Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[OH:2][C@H:3]1[CH2:12][C@H:11]([O:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]2[C:5]([CH:6]=[CH:7][C@H:8]([CH3:31])[C@@H:9]2[CH2:21][CH2:22][C@H:23]2[O:28][C:27](=[O:29])[CH2:26][C@H:25]([OH:30])[CH2:24]2)=[CH:4]1.[OH-].[Na+:33]>O1CCOCC1>[OH:30][C@H:25]([CH2:24][C@H:23]([OH:1])[CH2:22][CH2:21][C@@H:9]1[C@@H:10]2[C:5](=[CH:4][C@@H:3]([OH:2])[CH2:12][C@@H:11]2[O:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH:6]=[CH:7][C@@H:8]1[CH3:31])[CH2:26][C:27]([O-:28])=[O:29].[Na+:33]
Reactant: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)CC(C)(C)C)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O)CC(=O)O1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)CC(C)(C)C)[C@@H]2[C@H]1CC[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.5 ml of water was added to a solution of 32 mg (0.076 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-hydroxy-8-(3,3-dimethylbutyryloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H-pyran-2-one [prepared as described in Example 28, above], in 1 ml of dioxane, after which 0.8 ml (0.08 mmol) of a 0.1 N aqueous solution of sodium hydroxide was added to the mixture. The resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was lyophilized to give 35 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][OH:5].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=CCO)CCC=C(C)CCC(=O)C(C)C
Product: CC(=O)OCC=C(C)CCC=C(C)CCC(=O)C(C)C
Yield: 94.7 %

Procedure:
To a solution of 3,7,11-trimethyl-2,6-dodecadien-10-on-1-ol (47.6 g) in acetic anhydride (61 g), pryidine (16 g) is added, and the resultant mixture is allowed to stand while cooling with ice for 3 hours. The reaction mixture is poured on ice and extracted with ether. The ether extract is washed with aqueous saturated solution of sodium chloride, aqueous solution of sodium hydrogen carbonate and water in order, dried over magnesium sulfate and evaporated to give 1-acetoxy-3,7,11-trimethyl-2,6-dodecadien-10-one (53 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)N1CCOCC1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 77.4 %

Procedure:
Using the general method of Example 143, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with 4-morpholinecarbonyl chloride (830 mg, 5.51 mmol) to provide 1.6 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a white powder, m.p. 194–196° C. Analysis: Calculated for C21H28N6O3: % C, 61.15; % H, 6.84; % N, 20.37; Found: % C, 60.82; % H, 6.94; % N, 20.34.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.O[CH2:21][C@H:22]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[C@@H:23]1[CH2:27][C@@H:26]([CH:28]([CH3:30])[CH3:29])[C:25](=[O:31])[O:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:28]([C@@H:26]1[CH2:27][C@@H:23]([CH:22]2[CH2:21][N@@:32]2[S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[O:24][C:25]1=[O:31])([CH3:30])[CH3:29]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC(C)[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 0.17 h

