Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:13]=[CH:14]/[C:15]([O:17]C(C)(C)C)=[O:16])=[CH:5][C:4]=2[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:22])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:5][C:4]=2[CH2:3]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC(C)(C)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-tert-butyl 3-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate (165 mg, 0.55 mmol) in CH2Cl2 (10 mL) was treated with TFA (10 mL). After stirring at room temperature for 2 h, the solution was concentrated in vacuo. The resulting crude product was treated with anhydrous HCl in dioxane (4 mL, 4.0 M) and sonicated for 15 min. The off-white solid product was then isolated by filtration and dried under vacuum. Yield: 152 mg (quant); 1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.56 (d, J=16.1 Hz, 1H), 6.54 (d, J=16.1 Hz, 1H), 2.81 (s, 2H), 1.09 (s, 6H); ESI MS m/z 247 [C13H14N3O4+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12])[C:5]([Cl:23])=[O:6]
Reactant: COc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C(=O)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3,5-dichloro-4-methoxybenzoic acid (8.81 g), toluene (170 mL), N,N-dimethylformamide (5 droplets) and thionyl chloride (6.0 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and then used for the synthesis of (c).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][C:20]([NH2:22])=[O:21])=[C:7]([CH3:18])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][C:20]([NH2:22])=[O:21])=[C:7]([CH3:18])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1)[CH3:34]
Reactant: Cc1c(CC(N)=O)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCOc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Yield: 710 %

Procedure:
Using the procedure in Example 33, 147 mg (0.5 mmol) of 6-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide was reacted with 20 mg (0.5 mmol) of 60% NaH/mineral oil and 0.08 mL (0.05 mmol) of ethyl 5-bromovalerate. After chromatography on silica (eluting first with 50% EtOAc/hexane, then EtOAc) and crystallization from MeOH/CH2Cl2 there was obtained 150 mg (71% yield) of 5-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-6-yl]oxy]pentanoic acid ethyl ester, mp, 123°-135° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:22](=[O:24])[NH2:23])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])(C)(C)C.C(OCC)C>Cl.C(OCC)(=O)C>[ClH:19].[Cl:19][C:18]([Cl:20])([Cl:21])[CH2:17][O:16][C:14](=[O:15])[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]([NH2:7])[C:22](=[O:24])[NH2:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NC(=O)[C@@H](N)CCCCNC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 181.7 %

Procedure:
[(1S)-1-carbamoyl-5-(2,2,2-trichloroethoxycarbonylamino)pentyl]carbamic acid tert butyl ester (39.5 g; 94 mmole) was dissolved in a solution of hydrogen chloride in ethyl acetate (1.5 M, 300 ml) and stirred for 30 min. Diethyl ether (300 ml) was added and the precipitate was filtered and dried to afford 30.5 g of ((5S)-5-amino-5-carbamoylpentyl)carbamic acid 2,2,2-trichloroethyl ester hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([NH:15]C(=O)C)=[C:13]([CH3:19])[CH:12]=[CH:11][N:10]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:32](OCCC(C)C)=O.O.[OH-].[Li+]>O.C(O)C.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:19]=[N:32][NH:15][C:14]=12
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1c(C)ccnc1-c1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Clc1ccc(-c2nccc3cn[nH]c23)c(Cl)c1
Reaction time: 22 h
Yield: 68.6 %

Procedure:
To a mixture of N-[2-(2,4-dichloro-phenyl)-4-methyl-pyridin-3-yl]-acetamide (30; 0.787 g, 2.67 mmol), 30 mL of benzene, acetic anhydride (0.780 mL, 8.27 mmol), and potassium acetate (0.330 g, 3.36 mmol) at 78° C. was added isoamyl nitrite (0.572 mL, 4.27 mmol), and the yellow mixture was stirred for 22 h. After cooling, the mixture was filtered and concentrated to an orange oil. To the oil was added 21 mL of ethanol, 7 mL of water, and lithium hydroxide monohydrate (0.339 g, 8.80 mmol). The orange mixture was stirred for 3 h, then concentrated to remove ethanol. The orange residue was partitioned between 50 mL of diethyl ether and 50 mL of a 10% aqueous NaOH solution, and the aqueous layer was extracted with 50 mL of diethyl ether. The combined organic layers were washed with 100 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, loaded onto silica gel and concentrated. Column chromatography (0→20% EtOAc/hexanes) afforded of 7-(2,4-dichloro-phenyl)-1H-pyrazolo[3,4-c]pyridine (31; 0.484 g; 67%) as a foamy pale yellow solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][C:13]=12.O>C(Cl)Cl>[N+:12]1([O-:9])[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][C:13]=12
Reactant: CCOC(=O)N1Cc2cccnc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1Cc2ccc[n+]([O-])c2C1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
mCPBA (7.3 g, 30 mmol) was added into a solution of ethyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (5 g, 26 mmol) in CH2Cl2 (200 mL) and stirred for 2 hours. The reaction was poured into water and extracted with CH2Cl2. The organic layer was washed with aqueous sodium bisulfate, NaHCO3 and brine, dried with Na2SO4, filtered and concentrated to afford the title compound (4 g, 74% yield) as a white solid.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[CH:14]=[O:15])#[N:10]>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C>[CH:1]1([O:6][C:18]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=2[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.3 %

