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is mixed with 10 ml of ether containing 16% hydrogen chloride, and after 85 minutes, the mixture is concentrated under reduced pressure. The residue [benzyl α-(3ξ-chloroacetyl-2-phenylacetyl-7-oxo-4 -oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate (IR: νmaxCHCL3 1786, 1724, 1674 cm-1)], is dissolved in 100 ml of acetic acid and mixed with 10 g of zinc powder which has preliminarily been washed with hydrochloric acid, water, ethanol and ether, and stirred at room temperature for 1.5 hours. The reaction mixture is filtrated, and the filtrate poured into 90 ml of ice water and extracted with methylene chloride. The extract is washed with water, an aqueous solution of sodium hydrogencarbonate and then water, dried on sodium sulfate and concentrated under reduced pressure. The residue (9.68 g) is purified by chromatography on 200 g of silica gel containing 10% water and eluted with a mixture of benzene and ethyl acetate (7:1) to yield 7.208 g of benzyl α-(3ξ-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)-α-isopropylideneacetate in 79.7% yield.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[Cl:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([N:57]2[N:61]=[CH:60][CH:59]=[N:58]2)[C:49]=1[C:50](O)=[O:51]>>[Cl:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([N:57]2[N:61]=[CH:60][CH:59]=[N:58]2)[C:49]=1[C:50]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:51]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1c(Cl)cccc1-n1nccn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(Cl)cccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.265 mmol) and 2-chloro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 15; 71 mg, 0.318 mmol) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10]C)=[O:9])[O:5][C:6]=1[CH3:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][C:6]1[O:5][C:4]([C:8]([OH:10])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Br)c(C)o1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc(C(=O)O)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 85.5 %

Procedure:
To a solution of methyl 4-bromo-5-methyl-2-furancarboxylate (500 mg, 2.28 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (950 mg, 4.57 mmol)[prepared according to Preparation 7] and potassium carbonate (315 mg, 2.28 mmol) in 1,4-dioxane (8 mL) and water (2.0 mL) was added bis(tri-t-butylphosphine)Palladium (0) (117 mg, 0.23 mmol). The mixture was heated to 80° C. and after 15 h the reaction mixture was concentrated. The residue was partitioned between DCM and water. The organic layer was concentrated and dissolved in tetrahydrofuran (THF) (8.0 mL). The solution was treated with 6N aqueous solution of sodium hydroxide (3.80 mL, 22.83 mmol) and heated to 75° C. After 15 h, the reaction mixture was concentrated and partitioned between DCM and water. The aqueous layer was acidified to pH ˜3 with 2N HCl aqueous solution and extracted several times with DCM. The organic fractions were combined and concentrated to afford the title compound as a yellow solid (401 mg, 1.95 mmol, 85% yield): LC-MS (ES) m/z 207 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[C:13]([N:31]3[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32]3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2]>CO>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([N:31]3[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32]3)=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1ccn(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Solvent: CO
Product: CCOC(=O)c1ccn(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCCNC2)c1

Procedure:
tert-Butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-(ethoxycarbonyl)-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (3 mg, 0.005 mmol) was dissolved in methanol (1 mL) and absorbed onto a TsOH solid phase extraction cartridge. After 1.5 h the cartridge was eluted with 7M ammonia in methanol. The eluent was evaporated to dryness to give ethyl 1-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:5][C:4]=1[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(C=O)cc1CCOc1ccc(C(F)(F)F)cc1
Product: COc1ccc(CC2SC(=O)NC2=O)cc1CCOc1ccc(C(F)(F)F)cc1

Procedure:
Using 4-methoxy-3-{2-[4-(trifluoromethyl)phenoxy]ethyl}benzaldehyde and 2,4-thiazolidine dione, 5-(4-methoxy-3-2-[4-(trifluoromethyl)phenoxy]ethylbenzyl)-1,3-thiazolane-2,4-dione was obtained in the same method as in Production Example 27c) and then in Example 29).
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[CH:3](Br)[C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]=2[CH:5]=1.C1OCCOCCOCCOCCOCCOC1>>[CH3:14][C:10]1([CH3:15])[CH2:9][CH2:8][C:7]([CH3:16])([CH3:17])[C:6]2[CH:5]=[C:4]([C:3]#[C:2][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:13]=[CH:12][C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(Br)C(Br)c3ccc(C#N)cc3)ccc21
Agent: C1COCCOCCOCCOCCOCCO1
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Temperature: 50 °C
Reaction time: 10 h
Yield: 43.3 %

Procedure:
6.7 g (0.014 mole) of 1,2-dibromo-1-(4-cyanophenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethane (cf. Example 6a) were suspended in 26 ml of petroleum ether. After the addition of 3.2 g (0.028 mole) of potassium tert.-butylate, the temperature of the reaction mixture increased to 50° C. The mixture was refluxed for 1 hour, 20 mg (0.1 mole) of 18-crown-6 were added, and refluxing was continued for a further 10 hours. Thereafter, the mixture was poured onto 500 ml of ice water and extracted twice with petroleum ether, and the organic phase was washed with water, dried over sodium sulfate and evaporated down under reduced pressure to give 4.3 g of crude product. Recrystallization from ethanol gave 1.9 g (43%) of the title compound of melting point 166° C.