Procedure:
5.9 ml of a solution of diethyl azodicarboxylate in toluene (40%) (12.9 mmol) was added to a solution of 4.00 g of N-{(S)-2-hydroxy-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (1f) (10.7 mmol) and 3.38 g of triphenylphosphine (12.9 mmol) in tetrahydrofuran (100 ml) under ice-cooling over 10 minutes, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 3.40 g of the title compound (yield: 89%).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1>CN(C)C=O>[CH:3]1([CH2:9][CH2:10][O:11][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([C:21]([F:22])([F:24])[F:23])[CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCCC1CCCCC1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCC2CCCCC2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
Sodium hydride (343.2 mg, 8.58 mmol, 60% dispersed oil) was slowly added to cyclohexaneethanol (1 g, 7.8 mmol) dissolved in 30 ml of dried dimethylformamide under nitrogen at room temperature while stirring. The mixture was further stirred at room temperature for 30 minutes. Then, 4-fluoro-2-(trifluoromethyl)benzaldehyde (1.2 g, 7.8 mmol) dissolved in dried dimethylformamide was added thereto over 10 minutes and stirred at room temperature for 18 hours until the initial product disappeared. Subsequently, ice water was added thereto, and the resulting mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on the silica gel column (hexane:ethyl acetate-20:1) to afford the intermediate, 4-(2-cyclohexylethoxy)-2-(trifluoromethyl)benzaldehyde (1.77 g, yield: 75.6%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10](O)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BrH:13]>C(O)(=O)C.C(Cl)Cl>[Br:13][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:11]
Reactant: Br
Reactant: CC(O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(Br)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
26.15 g (156 mmol) of 1-(3-nitrophenyl)ethanol are dissolved in 130 ml of glacial acetic acid, and 55 ml (313 mmol) of 33% HBr in glacial acetic acid are added dropwise with ice cooling. The reaction mixture is stirred at room temperature for 5 days. The mixture is subsequently diluted with 300 ml of DCM, washed with 3×200 ml of H2O and 200 ml of saturated NaHCO3 solution, dried over sodium sulfate and evaporated to dryness, and the residue is crystallised from petroleum ether.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH:7]=O.Cl.[NH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]1[C:24]2[CH:25]=[CH:26][N:27]=[C:28]([Cl:33])[C:29]=2[CH:30]=[CH:31][CH:32]=1)(=[O:22])=[O:21].CCN(CC)CC.[BH4-].[Na+]>CO>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]1[C:24]2[CH:25]=[CH:26][N:27]=[C:28]([Cl:33])[C:29]=2[CH:30]=[CH:31][CH:32]=1)(=[O:21])=[O:22]
Reactant: NCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Reactant: O=CCOc1ccccc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCNCCOc1ccccc1C(F)(F)F)c1cccc2c(Cl)nccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A 4.2 mL of the (2-trifluoromethyl-phenoxy)-acetaldehyde stock solution (˜0.69 mmol) is added to a stirred mixture of 1-chloro-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide hydrochloride (200 mg, 0.621 mmol), 4 Å molecular sieve (400 mg) and NEt3 (0.19 mL, 1.4 mmol) in anhydrous CH3OH (5 mL) at ambient temperature under nitrogen. The resultant mixture is stirred for 16 hours. The mixture is cooled to 0° C. before it is treated with powdered sodium borohydride (53 mg, 1.4 mmol). The mixture is stirred at 0° C. for 1 hour and at ambient temperature for another 1 hour. After filtration and subsequent concentration in vacuo, the crude product is chromatographed on silica (gradient 0-5% CH3OH in CH2Cl2) to give 92 mg (0.19 mmol, 31% yield) of 1-chloro-isoquinoline -5-sulfonic acid {2-[2-(2-trifluoromethyl-phenoxy)-ethylamino]-ethyl}-amide. ESIMS: m/z 474 [(M+H)+, 35Cl], 476 [(M+H)+, 37Cl].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:28])[CH:6]=[CH:7][C:8]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]([CH3:27])([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH3:16])=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38].O>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]([CH3:16])([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH3:27])=[N:11][N:10]=1)[O:28][CH2:36][C:37]([NH2:39])=[O:38]
Reactant: Cn1c(-c2ccc(O)cc2Cl)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Reactant: NC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccc(OCC(N)=O)cc2Cl)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
3-chloro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}phenol monohydrochloride (40 mg) was suspended in DMF (2 ml), potassium carbonate (64 mg) and 2-bromoacetamide (26 mg) were added thereto, followed by stirring at 60° C. for 30 minutes. The reaction solution was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 100:5). The resulting residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to obtain 2-(3-chloro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}phenoxy}acetamide monohydrochloride (17 mg), as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](NC(=O)[C@@H](NC(=O)C(NC(OC(C)(C)C)=O)C2C=CC(OCCOC)=CC=2)CC2C=CC=CC=2)[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COCCOc1ccc(C(NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2nc(C(=O)OC)cs2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cscn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-((S)-2-{2-tert-Butoxycarbonylamino-2-[4-(2-methoxy-ethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (a mixture of two epimers, R/S=85:15) (0.21 g, 0.343 mmol) was dissolved into dry dichloromethane (20 mL) and trifluoroacetic acid (2 mL, 26 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The residue was cooled in an ice bath, then neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated to give crude 2-((S)-2A2-amino-2-[4-(2-methoxy-ethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a white foam (a mixture of two epimers, R/S=85:15) (0.16 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: CC(C)CN
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 140 °C

Procedure:
4-Chloro-N-isobutylphthalimide is prepared as described in Example 2, starting with 10 g of 4-chlorophthalic anhydride, 5.4 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 100 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 16 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is taken up in 100 cm3 of saturated aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 12 g of 4-chloro-N-isobutylphthalimide are thus obtained in the form of a white powder. (Rf=0.85, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.[CH:34](OCC)=[O:35]>>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][N:15]([CH:34]=[O:35])[CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: CCOC=O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(C=O)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C

