Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:9]([CH2:23]O)=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:12]=1.C(N(S(F)(F)[F:36])CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[F:36][CH2:23][C:9]1[C:8]([O:7][C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([O:3][C:2]([F:28])([F:29])[F:1])[CH:5]=2)=[N:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-[3-(trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole-4-methanol (i.e. the product of Example 5, Step I, 0.075 g, 0.18 mmol) in anhydrous dichloromethane (4 mL) cooled to −78° C. was added (diethylamino)sulfur trifluoride (0.032 mL, 0.24 mmol). The mixture was stirred for 2 h during which time the temperature increase to −30° C. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (5 mL), extracted with ethyl acetate (3×15 mL), and washed with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product which was purified by chromatography on silica gel eluting with 0 to 10% ethyl acetate in hexanes to obtain the title compound (0.052 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Br[CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)N(c1ccc(Cl)cc1)C1CCNCC1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: O=C(Cc1ccccc1)N(c1ccc(Cl)cc1)C1CCN(C2CCCC2)CC1
Reaction time: 30 h

Procedure:
to a stirred and warm (40° C.) mixture of 5 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide and 200 parts of nbutanol is added 3.75 parts of bromocyclopentane and the whole is stirred and refluxed for 21h.30. Then a second portion of 5 parts of bromocyclopentane is added and stirring at reflux temperature is continued for another 30 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The oily residue solidifies on triturating in 1,1'-oxybisethane. The solid product is filtered off and crystallized from 1,1'-oxybisethane, yielding 1.1 parts of N-(4-chlorophenyl)-N-(1-cyclopentyl-4-piperidinyl)benzeneacetamide; mp. 139.5° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:16]1[N:20]([CH2:21][CH2:22][O:23][CH2:24][CH3:25])[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[N:17]=1>CN(C)C=O>[CH2:24]([O:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[N:17]=[C:16]1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH3:25]
Reactant: CCOC(=O)N1CCC(O)CC1
Reactant: CCOCCn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1c(OC2CCN(C(=O)OCC)CC2)nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a stirred mixture of 34.64 parts of ethyl 4-hydroxy-1-piperidinecarboxylate and 940 parts of N,N-dimethylformamide were added portionwise 10 parts of a sodium hydride dispersion 50% at room temperature under nitrogen atmosphere. Upon complete addition, stirring was continued for 1 hour at room temperature. A solution of 45 parts of 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole in N,N-dimethylformamide was added dropwise at 50° C. Upon completion, the whole was stirred overnight at 50° C. The reaction mixture was poured into ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 50 parts (69.1%) of ethyl 4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]oxy]-1-piperidinecarboxylate as a residue (compound 19).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[CH3:19])=[CH:9][C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[O:25]1[C:27]2([CH2:32][CH2:31][S:30][CH2:29][CH2:28]2)[CH2:26]1.C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[C:1]([NH:4][C:5]1[C:10]([C:11]2[C:12]([CH3:19])=[CH:13][C:14]([O:18][CH2:26][C:27]3([OH:25])[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[CH:15][C:16]=2[CH3:17])=[CH:9][C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1CC2(CCS1)CO2
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(-c2c(C)cc(O)cc2C)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(NC(C)=O)c(-c2c(C)cc(OCC3(O)CCSCC3)cc2C)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 39.3 %

