Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:2]1.[NH2:22][C@@H:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]([NH:26][CH3:27])=[O:25]>>[CH3:30][C:29]([CH3:32])([CH3:31])[CH2:28][C@H:23]([NH:22][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[C:9]([O:8][CH2:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:14]=1)=[O:17])[C:24](=[O:25])[NH:26][CH3:27]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinic acid and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=446.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[NH4+:11].C1COCC1>O>[Br:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-2,4-dichloropyrimidine (10.0 g, 44 mmol), concentrated ammonium hydroxide (100 mL) and THF (150 mL). The resulting mixture was magnetically stirred at room temperature for 12 h. Work-up: the reaction mixture was diluted with water (100 mL) and then extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 11 g (quantitative) of the product as a white solid. MS m/z: 208 (M+H+).
Reaction SMILES: [CH2:1]([C@H:3]1[NH:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].C([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)NC1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([O:16][CH3:15])[CH:18]=2)[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2]
Reactant: CC[C@H]1Nc2ccc(F)cc2NC1=O
Reactant: COc1cccc(C(=O)Cl)c1
Agent: CC[C@@H]1C(=O)Nc2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Product: CC[C@@H]1C(=O)Nc2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Yield: 76 %

Procedure:
(3R)-3-Ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) was treated with 3-methoxybenzoyl chloride according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-3-ethyl-7-fluoro-4-(3-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (76%). MS (ESI) m/z 329 ([M+H]+); MS (ESI) m/z 327 ([M−H]−); HRMS: calcd for C18H17FN2O3, 328.12238; found (ESI+), 329.12924.
Reaction SMILES: [C:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=1)[CH:14]1[O:16][CH2:15]1.[C:26]([O:31][CH2:32][CH2:33][OH:34])(=[O:30])[C:27]([CH3:29])=[CH2:28].N([C:44](C)(CC)[C:45]([O-:47])=O)=NC(C)(CC)C([O-])=O>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=1)[CH:14]1[O:16][CH2:15]1.[C:26]([O:31][CH2:32][CH2:33][OH:34])(=[O:30])[C:27]([CH3:29])=[CH2:28].[CH3:15][O:16][CH2:14][CH2:13][O:17][CH2:18][CH2:19][O:47][CH2:45][CH3:44]
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: C=C(C)C(=O)OC1CCCCO1
Agent: C=C(C)C(=O)OCCO
Agent: C=Cc1ccc(OCC2CO2)cc1
Solvent: CCCCCCC
Solvent: CC(=O)CC(C)C
Product: CCOCCOCCOC
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 57.0 g (0.36 mol) of 2-tetrahydropyranyl methacrylate, 31.7 g (0.18 mol) of p-vinylphenyl glycidyl ether, 7.8 g (0.06 mol) of 2-hydroxyethyl methacrylate and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in diethylene glycol ethyl methyl ether, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A-6 (2-tetrahydropyranyl methacrylate/p-vinylphenyl glycidyl ether/2-hydroxyethyl methacrylate) as a diethylene glycol ethyl methyl ether solution.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][C:17]=2[CH3:32])[C:10]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:9]1=2)=[O:6].[C:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[CH3:40].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C:39]([N:42]1[CH2:47][CH2:46][N:45]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:33])[C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[CH:18][C:17]=3[CH3:32])[C:10]3[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:9]2=3)=[O:6])[CH2:44][CH2:43]1)(=[O:41])[CH3:40]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CCCCl)c3cc(Cl)ccc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCN(CCCC(=O)OC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)CC1
Yield: 51.5 %

