Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].P(OC)(OC)(O[CH3:18])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:13])([F:14])[F:12])=[N:8][N:9]([CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: COP(=O)(OC)OC
Product: CCOC(=O)c1cn(C)nc1C(F)(F)F
Temperature: 180 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of 4.16 g of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (20 mmol) and 10 ml of trimethyl phosphate (86.4 mmol) is stirred at a temperature of 180° C. for 16 hours. 200 ml of an ice-water mixture are then added. The resulting reaction product is filtered, washed with water and dissolved in 50 ml of ethyl acetate. The organic phase is washed twice with 50 ml of saturated sodium chloride solution each time and dried over sodium sulfate and concentrated by evaporation. 4.0 g (90% of theory) of 3-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester are obtained in the form of crystals (m.p. 55-57° C.).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][NH:3]1.[O:14]1[CH:18]=[CH:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[O:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[N:3]1[CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6](=[O:8])[NH:7][C:2]1=[O:1]
Reactant: CCOC(=O)c1c[nH]c(=O)[nH]c1=O
Reactant: C1=COCC1
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CCCO2)c(=O)[nH]c1=O
Temperature: 75 °C
Yield: 40.6 %

Procedure:
A mixture of 5.52 g. (30 mmoles) of ethyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate, 15 g. of 2,3-dihydrofuran and 15 ml. of pyridine is heated at 135° C. for 6 hours. The reaction mixture is concentrated to dryness under reduced pressure and, with the addition of 20 ml. of water, the pyridine is azeotropically removed. The residue is dissolved in 50 ml. of 50% ethanol and heated at 75° C. for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is stirred well with 40 ml. of chloroform. Then, 0.9 g. of insoluble ethyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate is recovered. The mother liquor is concentrated to dryness and the residue is recrystallized from 15 ml. of ethanol to give 3.1 g. (yield: 40.6%) of ethyl 1-(2-tetrahydrofuryl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate, melting point: 125° C.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][C:5]=1[Cl:41].[OH-].[Na+]>CO>[Cl:41][C:5]1[CH:6]=[C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])[CH:8]=[CH:9][C:4]=1[C:3]([OH:42])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)c(Cl)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 1 h

Procedure:
4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-chloro-benzoic acid methylester (54 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH (1N, 2 mL) and the mixture was stirred for 1 hr. at 55° C. The solvent was removed and the residue was treated with 1 N HCl to make the mixture acidic. The white suspension was extracted with EtOAc (3×10 mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 40 mg. MS (ES+) m/z Calcd: [(M+H)+]: 620. found: 620.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([B:10]([C:12]2[C:17]([CH3:18])=[C:16]([Cl:19])[C:15]([CH3:20])=[CH:14][C:13]=2[CH3:21])F)[C:3]=1[CH3:22].[C:23]1([CH3:42])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[B:31]([C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][C:34]=1[CH3:41])F>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([B:10]([C:12]2[C:17]([CH3:18])=[C:16]([Cl:19])[C:15]([CH3:20])=[CH:14][C:13]=2[CH3:21])[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([B:31]([C:33]3[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][C:34]=3[CH3:41])[C:24]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[CH3:42])[CH:3]=2)[C:3]=1[CH3:22]
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)c(Cl)c2C)c(C)c1Cl
Product: Cc1cc(C)c(B(c2cccc(B(c3c(C)cc(C)c(Cl)c3C)c3c(C)cc(C)c(Cl)c3C)c2)c2c(C)cc(C)cc2C)c(C)c1
Yield: 86 %

Procedure:
The compound is prepared by Method B described above in a yield of 86%, using 1 equivalent of bis(chloromesityl)fluoroborane and 1 equivalent of dimesitylfluoroborane. Physical data are given in Table 1.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:20]([NH:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Yield: 7.7 %

Procedure:
A mixture of 7-amino-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (0.154 g, 0.49 mmol), acetic anhydride (0.14 mL, 1.5 mmol), triethylamine (0.14 mL, 1.0 mmol) and a catalytic amount of 4-(N,N-dimethylamino)pyridine are stirred under N2 at room temperature for 18 h. The reaction is then quenched by addition of ice water. The dark precipitate is collected by Buchner filtration and is purified by preparative tlc (Rf=0.25, 7% MeOH/CHCl3). Recrystallization from EtOH gives 7-acetylamino-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (13.5 mg, 7.7%). 1H NMR (DMSO) δ 10.92 (1H, s), 10.22 (1H, s), 9.64 (1H, s), 8.70 (1H, s), 8.28 (1H, s), 8.21 (1H, s), 7.88 (1H, d, J=7.7 Hz) 7.41-7.34 (3H, m), 2.16 (3H, s).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH:8]2[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1.Br[C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1>>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[CH:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[CH:26][NH:27]4)=[CH:23][CH:22]=3)=[CH:4][CH:5]=1)[CH2:9]2
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: C[Sn](C)(C)c1ccc(OC2CN3CCC2CC3)cc1
Product: c1cc2ccc(-c3ccc(OC4CN5CCC4CC5)cc3)cc2[nH]1