Procedure:
A solution of cyclopentanol (1.15 g, 0.013 mol), in DMF (50 ml) was cooled to 0° C. Sodium hydride (1.54 g, 0.016 mol) was added portionwise to the solution and the mixture stirred at 0° C. for 10 minutes after complete addition. 3-Cyano-4-fluorobenzaldehyde (commercial) (2.0 g, 0.013 mol) was then added and the mixture allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0° C. and brine was added, the mixture was diluted with ethyl acetate (˜25 ml) and partitioned, the organic layer was washed with water (˜30 ml) and passed through a phase separating cartridge to dry. The solution was concentrated in vacuo and the residue purified by Biotage SP4, 40M with 20-60% ethylacetate/hexane as eluant. The product containing fractions were concentrated in vacuo to yield the title compound (1.02 g, 4.2 mmol) as a yellow liquid. MS (ES): requires C13H13NO2 215; found 216 (MH+).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=O)[CH:12]([F:14])[F:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.CC1C=CC(S(O)(=O)=O)=CC=1.O.[NH:28]1[CH:32]=CC=[N:29]1>C1(C)C=CC=CC=1>[F:13][CH:12]([F:14])[C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:28]([CH3:32])[N:29]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Reactant: c1cn[nH]c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
The aminal (1.00 g, 2.81 mmol) was dissolved in 7 mL of toluene. Then, ethyl α-ethoxymethylene-4,4-difluoro-3-oxobutyrate (1.25 g, 5.62 mmol) and p-TsOH (107 mg, 0.56 mmol) were added, followed by water (101 mg, 5.62 mg). The mixture was stirred at rt for 90 min, then GC control showed >97% conversion to the pyrazole. The reaction mixture was extracted with water (2×1 mL); then, the organic phase was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, cyclohexane/EtOAc 100:0→70:30) to give the product (840 mg, 4.12 mmol, 73% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[NH:8][C:9](=[O:18])[C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=1)[CH3:2].[OH-].[Na+].C(O)(=O)C>O>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[NH:8][C:9](=[O:18])[C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Nc2ccccc2OCC)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccccc1Nc1ncc(C(=O)O)c(=O)[nH]1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
Ethyl 1,6-dihydro-2-(2-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (3.4 g) and sodium hydroxide (1 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate thus obtained is added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(2-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (2 g). M.p. 226°-228° C.
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([CH:39]([NH2:41])[CH3:40])=[CH:36][C:35]=2[CH:42]=1>ClCCl.O>[F:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([CH:39]([NH:41][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:40])=[CH:36][C:35]=2[CH:42]=1
Reactant: CC(N)c1cc2cc(F)ccc2o1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Solvent: O
Product: CC(C)OC(=O)N[C@H](C(=O)NC(C)c1cc2cc(F)ccc2o1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
4.7 g of N-methylpiperidine was added to a solution containing 9.7 g of N-isopropoxycarbonyl-L-valine dissolved in 100 ml of dichloromethane, at -20° C. and the mixture was stirred for 15 minutes at the same temperature. Subsequently, 6.5 g of isobutyl chloroformate was added to the mixture at -30° C. and then the whole mixture was stirred between -30° C. and -20° C. for 30 minutes. 8.5 g of 1-(5-fluoro-2-benzofuranyl)ethylamine was then added to the mixture at -50° C. The mixture was allowed to sit and warm naturally to room temperature and then stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus obtaining 10.6 g of the desired product in the form of a white powder.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[N-:13]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([S:2]([CH3:1])(=[NH:13])=[O:3])=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
23.65 g (127.7 mmol) (RS)-1-(methylsulfinyl)-4-nitrobenzene in 130 ml chloroform are treated with 9.32 g (143.4 mmol) sodium azide. The mixture is slowly treated with 32.4 ml of concentrated sulfuric acid at 0° C. and then slowly heated to 45° C. After 16 hrs, the mixture is cooled to room temperature, treated with ice-water and extracted with chloroform. This organic phase is discarded. The aqueous phase is basified with 2N NaOH solution and extracted with DCM. The combined organic phases are washed with saturated NaCl solution, dried (Na2SO4), filtered and concentrated. 17.17 g (88.4 mmol, corresponding to 63% of theor.) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:46]1([C@@H:52]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)[C:53](O)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:53](=[O:54])[C@@H:52]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:56]3[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccc(F)cc2)cc1
Reactant: O=C(O)[C@@H](c1ccccc1)N1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1
Yield: 58.3 %

Procedure:
The product from Example 114A (0.26 g, 0.42 mmol) and (R)-2-phenyl-2-(piperidin-1-yl)acetic acid (0.12 g, 0.55 mmol) was processed as in Example 81A to give 0.20 g (58%) of the title compound as a white solid.