Procedure:
7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-chlorobutyrate (0.5 g) was dissolved in acetonitrile (10 ml). 1-Acetylpiperazine (0.35 g), sodium iodide (0.41 g), and sodium carbonate (0.19 g) were added to the solution, and the mixture was heated under reflux for 19 hours. The reactant was poured into water, and the mixture was extracted with ethyl acetate, washed with water, dried over sodium carbonate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1→100:10) to obtain 0.3 g of 7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-(4-acetylpiperazin-1-yl)butyrate as colorless oil.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].O.[OH-].[Li+].O.CO>O1CCCC1>[C:1]([NH:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)NC(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)NC(C)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
A mixture of methyl 4-(1-acetamidoethyl)benzoate (2.0 g, 9.0 mmol), lithium hydroxide monohydrate (2.0 g, 48.3 mmol), water (20 mL) and methanol (20 mL) in tetrahydrofuran (60 mL) was stirred at 20° C. for 12 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(1-acetamidoethyl)benzoic acid as a white solid (1.5 g, 80%). LRMS (M+H+) m/z: calcd 207.09. found 207.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=O)=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:15])(=[O:12])=[O:10])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc(S(=O)(=O)Cl)cc1
Yield: 80.4 %

Procedure:
20.6 g (0.1 mole) of sodium 4-vinylbenzenesulfonate was added to 200 ml of chloroform, and with stirring, 27.1 g (0.13 mole) of phosphorus pentachloride was gradually added at 5° C. After the addition, the mixture was stirred further for 1 hour. Chloroform was removed, and the product was washed with water and purified with ether to afford 16.3 g (yield 80.5%) of 4-vinylbenzenesulfonyl chloride. The resulting 4-vinylbenzenesulfonyl chloride was dissolved in 200 ml of toluene, and 14.8 g (0.08 mole) of p-aminodiphenylamine and 8 g of triethylamine were gradually added to the resulting solution. The mixture was stirred at 0° C. for 2 hours. The resulting precipitate was separated to afford 23.4 g (yield 83%) of N-(4-anilino)-phenyl-4-vinylbenzenesulfonamide having a melting point of 135° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC(=O)[NH:27][C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:30]3[CH2:31][CH2:32][C@H:28]([NH2:27])[CH2:29]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: O
Solvent: CN1CCOCC1
Product: N[C@H]1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)C1
Temperature: 60 °C
Yield: 21.6 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (700 mg, 2.65 mmol) obtained in Step 6 of Example 1, (S)-(pyrrolidin-3-yl)carbamic acid tert-butyl ester (740 g, 3.98 mmol), 1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (710 mg, 3.72 mmol) and N-methylmorpholine (0.608 mL, 5.32 mmol) in a similar manner to Example 5, was dissolved in methanol (1.5 mL) and the solution was added with 4 mol/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 60 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate, followed by extraction. The crude product was crystallized from acetone to obtain Compound 159 (190 mg, 22%).
Reaction SMILES: C([O:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH2:8][NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:20]([O:22]C)=[O:21])(=O)C.O.[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C.O>[OH:4][C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH2:8][NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCC(=O)c1ccccc1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)ccc12)c1ccccc1O
Temperature: 60 °C
Yield: 48.3 %