Procedure:
The product of Example 2A (300 mg, 0.8 mmol) was coupled with 6-bromoindole (Aldrich, 196 mg, 1 mmol) according to the procedure in 2B. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as a solid (30 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) δ 1.45–1.58 (m, 1H), 1.64–1.90 (m, 2H), 2.01–2.15 (m, 1H), 2.17–2.24 (m, 1H), 2.75–3.04 (m, 5H), 3.30–3.42 (m, 1H), 4.53–4.61 (m, 1H), 6.43 (dd, J=3.1, 0.7 Hz, 1H), 6.97 (dt, J=8.8, 2.6 Hz, 2H), 7.21–7.27 (m, 2H), 7.52–7.60 (m, 4H) ppm. MS (DCl/NH3): m/z 319 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]1([C:18]([O:20]C)=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[Li+:22].[OH-]>>[CH3:1][C@:2]1([C:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=1.[Li+:22]
Reactant: COC(=O)[C@@]1(C)CCCN1Cc1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Product: C[C@]1(C(=O)[O-])CCCN1Cc1cccc(C(F)(F)F)c1

Procedure:
The title compound (D17) (37 mg) was prepared according to the general procedure for esters hydrolysis starting from (R)-methyl 2-methyl-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D10) (47 mg). (LiOH: 2 eq; reaction time: 18 hrs).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:28]Br.C([O-])(=O)C.[K+]>C(O)(=O)C>[Br:28][C:23]1[C:24]2[C:19](=[CH:18][C:17]([C:9]3[O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:8]=3[CH2:7][CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1[OH:27]
Reactant: Oc1ccc2cc(-c3oc4ccccc4c3CCC3CCCC3)ccc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Oc1ccc2cc(-c3oc4ccccc4c3CCC3CCCC3)ccc2c1Br
Yield: 74.4 %

