Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13]3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>O1CCCC1>[NH:1]([C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][N:12]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:13]3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)[C:26]([CH3:27])=[O:28]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2CC3CC(CN(Cc4ccccc4)C3)C2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(=O)N2CC3CC(CN(Cc4ccccc4)C3)C2)cc1
Reaction time: 8 h

Procedure:
80.2 g (0.24 mole) of 3-(4-aminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane (cf. European Pat. No. 62,199) were dissolved in 500 ml anhydrous tetrahydrofuran and cooled with ice. 23.5 g (0.3 mole) of acetyl chloride, dissolved in 50 ml of tetrahydrofuran, were added dropwise, followed by 48.6 g (0.48 mole) of triethylamine at room temperature. The entire mixture was stirred overnight and then evaporated down under reduced pressure. The residue was taken up in water and the solution was extracted 3 times with methylene chloride. The combined organic phases were washed with water, dried and evaporated down under reduced pressure. Yield: 78.1 g, mp.: 208° C.
Reaction SMILES: [CH2:1]([C:4]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][C:7]2([O:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CI.[C:23]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:23][O:19][C:18](=[O:20])[CH2:17][C:4]1([CH2:1][CH:2]=[CH2:3])[CH2:16][CH2:15][C:7]2([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12]2)[CH2:6][CH2:5]1
Reactant: C=CCC1(CC(=O)O)CCC2(CC1)OCC(C)(C)CO2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCC1(CC(=O)OC)CCC2(CC1)OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (9-allyl-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetic acid (0.50 g), methyl iodide (0.12 mL), K2CO3 (0.37 g), and N,N-dimethylformamide (5 mL) is stirred at room temperature overnight. 10% aqueous K2CO3 solution is then added and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (MgSO4), and concentrated to give the crude title compound that is used without further purification. Yield: 0.36 g (crude); LC (method 6): tR=1.65 min; Mass spectrum (ESI+): m/z=297 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([OH:3])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.C(Cl)(Cl)Cl>[CH3:15][C:10]1[C:9]2[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:6]3[C:14]=2[C:13]([C:1](=[O:3])[CH2:4][CH2:5]3)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2c(C)cccc2n1CCC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3=O
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A mixture of ethyl 1-(2-carboxyethyl)- 4-methyl-1H-indole-2-carboxylate (1.00 g, 3.63 mmol), thionyl chloride (1.35 g, 11.4 mmol) and chloroform (16 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and dichloromethane (80 ml) was added to the residue, followed by stirring at room temperature. Subsequently, aluminum chloride (2.02 g, 15.1 mmol) was added and the resulting mixture was stirred at room temperature for 1.5 hours and then heated under reflux for 0.5 hour. The reaction mixture was added to a mixture of water (300 ml) and 35% hydrochloric acid (1.5 ml), followed by extraction with chloroform (three times). The extract solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/97) to obtain ethyl 5,6-dihydro-9-methyl-6-oxo-4H-pyrrolo-[3,2,1-ij]quinoline-2-carboxylate (0.53 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][CH:34]1[C:41](=[O:42])[N:40]2[CH:35]1[S:36][CH2:37][C:38]([CH3:59])=[C:39]2[C:43]([O:45][CH:46]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>C(Cl)Cl>[CH:46]([O:45][C:43]([C:39]1[N:40]2[CH:35]([S:36][CH2:37][C:38]=1[CH3:59])[CH:34]([NH:33][C:27](=[O:29])[C:26](=[N:30][O:31][CH3:32])[C:24]1[N:25]=[C:21]([NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=1)[C:41]2=[O:42])=[O:44])([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
A solution of 2-(2-tritylamino-thiazol-4-yl)-2-methoxyimino-acetic acid (syn isomer) (7.2 g) in methylene chloride (22.5 cc) is added, in a single shot, to a solution of 7-amino-2-benzhydryloxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3.15 g) in methylene chloride (31.5 cc). The temperature rises from 8° to 14° C. The mixture is kept stirred for one hour 15 minutes, during which the temperature rises to 20° C., and is then washed with 0.5 N hydrochloric acid (10 cc), distilled water (10 cc) and a saturated sodium bicarbonate solution (20 cc). The insoluble matter formed is filtered off, and the organic phase is washed again with distilled water (2×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is chromatographed on a column (diameter: 3 cm, height: 33 cm) containing silica gel (125 g), elution being carried out with a 20:80 (by volume) mixture of ethyl acetate and cyclohexane (1.2 liters) and then with a 40:60 (by volume) mixture (1 liter), and 50 cc fractions of eluate being collected. Fractions 31 to 44 are evaporated and 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetamido]-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene, syn isomer (2.8 g) is obtained in the form of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:4]2[C:3]=1[O:12][CH:21]([C:20]([F:19])([F:29])[F:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: COc1cc(Cl)c(O)c(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(OC)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 3-chloro-2-hydroxy-5-methoxybenzaldehyde prepared as in Step 1 (9.00 g, 48.2 mmole), K2CO3 (6.67 g, 48.2 mmole) and ethyl 4,4,4-trifluorocrotonate (8.65 mL, 57.9 mmole) in anhydrous DMF (20 mL) under a dry N2 atmosphere was stirred at room temperature for 30 minutes and was then heated to 85° C. for 3 h. Additional ethyl 444-trifluorocrotonate (3.00 mL, 20.1 mmole) was then added and the mixture was stirred at 85° C. overnight. The mixture was then cooled and poured into 1 N HCl (200 mL). Following extraction with EtOAc (3×200 mL), the combined extracts were washed with 0.25 N NaOH until the washes were basic, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by crystallization from ethanol to give 11.0 g (68% yield) of the product as a yellow crystalline solid: 'H NMR (dmso-d6/300 MHz) 7.92 (s, 1H), 7.18 (d, 1H, J=2.8 Hz), 7.13 (d, 1H, J=2.8 Hz), 6.05 (q, 1H, J=7.3 Hz), 4.21-4.29 (m, 2H), 3.73 (s, 3H), 1.26 (t, 3H, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([F:22])[CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:22][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:23])[CH:29]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2F)CC1
Reactant: Cc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)ccn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A 25 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4-[(4-bromo-2-fluorophenyl)methyl]piperazine-1-carboxylate (1.00 g, 2.68 mmol, 1.00 equiv), (2-methylpyridin-4-yl)boronic acid (0.737 g, 5.38 mmol, 2.01 equiv), Tetrakis(triphenylphosphine)palladium (0.311 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.10 g, 7.96 mmol, 2.97 equiv), dioxane (10 mL) and water (2 mL). The resulting solution was stirred overnight at 75° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/2) to yield 0.600 g (58% yield) of tert-butyl 4-[[2-fluoro-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 386 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[N:12]1C=NC=N[CH:13]=1.N1CCCCC1>CO>[N:1]1[C:2]2[C:3](=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=2)[C:4]([OH:5])=[N:12][CH:13]=1
Reactant: c1ncncn1
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: CO
Solvent: C1CCNCC1
Product: Oc1ccc2ncnc(O)c2c1
Temperature: 0 °C
Yield: 72.3 %