Procedure:
Dissolve 3-[(2-acetoxyphenacyl)amino]-2-carbmethoxy-6-chloroindole (800 mg, 2.15 mmol) in tetrahydrofuran/water (20 mL, 1/1). Add lithium hydroxide monohydrate (932 mg, 8.5 mmol). Seal the flask and warm to 60° C. for 3 hours. Dilute with ethyl acetate/water, acidify and separate the organic phase. Dry, precipitate with hexane and filter the solid to give the title compound (358 mg, 50%); mp 198°-200° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][OH:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@@H]1[C@H](CO)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=C[C@@H]1[C@H](COC(C)=O)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (54.2 g, 0.17 mol) and 4-(dimethylamino)pyridine (0.5 g, 4.1 mmol), in anhydrous pyridine (400 mL) was reacted with acetic anhydride (30 mL, 0.32 mol) at 0° C. for 1 hour then allowed to warm to room temperature. The reaction was stirred an additional 16 hours. The pyridine was removed in vacuo at 30° C. The residue was partitioned between ethyl acetate (100 mL) and of water (400 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL) and the combined ethyl acetate layers were washed with brine, dried with MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 49.6 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1.C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([OH:14])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 2.2 g of trans (4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester, 4 g of triphenyl-phosphine, 4.2 g of 4-nitrobenzoic acid, 120 mL of benzene and 10 mL of THF was added 3.5 g of diisopropyl-azo-di-carboxylate over 5 min. The mixture was allowed to stir at room temperature for 4 h and then concentrated under reduced pressure, taken up in 250 mL of dichloromethane and filtered and again concentrated. Chromatography on silica gel eluting with a gradient of 2%-20% ethyl acetate in hexane gave 1.2 g of product as a crystalline solid; 1H NMR (400 MHz, CDCl3) 8.3 (d, 2H), 8.2 (d, 2H), 3.8 (br m, 1H), 3.6 (br m, 1H), 2.4 (d, 1H), 2.1-1.6 (complex m, 8H), 1.45 (s, 9H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[CH:4]=1.Cl>[Fe].CO>[F:1][CH:2]([F:12])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cccc(C(F)F)c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1cccc(C(F)F)c1
Yield: 97.8 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-28 by using 1-(difluoromethyl)-3-nitrobenzene (1.0 g, 5.0 mmol), Iron powder (3.0 g, 15.0 mmol), conc. HCl (5 mL) and methanol (20 mL) to afford 0.700 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.36 (br s, 2H), 6.62-6.82 (m, 4H), 7.11 (t, J=7.8 Hz, 1H); MS (m/z): 144.05 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:34][C:35]3[CH:36]=[C:37]([C:45]([F:47])([F:48])[F:46])[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)c1
Yield: 85.2 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (85 mg, 0.19 mmol) in CH3CN (5 ml) was added 1-Bromomethyl-3,5-bis-trifluoromethyl-benzene (88.0 mg, 0.29 mmol), and diisopropylethylamine (66 μl, 0.38 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (109 mg, 85%). Calcd for C35H36F9NO2 (M+H) 673.65, Found 675.4
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[C:13]([CH2:26]O)=[N:14][C:15]2[C:16]([CH3:25])([CH3:24])[CH2:17][CH2:18][C:19]([CH3:23])([CH3:22])[C:20]=2[N:21]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.CCCCCC.O>[CH3:11][C:12]1[C:13]([CH3:26])=[N:14][C:15]2[C:16]([CH3:25])([CH3:24])[CH2:17][CH2:18][C:19]([CH3:23])([CH3:22])[C:20]=2[N:21]=1
Reactant: Cc1nc2c(nc1CO)C(C)(C)CCC2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CS(C)=O
Product: Cc1nc2c(nc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
A solution of 923 μl of dimethylsulfoxide in 2 ml of dichloromethane was added dropwise to a solution of 797 μl of oxalyl chloride in 6 ml of dichloromethane at −60° C. under a nitrogen gas stream, followed by stirring for 5 minutes. To the reaction mixture, a solution of 1 g of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylquinoxaline-2-methanol in 6 ml of dichloromethane was added dropwise and the resulting mixture was stirred for 15 minutes. Triethylamine (4.8 ml) was then added dropwise to the reaction mixture, followed by stirring for 5 minutes. After the reaction mixture was raised to room temperature and stirred for 15 minutes, water was added thereto. The resulting mixture was extracted with dichloromethane. The organic layer was successively washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 10% ethyl acetate/n-hexane), whereby 940 mg of the title compound were obtained in the form of a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1.CC(C)([O-])C.[Na+]>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].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>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]2)=[CH:3][N:4]=1
Reactant: OCCC1CCNCC1
Reactant: Brc1cncc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: OCCC1CCN(c2cncc3ccccc23)CC1
Yield: 65.7 %

Procedure:
The process is performed according to the protocol described in Example 2 (step 2.1). Starting with 1 g (4.81 mmol) of 4-bromoisoquinoline, 0.683 g (5.29 mmol) of 2-(4-piperidyl)ethanol, 1.11 g (11.50 mmol) of sodium tert-butoxide, 0.090 g (0.144 mmol) of BINAP and 0.044 g (0.048 mmol) of tris(dibenzylideneacetone)dipalladium, and after chromatography on silica gel, eluting with a 97/3 and then 95/5 mixture of dichloromethane and methanol, 0.810 g of product is obtained in the form of a viscous green liquid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH:17]=[O:18])=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC([O-])=O.[Na+].[BH3-]C#N.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][OH:18])=[CH:15][N:16]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ncc(CO)s1)C(CC1CCCCC1)n1cnc2ccc(F)cc2c1=O
Reaction time: 0.5 h

