Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])[CH2:18]/[C:19](=[N:27]\[OH:28])/[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[Li+].[OH-].C(O)=O>O1CCOCC1.O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=3)=[CH:16][CH:15]=2)[CH2:18]/[C:19](=[N:27]\[OH:28])/[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=2)=[C:30]([F:36])[CH:31]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(C/C(=N\O)c3ccnc(C)c3)c3ccc(Cl)cc3F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: O=CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(/C(CC(c2ccc(-c3csc(C(=O)O)c3)cc2)c2ccc(Cl)cc2F)=N/O)ccn1
Temperature: 100 °C
Yield: 98.6 %

Procedure:
To a solution of 4-{4-[1-(4-chloro-2-fluoro-phenyl)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-propyl]-phenyl}-thiophene-2-carboxylic acid ethyl ester (15 mg) in dioxane/water (1.5 mL, 1:1) was added LiOH (7.2 mg) and the reaction mixture heated by microwave irradiation to 100° C. for 30 min. Formic acid was added to neutralize LiOH and the solvent mixture removed by evaporation under reduced pressure. Purification of the crude reaction product by silica column chromatography eluting with a mixture of dichloromethane/methanol (95:5, containing 4% formic acid) provided 14 mg (98%) of the title compound as an off-white powder, MS (ESI+): m/z=495.1 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[F:21][C:22]1[S:26][C:25]([NH2:27])=[N:24][CH:23]=1>>[F:21][C:22]1[S:26][C:25]([NH:27][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])=[N:24][CH:23]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: Nc1ncc(F)s1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2ncc(F)s2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluoro-phenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 5-Fluoro-thiazol-2-ylamine (CAS: [64588-82-5], WO2006016178 instead of 3-Chloroaniline to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=350.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH:17]1[CH2:20][CH2:19][CH2:18]1>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:17]3[CH2:20][CH2:19][CH2:18]3)[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: C1CNC1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCC1)OC2

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), azetidine (0.10 ml, 1.5 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 283 (M+, 1), 123 (4), 77 (6), 71 (5), 70 (bp).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CC[CH:17]([N:20]=[C:21]=NC2CCCCC2)CC1.CNC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:11])[N:20]([CH3:21])[CH3:17])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CNC
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a solution of (R)-2-tert-Butoxycarbonylamino-propionic acid (1.78 g, 9.43 mmol) in DCM (7.85 mL) was added portion wise DCC (2.14 g, 10.37 mmol) cooled in an ice bath. After stirring at room temperature for 30 min, dimethylamine (2 M in THF) (6.13 mL, 12.25 mmol) was added. The resulting solution was stirred overnight (18 h) until reaction was completed. The reaction mixture was filtered through silica gel and eluted with Ethyl acetate. Then the filtrate was evaporated off. The solvent was removed to yield (1.71 g, 7.12 mmol, 76% yield, 90% purity) ((R)-1-Dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:15]#[N:16].[O:17]1[CH:21]=[N:20][N:19]=[C:18]1[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:17]1[CH:21]=[N:20][N:19]=[C:18]1[C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=2[C:15]#[N:16])=[CH:24][CH:23]=1
Reactant: CC[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Reactant: Nc1ccc(-c2nnco2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3nnco3)cc2)n1)C(N)=O
Reaction time: 20 h
Yield: 53.6 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)butanamide (70 mg, 0.292 mmol), 4-(1,3,4-oxadiazol-2-yl)aniline (60 mg, 0.372 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(6-(4-(1,3,4-oxadiazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)butanamide (57 mg).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:4][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)(=[S:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=S)OCc1ccccn1
Yield: 91.3 %

Procedure:
Potassium thioacetate (8.4 g, 73 mmol), 2-picolyl chloride hydrochloride 1 (6.0 g, 37 mmol) and potassium carbonate (5.0 g, 37 mmol) were stirred in DMF (35 mL) at room temperature (20-22°) for 18 h. The reaction mixture was poured into water (200 mL). The resultant mixture was extracted with Et2O (2×50 mL). The combined organic phases were washed with water and brine, dried (MgSO4), filtered and concentrated to give 2-picolyl thioacetate as a pale brown liquid (5.65 g). The product was used without purification.
Reaction SMILES: CC(C)([O-])C.[K+:6].C([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=1)(=O)C>O1CCCC1>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([O-:10])=[CH:12][CH:13]=1)=[CH2:16].[K+:6]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc([O-])cc1
Reaction time: 0.5 h