Procedure:
A mixture of 2-amino-5-hydroxybenzoic acid (19.64 g, 128 mmol), 1,3,5-triazine (15.6 g, 192 mmol), and piperidine (9 mL, 92.4 mmol) were heated to 60° C. in methanol (60 mL) for 2 hours. After cooling to 0° C., the mixture was filtered. The solid was washed with cold methanol and dried under high vacuum to provide the product (15 g, 72%) as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc(CN([C@H]2CCN(Cc3cccc(C#N)c3)C2=O)S(=O)(=O)c2ccc3ccc(OC)cc3c2)cc1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 4-methoxybenzyl chloride. The crude product is purified by column chromatography eluting with 50% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:22][O:21][C:19](=[O:20])[CH:18]([O:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][C:4]=2[F:16])=[CH:12][CH:11]=1)[CH3:23]
Reactant: COC(=O)C(C)Br
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the 4-(4-bromo-2-fluorophenoxy)phenol (5.66 g, 0.02 mol) from Step V, methyl 2-bromoproprionate (3.34 g, 0.02 mol) and potassium carbonate (3.06 g, 0.22 mol) in DMSO (30 ml) was stirred, under an atmosphere of nitrogen, at room temperature for 18 hours. The mixture was poured into water (300 ml), and the resulting mixture extracted with ether (2×100 ml). The ether extracts were combined, washed with water (100 ml), dried (MgSO4), and the solvent evaporated to give the desired 2-[4-(4-bromo-2-fluorophenoxy)phenoxy]propionic acid; methyl ester as a yellow oil (6.0 g, 81%); RI=1.5628; NMR (CDCl3) was consistent with the assigned structure. The carbon and hydrogen content was as follows:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:17](=[O:23])[N:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: Nc1ccccc1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(-c3ccccc3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aniline (0.74 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (0.73 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.34 g, 46%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21](O)=[O:22])[CH:14]=[N:13]2)[CH2:8][C@@H:7]1[CH3:24])=[O:5])[CH3:2].[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:35][CH2:34][C@@H:33]([N:36]2[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45](O)=[O:46])[CH:38]=[N:37]2)[CH2:32][C@H:31]1[CH3:48])=[O:29])[CH3:26].C(Cl)(=O)C([Cl:52])=O>C(Cl)Cl.CN(C=O)C>[Cl:52][C:21]([C:15]1[CH:14]=[N:13][N:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C@@H:7]([CH3:24])[CH2:8]2)[C:16]=1[C:17]([F:20])([F:19])[F:18])=[O:22].[Cl:52][C:45]([C:39]1[CH:38]=[N:37][N:36]([C@@H:33]2[CH2:34][CH2:35][C@@H:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[C@H:31]([CH3:48])[CH2:32]2)[C:40]=1[C:41]([F:44])([F:43])[F:42])=[O:46]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@@H]1C
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)[C@@H]1CC[C@@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@H]1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC[C@@H](n2ncc(C(=O)Cl)c2C(F)(F)F)C[C@H]1C
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)Cl)c2C(F)(F)F)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a slightly cloudy mixture of 1-((1R,3R,4R)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid compound with 1-((1S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1:1) (0.300 g, 0.431 mmol) in DCM (17.23 ml) was added oxalyl chloride (0.091 ml, 1.077 mmol) followed by DMF (1 drop) and the light-yellow slightly cloudy reaction mixture was stirred at room temperature. After 1.5 h, the mixture was concentrated in vacuo to give (1R,2R,4R)-ethyl 4-(4-(chlorocarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexane carboxylate compound with (1S,2S,4S)-ethyl 4-(4-(chlorocarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexane carboxylate (1:1) as light-yellow syrup.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH3:17])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=[O:9].C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[C:34]([S:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH3:17])[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)=[O:9])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](NC(=O)N(CCS)CCc1ccccc1)C(=O)N1CCN(C)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)N(CCSC(=O)c1ccccc1)CCc1ccccc1)C(=O)N1CCN(C)CC1