Procedure:
To a solution of ethyl 6-(acetylamino)-4′-hydroxy-2′,6′-dimethylbiphenyl-3-carboxylate (490 mg, 1.50 mmol) and 1-oxa-6-thiaspiro[2.5]octane (224 mg, 1.72 mmol) in N,N-dimethylformamide (8 mL) was added potassium carbonate (238 mg, 1.72 mmol), and the mixture was stirred at 80° C. for 10 hr. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=2/3), and then by basic silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/2) to give the title compound (270 mg, yield 39%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:22][O:23][CH3:24])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:25]([O:27]CC)=[O:26].[OH-].[Na+].O1CCCC1>C(O)C>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:22][O:23][CH3:24])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)c1cc2cccc(N(COC)S(=O)(=O)c3cccs3)c2n1COC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCN(c1cccc2cc(C(=O)O)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-[(methoxymethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (4.43 g), 8N aqueous sodium hydroxide solution (2.5 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (3.86 g, yield 93%) as colorless crystals. melting point 183-184° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:8]1[NH:9][C:10]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cccc(F)c2[nH]1
Product: Fc1cccc2nc(Cl)[nH]c12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1′-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at RT. The reaction mixture was stirred overnight at RT and then heated for 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH (1.5 ml) was added and the mixture stirred for 30 minutes. The mixture was diluted with water (40 ml) and the resultant brown solid was collected by filtration, washed with water and then dried in vacuo to afford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m/z: (ES−) M-H−, 151.19. b) A solution of 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.7 g, 4.60 mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) was heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and excess phosphorus oxychloride was evaporated in vacuo. The residue was neutralized slowly (Care: exotherm) with saturated sodium bicarbonate solution (10 ml), and the mixture was then extracted with EtOAc (3×20 ml). The combined organic layers were washed with saturated brine and then dried over Na2SO4, filtered and evaporated to afford 2-chloro-7-fluoro-1H-benzo[d]imidazole (0.740 g, 94%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 7.01-7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m/z: (ES+) MH+, 171.20. c) 2-Chloro-7-fluoro-1H-benzo[d]imidazole (1.7 g, 9.97 mmol) was charged to a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40% EtOH solution, 50 ml, 9.97 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The mixture was evaporated and the residue dissolved in MeOH and then added to an SCX column. The column was eluted with 7N ammonia in MeOH and fractions containing product were evaporated to leave a brown oil. The oil was purified by flash chromatography on silica, eluting with a gradient of 5 to 20% MeOH in DCM. Pure fractions were evaporated to afford 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.230 g, 75%); 1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67-6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d); m/z: (ES+) MH+, 166.00.
Reaction SMILES: [O:1]1[C:3]2[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1=2.[H][H].[O-2].[O-2].[O-2].[Al+3].[Al+3]>[Pd]>[CH:2]1([OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1=CC2=C(CCCCCCCC1)O2
Reactant: [H][H]
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Product: OC1CCCCCCCCCCC1
Yield: 20 %

Procedure:
Also, it is known that epoxidized cycloalkanes and/or epoxidized cycloalkenes can be produced by epoxidizing corresponding cycloalkenes with a high yield. If the epoxidized compounds can be converted to corresponding cycloalkanones and cycloalkanols with a high efficiency, the cycloalkanones and the cycloalkanols can be expected to be obtained at a high yield. However, only a small number of reports can be found on methods of converting an epoxidized cycloalkane and/or an epoxidized cycloalkene to a mixture of cycloalkanone with cycloalkanol. For example, J. Mol. Catal., Vol. 69, pages 69 to 103 (1991) discloses a method of hydrogenating a monoepoxycyclododecadiene with hydrogen in the presence of a catalyst comprising palladium carried on a carrier consisting of γ-alumina, under a hydrogen gas pressure of 1.3 MPa at a temperature of 90° C. In this method, cyclododecanol was produced with a yield of 20% or less and no cyclododecanone was produced. When a catalyst comprising palladium carried on a carrier consisting of titania or silica was used in place of the above-mentioned palladium catalyst carried on γ-alumina, the yield of cyclododecanol was low and unsatisfactory.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]([NH2:7])=[O:6])[CH3:4].O=[C:9]([CH3:17])[CH2:10][CH2:11][C:12](OCC)=[O:13]>>[CH3:4][C@H:3]1[N:2]2[C:12](=[O:13])[CH2:11][CH2:10][C@@:9]2([CH3:17])[NH:7][C:5]1=[O:6]
Reactant: CCOC(=O)CCC(C)=O
Reactant: CC(N)C(N)=O
Agent: Cl
Product: C[C@@H]1C(=O)N[C@]2(C)CCC(=O)N12

Procedure:
DL-Alaninamide hydrochloride (6.9 g), 0.055 mol) and ethyl 4-oxopentanoate (6.7 g, 0.043 mol) were reacted together according to the procedure of Example 2 to give the title compound, 1.65 g (22.8%), m.p. 184°-192° . NMR (DMSO-d6 : deltaH =8.80 (bs, 1H, NH); 3.90 (q, J=7.5 Hz, 1H, CHCH3) 3.00-2.00 (c.a., 4H, CH2CH2); 1.42 (s, 3H, C--CH3); 1.22 (d, J=7.5 Hz, 1H, CHCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[NH2:14][C:13]1[CH:12]=[C:11]([F:10])[C:17]([F:18])=[CH:16][C:15]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=Cc1ccccc1Cl
Product: Nc1cc(F)c(F)cc1C(=O)c1ccccc1Cl