Reaction SMILES: Cl.[CH2:2]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[CH2:4][N:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].O>C(Cl)Cl>[F:24][C:25]([F:35])([F:36])[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([N:8]1[CH2:7][C:6]2[CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][C:5]=2[CH2:9]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC2=C(CNC2)C1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2=C(C1)CN(C(=O)c1ccccc1C(F)(F)F)C2
Reaction time: 2 h

Procedure:
tert-Butyl 3,4,5,6-tetrahydro-1H-pyrrolo[3,4-C]pyrrole-2-carboxylate hydrochloride (30 g, 121.6 mmol) was suspended in 700 ml of methylene chloride, triethylamine (50.7 ml, 364.8 mmol) was added with ice bath cooling, and 2-(trifluoromethyl)benzoyl chloride (25.22 ml, 171.2 mmol) was slowly added dropwise. The brown suspension was stirred for 2 h, in the course of which it was allowed to come to RT. The reaction mixture was admixed with water, and the organic phase was removed, dried and concentrated by rotary evaporation. The crude product (56.8 g) was converted further without purification.
Reaction SMILES: [Si]([CH:5]=[N+:6]=[N-:7])(C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[CH:16][C:17]2[N:21]=[C:20]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[C:42]([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=5)=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[NH:19][C:18]=2[CH:49]=1>C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[N:21]=[C:20]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[C:42]([C:43]6[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=6)=[CH:41][C:38]([C:39]6[N:40]=[N:7][NH:6][CH:5]=6)=[CH:37][N:36]=5)=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[NH:19][C:18]=2[CH:49]=1
Reactant: N#Cc1cnc(-c2ccc(CN3CCC(c4nc5ccc(F)cc5[nH]4)CC3)cc2)c(-c2ccccc2)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc2nc(C3CCN(Cc4ccc(-c5ncc(-c6c[nH]nn6)cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a solution of TMS diazomethane (2 M in hexanes, 0.205 mL, 0.410 mmol) in anhydrous THF (1 mL) was added n-butyl lithium (2.5 M in hexanes, 0.164 mL, 0.410 mmol) dropwise@−5° C. The mixture was stirred to 20 min@−5° C. when this solution was added dropwise to a mixture of 6-(4-{[4-(6-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (4-1, 0.050 g, 0.103 mmol) in THF (1 mL)@−5° C. The reaction was allowed to stir@−5° C. for 3 hr when it was quenched with saturated aqueous Na2HCO3 and extracted with CH2Cl2 (3×15 mL). The combined organics were dried (anhydrous Na2SO4), filtered, and concentrated. The residue was taken up in THF (2 mL) and TBAF (1 M in THF, 0.205 mL) was added. The reaction was heated to 60° C. for 2 hr, at which time it was cooled and concentrated. The resulting residue was taken up in DMF and purified by reverse phase HPLC (8-1; 5% CH3CN: 95% H2O+0.01% TFA to 95% CH3CN: 5% H2O+0.01% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 9.74 (bs, 1H), 9.20 (d, J=2.20, 1H), 8.65 (bs, 1H), 8.29 (d, J=2.21, 1H), 7.60-7.70 (m, 1H), 7.25-7.55 (m, 12H), 7.18 (t, J=7.08, 1H), 4.35 (s, 2H), 3.50 (d, J=12.06, 2H), 3.25-3.39 (m, 1H), 3.09-3.20 (m, 2H), 2.29-2.39 (m, 2H), 1.97-2.10 (m, 2H). HRMS m/z (M+H) Calcd: 530.2463, found: 530.2454.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:10]1[C:15]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.O>C1(C)C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:15]2[C:10]([N:5]3[CH2:6][CH2:7][CH2:8][C:4]3=[O:3])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(C(=O)c2cccnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)c2cccnc2N2CCCC2=O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.3 g of 60% sodium hydride in 20 ml of toluene is added 5.1 g of 2-oxopyrrolidine, followed by addition of 7.4 g of 2-chloro-3-(4-methoxybenzoyl)pyridine. The mixture is stirred at 50° C. for 1 hour. After the reaction mixture is poured into water, the toluene layer is washed with water and the solvent thereof is distilled off. The residue is recrystallized from a mixed solvent of isopropyl ether and ethyl acetate to give 3-(4-methoxybenzoyl)-2-(2-oxopyrrolidin-1-yl)pyridine, m.p. 76°-77° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:32])([F:31])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][N:27]=[N:26]2)=[CH:21][CH:20]=1.FC1C=C(F)C=CC=1[C@]1([C@H](OC2N(C3C=CC(OCC(F)(F)F)=CC=3)N=NN=2)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[C:29](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:32])[F:31])=[CH:24][CH:23]=2)[N:26]=[N:27]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]nnn1-c1ccc(OCC(F)(F)F)cc1