Procedure:
Following the procedure described in Step 4 of Example 1, 6-[3-(2-cyclopentylethyl)-1-benzofuran-2-yl]-2-naphthol (0.671 g, 1.88 mmol) was brominated with bromine (0.11 mL, 2.2 mmol) and potassium acetate (1.91 g, 19.5 mmol) in glacial acetic acid (19 mL). Purification by flash chromatography using 100% hexane and 1-30% chloroform in hexane as eluants afforded 1-bromo-6-[3-(2-cyclopentylethyl)-1-benzofuran-2-yl]-2-naphthol as a light brown semi-solid (0.609 g). 1HNMR (300 MHz, DMSO-d6): δ10.75 (s, 1H), 8.25 (s, 1H), 8.15 (d, 1H, J=8.6 Hz), 7.95-8.0 (m, 2H), 7.7 (d, 1H, J=8.6 Hz), 7.6 (d, 1H, J=8.6 Hz), 7.25-7.4 (m, 3H), 3.0 (t, 2H, J=8.6 Hz), 1.65-1.95 (m, 5H), 1.4-1.65 (m, 4H), and 1.1-1.25 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([CH2:18][OH:17])=[CH:20][CH:21]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: OCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(Cn2ccc3ncnc(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (304 mg) was added, and the mixture was stirred at room temperature for 30 min. 4-Hydroxymethylbenzyl chloride (377 mg) was added, and the mixture was stirred at room temperature for 16 hrs. After diluting with water (30 mL), the mixture was extracted with ethyl acetate/tetrahydrofuran (3:1, 80 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (383 mg) as a powder.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:27]([O:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:18][CH:19]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (12.9 g, 34.3 mmol) in DMF (130 mL) were added benzyl bromide (8.16 mL, 68.6 mmol) and NaHCO3 (5.77 g, 68.6 mmol). After stirred at room temperature overnight, the reaction mixture was diluted with EtOAc. The mixture was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was treated with 4M HCl in dioxane (30 mL) and stirred for 2 hours. The reaction mixture was concentrated and the resulted residue was rinsed with iPr2O to give (S)-2-amino-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (11.2 g). 1H NMR (400 MHz, DMSO-d6) δ 3.14 (dd, 1H, J=7.7, 12.0 Hz), 3.27 (dd, 1H, J=5.9, 12.0 Hz), 4.38 (dd, 1H, J=5.9, 7.7 Hz), 5.15 (s, 2H), 7.23-7.27 (m, 2H), 7.30-7.34 (m, 5H), 7.42-7.45 (m, 1H), 7.51 (dd, 1H, J=7.6, 7.6 Hz), 7.61-7.66 (m, 3H), 7.69 (dd, 1H, J=1.8, 1.8 Hz), 8.64 (bs, 2H); MS: m/z (MH+) 366.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][CH2:5]1.[CH:37]1([N:40]2[CH:45]=[CH:44][C:43](I)=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.O.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>[CH:37]1([N:40]2[CH:45]=[CH:44][C:43]([C:17]3[CH:18]=[CH:19][C:14]([C@@H:12]([N:8]4[CH2:7][CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:36])[CH3:35])([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:10][C:9]4=[O:11])[CH3:13])=[CH:15][CH:16]=3)=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(I)ccn1C1CC1
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccc(-c2ccn(C3CC3)c(=O)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A mixture of (S)-7-(2-hydroxy-2-methylpropyl)-7-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazepan-2-one (20 mg, 0.04 mmol), 1-cyclopropyl-4-iodopyridin-2(1H)-one (10 mg, 0.04 mmol), Pd(PPh3)4 (5 mg), and Na2CO3 (43 mg, 0.36 mmol) in toluene/EtOH/H2O (3 mL/2 mL/2 mL) was stirred under N2 at 100° C. for 2 h. The reaction mixture was diluted with water (5 mL), and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by preparative-HPLC to give (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-7-(2-hydroxy-2-methylpropyl)-7-phenyl-1,3-oxazepan-2-one (8 mg, yield 40%) LC-MS Method 4 tR=1.166 min, m/z=443.1; 1H NMR (CDCl3) d 0.85 (m, 5H), 1.10 (m, 6H), 1.43 (m, 1H), 1.52 (d, 3H), 2.18 (m, 2H), 2.20 (d, 1H), 2.36 (d, 1H), 2.79 (m, 1H), 3.12-3.35 (m, 2H), 4.00 (s, 1H), 5.59 (m, 1H), 6.30 (d, 1H), 6.70 (d, 1H), 7.18-7.32 (m, 6H), 7.45 (m, 4H)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][CH:22]=[CH:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[CH2:24][CH2:23][CH:22]2[O:31][CH:21]23)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC=C3)cc1
Solvent: ClCCl
Product: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC2OC32)cc1