Procedure:
A mixture of Example 1 (70.28 mg, 0.15 mmol) in ethyl formate (1 mL) in a sealed tube was heated at 70° C. overnight. After cooling to rt, the mixture was concentrated and purified by CombiFlash (eluent: 8% methanol in DCM) gave the product as a yellowish gel. 1H-NMR (400 MHz, CDCl3): δ 1.50-1.97 (m, 5H), 2.28 (br. s., 1H), 2.72 (br. s., 1H), 2.92-3.51 (m, 11H), 3.59-4.16 (m, 8H), 4.61-5.02 (m, 2H), 7.70 (br. s., 1H), 8.08-8.24 (m, 1H), 8.73 (br. s., 1H); LC/MS: C24H31F3N4O4: m/z 497.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][OH:14])=[CH:4][CH:3]=1.C1C(=O)N([Cl:22])C(=O)C1>CN(C)C=O>[Cl:22][C:11]1[S:10][C:9]([CH2:13][OH:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1sccc1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: OCc1sc(Cl)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-chlorophenyl)thiophen-2-yl]methanol (500 mg, 2.23 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), NCS (300 mg, 2.25 mmol, 1.01 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 20 ml of water. The resulting solution was extracted with 2×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (30/1-10/1). This resulted in 350 mg (55%) of [5-chloro-3-(4-chlorophenyl)thiophen-2-yl]methanol as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:28]([F:31])([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25](O)=[O:26])[C:22]=1[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:28]([F:30])([F:29])[F:31])=[N:20][N:21]([CH2:24][C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]([CH3:14])[CH3:15])=[O:26])[C:22]=1[CH3:23]
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
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
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.035 g, 0.16 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (0.039 g, 0.16 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.073 g, 0.19 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.045 mmol, 28%). 1H NMR (400 MHz, CDCl3) δ 7.99 (t, J=0.5 Hz, 1H), 7.74 (s, 1H), 7.35-7.24 (m, 2H), 7.20-7.11 (m, 2H), 4.92 (s, 2H), 3.02-2.90 (m, 1H), 2.39 (s, 3H), δ 1.13 (d, J=7.2 Hz, 6H); MS: (ES) m/z calculated for C19H18ClF4N5O [M+H]+ 444.1, found 443.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].CN(C)C=O.[C:21]1([CH2:27][O:28][CH2:29][CH2:30][CH2:31]Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>COC(C)(C)C.O>[C:21]1([CH2:27][O:28][CH2:29][CH2:30][CH2:31][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCCOCc2ccccc2)c1

Procedure:
To a 3-L reaction vessel was charged and stirred potassium carbonate (152 g), 3-hydroxybenzaldehyde (67.6 g), dimethylformamide (DMF, 250 mL) and 3-chloropropyl phenylmethyl ether (96.4 g) at 90° C. for ˜18 h. Water (567 mL) was added followed by tert-butyl methyl ether (907 mL). The bottom aqueous layer was separated and the organic layer washed with 1N sodium hydroxide (2×567 mL) and water (1×567 mL). The organic solution was concentrated to a minimum after which ethanol (200 proof, 907 mL) was added and the solution concentrated to a minimum and filtered though a 1-μm filter.
Reaction SMILES: C([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)(=O)C.C[O-].[Na+].Cl>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)COc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a 100 ml round flask were added 1.512 g methyl (4-acetoxy-phenoxy)-acetate dissolved in 50 ml anhydrous methanol, 0.364 g sodium methoxide. The mixture was stirred at room temperature for 1 hour. To the stirred mixture was added dilute HCl to adjust pH to weak acidity. The solvent was removed by evaporation. To the residue was added water. The solution was extracted with ethyl acetate for three times. The extract was dried, filtrated and evaporated to obtain 1.004 g of a brown solid, yield 85%. 1H-NMR (400 MHz, DMSO-d6, δ ppm) δ 3.679 (3H, s), 4.646 (2H, s), 6.672 (2H, d), 6.754 (2H, d), 9.0 (1H, s).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][N:11]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]3)=[O:22])[CH2:12]2)=[CH:19][CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a stirred solution of [(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (860 mg, 1.72 mmol) in CH2Cl2 (8 ml) was added TFA (2 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 680 mg (98%) of the title product as a white solid. ES-MS m/e: 401.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13]C(C)(C)C)=[O:12]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Solvent: Cc1ccccc1
Product: COC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Yield: 91.2 %

Procedure:
A solution containing 13.5 g of the product of Step B, 100 cm3 of toluene and 400 mg of hydrated p-toluene sulfonic acid was refluxed for 3 hours and then was evaporated to dryness under reduced pressure. The 11.2 g of residue were chromatographed over silica gel and was eluted with a 60-39-1 cyclohexane-ethyl acetate-acetic acid mixture. The eluate was evaporated to dryness under reduced pressure to obtain 9.6 g of (1R, cis)2,2-dimethyl-3-[(Z)-2-(methoxy carbonyl)-ethenyl]-cyclopropane-carboxylic acid melting at 110° C. and having a specific rotation of [α]D20 =+75.5°±2° (c=1% in CHCl3).
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C(O[Na])(C)(C)C.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][C:8]1[C:4]2[CH:3]=[C:2]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:30]=[CH:29][C:5]=2[S:6][C:7]=1[S:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:24]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11]
Reactant: C1COCCN1
Reactant: Cc1c(S(=O)(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)sc2ccc(Cl)cc12
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c(S(=O)(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)sc2ccc(N3CCOCC3)cc12
Yield: 52 %

Procedure:
1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-4-(3-trifluoromethyl-pyridin-2-yl)-piperazine (142.5 mg, 0.3 mmol), Pd2(dba)3 (13.7 mg, 0.015 mmol), t-BuONa (82.7 mg, 0.84 mmol) and the ligand (9 mg, 0.03 mmol) were mixed in a sealed tube which was flushed with N2. To this was added tolene (2 mL) and then morpholine (21 μL, 0.24 mmol). The resultant mixture was heated at 80° C. for 4 hours. The solvent was removed under vacuum and the crude product was purified with flash column chromatography to yield 4-{3-Methyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-5-yl}-morpholine in 52% yield (82 mg) as white solid. HRMS: calcd for C23H25F3N4O3S2+H+, 527.13929. found (ESI-FTMS, [M+H]1+), 527.1392.