Procedure:
A mixture of Compound 150 (0.2 g, 0.4675 mmol) and NaOAc (46 mg, 0.561 mmol) was dissolved in DCM:MeOH (20:1, 1 mL) and stirred for 30 min. To this solution was added NaBH3CN (0.056 mg, 0.891 mmol) and the mixture was stirred at RT overnight. The reaction was quenched with aqueous NaHCO3 and extracted into DCM. The organic layer was washed with water and dried over MgSO4. The crude product was purified via preparative HPLC. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88-1.31 (m, 6H) 1.73 (s, 5H) 1.99-2.10 (m, 1 H) 2.14-2.26 (m, 1H) 4.82 (s, 2H) 5.83 (dd, J=8.84, 7.07 Hz, 1H) 7.47 (s, 1H) 7.48-7.56 (m, 1H) 7.77 (dd, J=8.97, 4.67 Hz, 1H) 7.95 (dd, J=8.34, 2.78 Hz, 1H) 8.31 (s, 1H). [M+H] calc'd for C21H23FN4O3S, 431; found, 431.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].C([OH:23])C.OO>O>[CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]([NH2:11])=[O:23])=[C:8]([C:14]([F:15])([F:17])[F:16])[CH:7]=1)(=[O:4])=[O:5]
Reactant: CCO
Reactant: CN(C)S(=O)(=O)c1ccc(C#N)c(C(F)(F)F)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1
Temperature: 40 °C

Procedure:
A mixture of 4-(N,N-dimethylsulphamoyl)-2-trifluoromethylbenzonitrile (2.78 g), sodium hydroxide (130 mg) and ethanol was heated to 40° C. Hydrogen peroxide (7 ml of 30% solution) was then added and the mixture heated at 40° C. for 3 hours. After cooling the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue recrystallised from ethyl acetate/toluene to give 4-(N,N-dimethylsulphamoyl)-2-trifluoromethylbenzamide (1.39 g) as a white solid, m.p. 149°-156° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C(O[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29]C=[CH:27][C:26]=1OC(=O)C)(=O)C.[C:35](=[O:38])([O-])[O-].[K+].[K+]>>[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.[OH:6][C:21]1[CH:20]=[CH:19][C:18]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:35]([OH:38])=[CH:27][CH:26]=2)=[CH:17][CH:22]=1
Reactant: CC(=O)Oc1ccccc1CCc1ccccc1OC(C)=O
Reactant: O=C([O-])[O-]
Agent: O=C(O)c1cccc(C(=O)O)c1
Agent: [K+]
Product: Oc1ccc(CCc2ccc(O)cc2)cc1
Temperature: 245 °C

Procedure:
A charge consisting of 167 parts of isophthalic acid and 298 parts of 1,2-bis(acetoxyphenyl)ethane and 0.005 mols potassium carbonate per mol of 1,2-bis(acetoxyphenyl)ethane is placed in a reaction vessel equipped with a stirrer, condenser and receiver. The vessel is evacuated and purged with nitrogen three times. During the reaction a nitrogen blanket is maintained in the reactor. The temperature is raised to about 245° C. and acetic acid distills. The rate of distillation during the initial 67 percent of reaction is 1.82 ml mol-1 min.-1. The distillation rate tapers after 87 parts of acetic acid have distilled in 55 minutes. The temperature rises slowly to 270° C. during the initial stage. Thereupon the vessel is evacuated to a pressure of about 200 torr for about 5 minutes and the pressure is then slowly reduced to about 1 torr while the temperature is increased to about 290° C. When the amperage on the stirrer motor increases by 0.02 to 0.04 amps, the stirrer motor is switched off and the vacuum is released with nitrogen. A total of 112 parts of acetic acid (98 percent of theoretical) is collected. The rate of evolution of acetic acid during the vacuum stage is 1.67 ml mol-1 min.-1. The prepolymer is extruded from the vessel under slight nitrogen pressure and is reduced in a mill to a powder of particle size in the range of from 0.1 to 0.25 mm. The inherent viscosity of the prepolymer is 0.28. The prepolymer is off white in color.