Agent: C[C@@H](Oc1nnnn1-c1ccc(OCC(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1nnn(-c2ccc(OCC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 41.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.35 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.31 g of 1-[4-(2,2,2-trifluoroethoxy)phenyl]-5(1H,4H)-tetrazolone, a mixture (3:2, 0.22 g) of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,2-trifluoroethoxy)phenyl]-5(1H,4H)-tetrazolone and (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-[4-(2,2,2-trifluoroethoxy)phenyl]-1H-tetrazol-5-yloxy]ethyl]oxirane was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][C:27]1([CH2:39][NH2:40])[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28]1>C(#N)C>[CH3:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:11]([NH:40][CH2:39][C:27]1([CH3:26])[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28]1)=[O:13]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(CN)CCN(Cc2ccccc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(NC(=O)OC(C)(C)C)C(=O)NCC1(C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 14.1 g (75 mmole) of t-butoxycarbonyl-L-alanine in 135 ml of dry acetonitrile was treated with 12.5 g (77 mmol) of 1,1'-carbonyldiimidazole. After stirring at room temperature for one hour and gas evolution had ceased, the reaction mixture was heated at 60° for one hour cooled to room temperature and treated with 14.2 g (70 mmol) of 3-methyl-1-(phenylmethyl)-3-pyrrolidinemethanamine. The reaction mixture was stirred at room temperature for 18 hours and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate/water and the organic layer was separated, washed with water, dried (MgSO4), and evaporated in vacuo to give 23.9 g of the title compound.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:10](=[O:22])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])=[O:12])=O)(C)(C)C.O.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(OCC)C>C(#N)C>[C:29]1([CH3:39])[CH:30]=[CH:31][C:32]([S:35]([OH:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1.[NH2:8][CH:9]([CH2:23][C:24]([F:25])([F:26])[F:27])[C:10](=[O:22])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])=[O:12]
Reactant: Cc1ccc(NC(=O)C(=O)C(CC(F)(F)F)NC(=O)OC(C)(C)C)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(=O)C(N)CC(F)(F)F)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
194 mg (0.5 mmol) of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2′,4′-dimethyl-2-oxovaleranilide and 285 mg (1.5 mmol) of p-toluenesulphonic acid monohydrate were dissolved in 5 ml of acetonitrile by heating to reflux for 15 seconds. The solution was allowed to cool and was stirred at room temperature for 1 hour. 20 ml of diethyl ether were added to the resulting suspension and the crude 3(RS)-amino-5,5,5-trifluoro-2′,4′-dimethyl-2-oxovaleranilide p-toluenesulphonate (1:1) which formed as a white solid was filtered off.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.CO>ClC1C(Cl)=C(Cl)C=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:4]2[CH:5]=[CH:6][C:1]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:2][CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Clc1cccc(Cl)c1Cl
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A mixture of biphenyl (10 g, 0.065 mol) and 4-chlorobenzenesulphonyl chloride (13.69 g, 0.065 mol) in trichlorobenzene (3 mL) was heated with stirring to 110° C. Anhydrous ferric chloride (0.05 g, 0.0003 mmol) was added and stirring was continued at 150° C. for 16 h. The cooled solid was stirred with methanol (200 mL). The product was filtered, washed with methanol, dried, and recrystallised from acetic acid to give 4-(4′-chlorobenzenesulphonyl)biphenyl (13.9 g, 65%); m.p. 169° C. (lit. 171-173° C.).