Procedure:
1-[(2S)-2-[3-(2-Mercaptoethyl)-3-phenethylureido]propionyl]-4-methylpiperazine (Compound No. 30-1, 32.9 g)is dissolved in chloroform (87 ml) under a nitrogen atmosphere, and the solution is stirred. To the solution are added triethylamine (13.3 ml) and then benzoyl chloride (10.1 ml )dropwise under ice cooling, and the mixture is stirred for 25 minutes. The reaction mixture is concentrated under reduced pressure, a 10% aqueous sodium hydrogencarbonate solution is added to the residue, and the whole is extracted with ethyl acetate. The organic layer is washed with a 10% aqueous sodium hydrogencarbonate solution, water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give the titled compound (Compound No. 32-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17](=[O:22])C(Cl)(Cl)Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]2[CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:15]=3)[NH:16][C:17]2=[O:22])[CH2:25][CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1

Procedure:
In similar way as in Preparation Example 24, the title compound was synthesized from 5-chloro-2-trichloroacetylaminobenzophenone and 4-amino-1-benzylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([NH:22][CH2:23][CH2:24][O:25][Si](CC)(CC)CC)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(O)(=O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:33][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([NH:22][CH2:23][CH2:24][OH:25])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC[Si](CC)(CC)OCCNc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(NCCO)cn2)cc1Cl
Yield: 86.9 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-triethylsilanyloxy-ethylamino)-pyrazin-2-yl]-propionamide (100 mg, 0.17 mmol) in tetrahydrofuran (2 mL), water (0.5 mL), and acetic acid (2 mL) was stirred at 25° C. for 6 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 2/3 hexanes/ethyl acetate to 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxy-ethylamino)-pyrazin-2-yl]-propionamide (69 mg, 86%) as a white foam: (ES)+-HRMS m/e calcd for C21H27ClN4O4S (M+H)+ 467.1515, found 467.1517.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].[H][H]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].CN(C)C(=O)C>[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc2c(c1)COC2=O
Temperature: 60 °C
Yield: 65.1 %

Procedure:
In a hydrogenator, 23 l of N,N-dimethylacetamide, 1.65 Kg (8.39 moles) of 5-chlorocarbonylphthalide (prepared for example as described in J. Chem. Soc., 1931, 867–871) and 200 g of 5% Pd/BaSO4 are charged Hydrogen is then charged at 3 bar thereinto and the mixture is heated at 60±3° C. for a total of 48 hours. The mixture is cooled and, after removal of the catalyst by filtration, the filtrate is concentrated under vacuum at 75° C. up to a solid residue. The product is dispersed with 8 l of deionized water and, at 5÷10° C. under stirring, the pH of the mixture is adjusted to 7.0÷7.5 by addition of 2.3 l of 10% ammonium hydroxide solution After a 30-minute stirring, the product is filtered, washed with deionized water and dried under vacuum at 50° C. to give 885 g (65%) of desired product having m.p.=163÷165° C. (in J. Chem Soc. 1925, page 2290 a m.p.=159÷160° C. is given).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1ccc(I)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Clc1cc(I)ccc1CBr
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 84.8 %

Procedure:
To a solution of 2-chloro-4-iodotoluene (7.59 g) in carbon tetrachloride (76 ml) were added N-bromosuccinimide (5.89 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (Wako V-70, 281 mg) at room temperature and the mixture was stirred at 55° C. for 3.5 hr. The reaction mixture was allowed to cool to room temperature and thereto was added hexane (76 ml). Insoluble matter was filtered off. The filtrate was concentrated and the residue was again dissolved in hexane. The mixture washed successively with water, 5% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-chloro-4-iodobenzyl bromide (8.45 g) as an oil.