Procedure:
With ice cooling, 310 ml of a 1.0-M solution of potassium tertiary butoxide in tetrahydrofuran was stirred until a temperature of 5° C. was reached. To the solution, 50 grams (0.31 mol) of p-acetoxystyrene was added dropwise over 30 minutes. During this addition, the reaction solution was maintained at a temperature below 20° C. At the end of addition, the solution was allowed to stand under the conditions for 30 minutes, obtaining a yellowish orange colored tetrahydrofuran solution of potassium p-vinylphenolate. With stirring and ice water cooling, a solution of 67.28 grams (0.31 mol) of di-t-butyl dicarbonate in 60 ml of tetrahydrofuran was added dropwise to the reaction solution, which was maintained at a temperature below 20° C. At the end of addition, the reaction mixture was stirred for one hour at room temperature. It was combined with 30 ml of saturated saline water and shaken for subsequent decantation. The organic layer was dried over anhydrous sodium sulfate and the solvent distilled off. The oily residue was subjected to vacuum distillation, yielding 65 grams of a colorless oily product as a fraction of 90° to 92° C. /0.2 mmHg. It was p-t-butoxy-carbonyloxystyrene (GC 98.5%, yield 95.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:21]2[CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:25]1[CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2Br)C1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.349 g, 0.427 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.500 g, 4.27 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (ASW MedChem, Inc., New Brunswick, N.J., 1.893 g, 6.41 mmol), and potassium carbonate (3.54 g, 25.6 mmol) in 15 mL dioxane/7.5 mL water was heated to 100° C. for 1 hour. LC/MS showed product, so the reaction mixture was cooled to room temperature and the aqueous layer was removed. The organics were concentrated then purified directly by reverse phase column chromatography [Redisep Gold C18, 20-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielding tert-butyl 3-(2-bromo-5-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.040 g, 2.65 mmol, 62.0% yield). m/z (ESI) 413.9 (M+Na)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[S-:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+].Cl>C(O)C>[C:13]1([S:12][CH2:2][C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [S-]c1ccccc1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A mixture of 4-(bromomethyl)benzoic acid (10 g, 46.5 mmol), sodium thiophenoxide (6.15 g, 46.5 mmol), and ethanol (100 mL) was stirred for 1.5 hours under reflux. This mixture was cooled to room temperature and acidified with 1 N hydrochloric acid. The precipitate thus produced was collected, dissolved in ethyl acetate, and washed with water. The organic layer was concentrated under a reduced pressure to obtain the title compound (10 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][CH:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][CH:12]([C:14]1[CH:15]=[C:16]([O:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 110 °C
Yield: 82.6 %