Procedure:
A solution of a 3:1 mixture of N-(4-cyanophenyl)-N-(7,8-dihydro-1-naphthyl)-2,2,2-trifluoro acetamide and the corresponding 5,6-dihydro isomer (4.3 g, 13 mmol) and m-chloroperoxybenzoic acid (80-85%, 4.0 g, 19 mmol) (Aldrich) in methylene chloride (60 ml) was stirred for 50 minutes at room temperature. The solution was diluted with methylene chloride (100 ml), washed with saturated NaHCO3 solution (2×30 ml), dried (K2CO3), and concentrated in vacuo. The epoxide isomers were separated by chromatography on silica gel eluting with diethyl ether:hexane (7:13 to 9:11) and recrystallization of the enriched isomer from diethyl ether:hexane. The mother liqour was combined with some mixed fractions from the chromatography and purified by repeating the procedure. The combined solid was dried under high vacuum to give N-(4-cyanophenyl)-2,2,2-trifluoro-N-(1a,2,3,7b-tetrahydronaphth[1,2-b]oxiren-4-yl)acetamide (2.8 g). 1H NMR (CDCl3, 200 MHz) δ: 1.69 (dt, J=14,5 Hz, 1H, CH2), 2.03-2.25 (m, 1H, CH2), 2.31-2.69 (m, 2H, CH2), 3.70-3.78 (m, 1H, OCH), 3.90 (d, J=4 Hz, 1H, OCH), 7.29-7.42 (m, 4H, Ar), 7.50-7.60 (m, 1H, Ar), 7.63 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C19H13F3N2O2: C, 63.69; H, 3.66; N, 7.82. Found: C, 63.70; H, 3.66; N, 7.76.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6](C(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[H-].[Na+].[F:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.C(OCC)C>C1COCC1>[F:24][C:25]1[N:30]=[CH:29][C:28](/[CH:31]=[C:3](/[C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[NH:6][CH:5]=2)\[C:1]#[N:2])=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(F)nc1
Reactant: COc1ccc2c(c1)c(CC#N)cn2C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3ccc(F)nc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-5-methoxy-1H-indol-1-carboxylate (719 mg, 2.51 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added, under an argon atmosphere, NaH (106 mg, 80%, 3.52 mmol, 1.4 eq.). The mixture was stirred at room temperature for 2 hours, and then cooled to 0° C. before the addition of 6-fluoro-pyridine-3-carbaldehyde (440 mg, 3.52 mmol, 1.4 eq.) in anhydrous THF (6 mL). The reaction apparatus was protected from light and the mixture was stirred at 0° C. for 4 hours, and then quenched with a saturated aqueous ammonium chloride solution. The mixture was stirred again at room temperature for 4 hours and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 98:2) to afford, after trituration with diethyl ether, the compound (28) as a yellow powder (45 mg, 6%). IR νmax (cm-1): 2215 (νCN); 1H NMR (DMSO, 300 MHz): δ (ppm): 3.84 (3H, s, 5′-methoxy), 6.91 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.36 (1H, dd, J5″-4″=8.5 Hz, J5″-F=2.1 Hz, H5″), 7.41 (1H, d, J7′-6′=8.9 Hz, H7′), 7.49 (1H, d, J4′-6′=2.4 Hz, H4′), 7.76 (1H, s, H3), 7.78 (1H, s, H2′), 8.52 (1H, td, J5″-4″=J5″-F=10.1 Hz, J4″-2″=1.8 Hz, H4″), 8.67 (1H, d, J2″-4″=1.8 Hz, H2″), 11.66 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.6 (5′-methoxy), 102.0 (C4′), 108.2 (C2), 109.7 (1C, d, 2JC—F=37 Hz, C5″), 110.0 (C3′), 112.4 (C6′), 113.2 (C7′), 118.0 (C1), 124.0 (C3a′), 127.7 (C2′), 129.5 (1C, d, 4JC—F=4 Hz, C3″), 130.7 (C3), 132.3 (C7a′), 140.7 (1C, d, 3JC—F=8 Hz, C4″), 148.2 (1C, d, 3JC—F=15 Hz, C2″), 154.6 (C5′), 162.6 (1C, d, 1JC—F=237 Hz, C6″); ESI: 294.1 ([M+H]+), 316.1 ([M+Na]+), 348.1 ([M+Na+MeOH]+); HRESI-MS: m/z 294.1052 (calcd for C17H13N3OF, 294.1043).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccc(F)cc2)cc1
Yield: 89.2 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0372 g, 0.065 mmol) and LiOH (0.015 g, 0.645 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 2 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0318 g, 0.058 mmol, 90% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.43-7.49 (m, 2H), 7.15-7.19 (m, 1H), 7.09-7.14 (m, 2H), 7.02-7.08 (m, 3H), 5.78 (br. s., 1H), 5.07-5.15 (m, 2H), 2.74 (s, 3H), 2.28 (s, 3H), 1.25-1.37 (m, 4H), 1.23 (s, 9H), 0.78 (br. s., 6H). 4H of piperidine are missing. LCMS (M+H)=549.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]([CH3:36])([C:20]2[N:24]([CH3:25])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=2)[CH3:19])=[C:6]([CH:16]=1)[C:7]([NH:9][CH2:10][C:11]([O:13]CC)=O)=[O:8].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]([CH3:36])([C:20]2[N:24]([CH3:25])[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:34])([F:33])[F:35])=[N:22][N:21]=2)[CH3:19])=[C:6]([CH:16]=1)[C:7]([NH:9][CH2:10][C:11]([NH:40][CH:37]1[CH2:39][CH2:38]1)=[O:13])=[O:8]
Reactant: NC1CC1
Reactant: CCOC(=O)CNC(=O)c1cc(Cl)ccc1OC(C)(C)c1nnc(-c2ccccc2C(F)(F)F)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NCC(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl N-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoyl]glycinate (300 mg) was dissolved in ethanol (6 ml), and cyclopropylamine (0.395 ml) was added thereto, followed by stirring at room temperature for one hour. Potassium carbonate (240 mg) was added to the reaction solution, followed by stirring at 60° C. for 3 hours. Water and a 1M aqueous sodium hydroxide solution were added to the reaction solution, followed by stirring for 30 minutes, 1M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was dissolved in DMF (6 ml), WSC•monohydrochloride (220 mg), HOAt (156 mg) and cyclopropylamine (0.395 ml) were added thereto, followed by stirring at room temperature for one hour, and diisopropylamine (0.500 ml) was added thereto, followed by stirring for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, 1M aqueous sodium hydroxide solution and then saturated brine in this order, and concentrated under reduced pressure. The resulting solid was washed with diisopropylether to obtain, as a white solid, 5-chloro-N-[2-(cyclopropylamino)-2-oxoethyl]-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzamide (142 mg).