Procedure:
In a 30 mL large microwave vial, 2-chloro-5-nitropyridine (1.041 g, 6.57 mmol, 1 equiv) was dissolved in 5.5 mL of dimethylformamide. 3-(1-methylethyl)phenol (0.90 mL, 6.57 mmol, 1 equiv) and potassium carbonate (4.54 g, 32.8 mmol, 5 equiv) were added. The reaction mixture was heated under microwave irradiation for 1 hour at 110° C. (Biotage Initiator). The reaction mixture was filtered. The filtrated solid was washed with dichloromethane (30 mL). The volatiles were evaporated under vacuum. The crude compound was dissolved in dichoromethane (20 mL) and brine was added (20 mL). The compound was extracted 2 times with dichloromethane (2×20 mL) and 2 times with ethyl acetate (2×20 mL). The organic phase was dried over sodium sulphate. Evaporation afforded the title compound (1.402 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([NH:8][C:9](=O)[CH2:10][O:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]2[NH:14][C:9]([CH2:10][O:11][CH3:12])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCc1nc2cccc(Cl)c2[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
[step 1] 3-Chloro-2-nitroaniline (2.0 g, 11.6 mmol) was dissolved in dichloromethane (58 mL), triethylamine (2.6 mL, 18.5 mmol) and methoxyacetyl chloride (1.4 mL, 15.1 mmol) were added at 0° C., and the mixture was stirred under reflux for 18 hr. To the mixture was added 4 mol/L hydrochloric acid (90 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50) to give N-(3-chloro-2-nitrophenyl)-2-methoxyacetamide (1.7 g, 62%). [step 2] N-(3-Chloro-2-nitrophenyl)-2-methoxyacetamide (900 mg, 3.68 mmol) obtained in step 1 was dissolved in ethanol (7.4 mL), tin chloride dihydrate (4.0 g, 17.7 mmol) was added and the mixture was stirred at 100° C. for 4 hr. The mixture was adjusted to pH 10 with 4 mol/L aqueous sodium hydroxide solution and filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (710 mg, 98%).
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=O)[C:24]2=[O:32])=[CH:19][CH:18]=1.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([C:23]2([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=3)[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:24]2=[O:32])=[CH:38][CH:37]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)cc3)no2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.204 g, 1.0 mmol), 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D, 0.331 g, 1.0 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.383 g, 2.00 mmol) were stirred together in dichloroethane (5.0 mL) at room temperature for 2 hours under nitrogen. The reaction was then heated to 85° C. and stirred overnight. The reaction mixture was cooled, concentrated, loaded onto a SF25-40 column (Analogix®, Burlington, Wis.) and the product eluted using a gradient of 10% ethyl acetate/hexanes to 70% ethyl acetate over 30 minutes (Flow=30 mL/minute) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.10 (d, J=8.1, 2H), 7.75 (d, J=8.3, 2H), 7.44-7.31 (m, 4H), 7.08-6.94 (m, 4H), 4.90 (s, 2H), 3.57 (t, J=6.5, 2H), 2.84 (t, J=6.5, 2H); MS (DCI) m/z 500.1 (M+H)+.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[S:6][C:7]=1[CH2:8][CH3:9].[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:16]1([CH:2]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[C:3]2[CH:4]=[C:5]([CH:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)[S:6][C:7]=2[CH2:8][CH3:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCc1sc(C2CCSCC2)cc1C(Cl)C1CCCCC1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: CCc1sc(C2CCSCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a mixture of 4-{4-[chloro(cyclohexyl)methyl]-5-ethylthiophen-2-yl}tetrahydro-2H-thiopyran (1.91 g) synthesized above, methyl 4-aminobenzoate (1.68 g), sodium iodide (1.66 g) and N,N-dimethylacetamide (20 mL) was added sodium carbonate (1.18 g), and the mixture was stirred overnight at 100° C. under an argon atmosphere. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give a white solid. To a mixture of the obtained solid, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred with heating under reflux overnight, and concentrated under reduced pressure. The residue was dissolved in water (60 mL), and 1N hydrochloric acid (20 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (2.07 g, 84%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:26](=[O:39])[CH2:25]2)=[C:20]([Br:40])[CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[B-](F)(F)(F)F.COC1C([P@](CC[P@](C2C=CC=CC=2)C2C(OC)=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.C1CC=CCCC=C1.[Rh]>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:26](=[O:39])[CH2:25]2)=[C:20]([Br:40])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1ccc(C2CC(=O)N(COCC[Si](C)(C)C)S2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: COc1ccccc1[P@](CC[P@](c1ccccc1)c1ccccc1OC)c1ccccc1
Solvent: CCO
Solvent: C1=CCCC=CCC1
Product: COC(=O)[C@H](Cc1ccc(C2CC(=O)N(COCC[Si](C)(C)C)S2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A solution of methyl (2Z)-2-[(benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxo-2-[2-(trimethylsilyl)ethoxy]methylisothiazolidin-5-yl)phenyl]acrylate (0.24 g, 0.37 mmol) in ethanol (10 mL) was bubble with nitrogen. (R,R)-(−)-1,2-bis[(o-methoxyphenyl)(phenyl)phosphino]ethane (1,5-cyclooctadiene) rhodium (I) tetrafluroborate (3 mg, 0.004 mmol) was added to the reaction solution and nitrogen was bubble through. After five cycles of vacuum/H2, the reaction was processed at a H2 pressure of 50 psi at room temperature. After 18 h, the solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (5%–50% ethyl acetate/hexanes) to afford product as a white solid (0.22 g, 91%). 1H NMR (400 MHz, CDCl3): δ 7.47 (dd, J=13.3, 1.4 Hz, 1H), 7.33 (m, 5H), 7.24 (m, 1H), 7.14 (m, 1H), 5.47 (m, 1H), 5.06 (m, 4H), 4.10 (m, 1H), 3.72 (s, 3H), 3.65 (t, J=8.0 Hz, 2H), 3.43 (dd, J=17.5, 8.2 Hz, 1H), 3.18 (m, 2H), 3.04 (dd, J=17.5, 6.4 Hz, 1H), 0.97 (dd, J=8.4, 7.2 Hz, 2H), 0.01 (s, 9H). LCMS found for C27H35BrN2O8SSiNa (M+Na)+: m/z=677, 679.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[C:24]([CH2:25]O)=[C:23]([CH:27]([CH3:29])[CH3:28])[CH:22]=[N:21]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[C:24]([CH2:25][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=2)=[C:23]([CH:27]([CH3:29])[CH3:28])[CH:22]=[N:21]1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a 0° C. suspension of 4′-Hydroxy-2′-methylacetophenone (716 mg, 4.77 mmol), [2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-methanol (1.36 g, 4.77 mmol), tri-n-butylphosphine (1.78 mL, 7.15 mmol) in toluene (20 mL) is added ADDP (1.80 g, 7.15 mmol). The reaction is warmed to room temperature and is stirred overnight. The reaction is concentrated under reduced pressure and the residue is chromatographed (0% to 30% EtOAc/Hex) to yield the title compound (857 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.42-7.38 (m, 2H), 7.32-7.27 (m, 1H), 6.64-6.58 (m, 2H), 4.85 (s, 2H), 2.99 (sept, 1H, J=7.0 Hz), 2.50 (s, 3H), 2.49 (s, 3H), 1.30 (d, 6H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11](N)=[O:12])=[CH:7][S:8][CH:9]=1.[OH2:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11]([OH:19])=[O:12])=[CH:7][S:8][CH:9]=1
Reactant: NC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl
Reactant: O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cscc1Nc1c(Cl)cccc1Cl

Procedure:
30.1 g (0.1 mole) of 4-(2,6-dichloroanilino)-3-thiophenacetamide are warmed to 100° in 135 ml of concentrated sulfuric acid and 49 ml of water for 3 hours. The mixture is poured onto ice, and the precipitate of 4-(2,6-dichloroanilino)-3-thiophenacetic acid which has formed in filtered off. The precipitate is boiled up with diisopropyl ether and dried; it then melts at 179° to 180°.
Reaction SMILES: [C:1]([CH:3]([CH:8]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10](OC)=[O:11])[C:4]([O:6][CH3:7])=[O:5])#[N:2].[H][H]>CO.C(Cl)(Cl)Cl.CC(O)C.[Pt](=O)=O>[O:11]=[C:10]1[NH:2][CH2:1][C@@H:3]([C:4]([O:6][CH3:7])=[O:5])[C@H:8]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:9]1
Reactant: [H][H]
Reactant: COC(=O)CC(c1cc(F)c(F)cc1F)C(C#N)C(=O)OC
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CO
Product: COC(=O)[C@@H]1CNC(=O)C[C@H]1c1cc(F)c(F)cc1F
Reaction time: 0.08 h

Procedure:
To a solution of 26.4 g (83.8 mmol) of dimethyl 2-cyano-3-(2,4,5-trifluorophenyl)pentanedioate from Step B in 120 mL of methanol was added 5.0 g (22 mmol) of platinum(IV) oxide. The reaction mixture was shaken under 50 psi of hydrogen for 16 h at which point the reaction was diluted with 400 mL of a 3:1 mixture of chloroform and 2-propanol to dissolve the desired white solid, and filtered through a pad of Celite. The filter cake was successively washed with three portions of 400 mL of the above solvent mixture. The combined filtrate and washings were concentrated and then taken up in 150 mL of ethyl acetate, stirred for 5 min, then 150 mL of hexanes was added and stirred for 5 min. The white precipitate was filtered to afford the title compound which was used without further purification. LC/MS 288.3 (M+1).