Procedure:
(2-amino-4,5-difluorophenyl)-(2-chlorophenyl)-methanone (Xmm) was prepared by reacting 2-chlorobenzaldehyde with 0.30 moles of 3,4-difluoro aniline in a manner analogous to Example 1. MH+/Z=268.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[C:6]=1[CH3:13])(=[O:4])=[O:3].C(O)(=[O:16])C.C(OC(=O)C)(=O)C>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:12][OH:16])[C:6]=1[CH3:13])(=[O:4])=[O:3]
Reactant: Cc1c(S(C)(=O)=O)cc[n+]([O-])c1C
Reactant: CC(=O)O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: Cc1c(S(C)(=O)=O)ccnc1CO
Temperature: 80 °C

Procedure:
To a mixture of (4-Methanesulfonyl-2,3-dimethyl-pyridine)-1-oxide (24 g) and acetic acid (50 ml) was added acetic anhydride (28.2 ml), followed by heating to reflux and maintaining the same temperature for about 3 hrs. The reaction mass was cooled to 80° C. and methanol (25 ml) was added followed distilling off the solvent completely under vacuum. THF:methanol (125:25 ml), LiOH (7.5 g) was added to the crude at 25-30° C. followed by adding DCM (100 ml) to the reaction mixture and extraction with (2×150 ml) DCM. All the organic layers were combined and washed with saturated sodium chloride solution (25 ml). The organic layer was dried over sodium sulphate and distilled off completely under vacuum. Subsequently, n-hexane (100 ml) was added to the reaction mass, the compound filtered and washed with n-hexane (10 ml). The wet compound was then dried at 50-55° C. to yield 14 g of the title compound characterized by 1HNMR data (300 MHz): δ 2.58 (s, 3H), 3.13 (s, 3H), 4.62 (s, 1H), 4.80 (s, 2H), 7.86 (d, 1H), 8.68 (d, 1H) and mass [M]+: 202.06.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>>[C:6]1([C:4]2[C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[NH:1][C:18]3[N:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: Nc1cccnc1Cl
Product: c1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 190 °C
Yield: 26.9 %

Procedure:
A mixture of 19.7 g (0.1 mole) of 2-aminobenzophenone and 15.0 g (0.12 mole) of 3-amino-2-chloropyridine was heated under nitrogen atmosphere at 190° C. for 1.75 hr. The mixture was cooled to room temperature and partitioned between 3N aqueous sodium hydroxide and methylene chloride. The combined methylene chloride extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue, 32.7 g, was dissolved in benzene and chromatographed on a column of florisil packed in benzene, eluting with benzene and 1-2% acetone-benzene mixtures. After evaporation, the solid was crystallized from benzene to give 7.3 g product; m.p. 106°-108° C.
Reaction SMILES: Cl[C:2](OCC)=[O:3].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][OH:30])=[NH:28])=[CH:23][N:22]=1)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH2:35]([O:34][C:32]1[CH:31]=[C:17]([CH:16]=[C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][C:2](=[O:3])[O:30][N:29]=2)=[CH:23][N:22]=1)=[O:19])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N=C(NO)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2noc(=O)[nH]2)cn1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
Ethyl chloroformate (32 μL, 0.33 mmol) was added to a solution of 3,5-bis(benzyloxy)-N-{5-[(hydroxyamino)(imino)methyl]pyridin-2-yl}benzamide (140 mg, 0.30 mmol) in pyridine (5 mL). This solution was heated at reflux overnight. The mixture was cooled and concentrated under reduced pressure. DCM and methanol were used to dissolve the remaining material and the solution was washed with water. The organic solution was concentrated under reduced pressure and the residue was purified on silica by MPLC (eluting firstly with 5% methanol/DCM then 10% methanol/DCM). The title compound was obtained as a colourless solid (103 mg, 70%). 1H NMR δ (d6-DMSO): 5.19 (4H, s); 6.87 (1H, s); 7.28-7.46 (12H, m); 8.21 (1H, dd); 8.38 (1H, d); 8.79 (1H, s); 11.14 (1H, br s); m/z (LCMS; ESI+) 495 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[C:25]([CH3:27])([CH3:26])[O:24][C:23]([NH:28][C:29]45[CH2:36][CH:35]6[CH2:37][C:31]([C:38](=[O:40])[NH2:39])([CH2:32][CH:33]4[CH2:34]6)[CH2:30]5)=[N:22][S:21]3(=[O:42])=[O:41])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)CCC.[H][H].Cl>CO.[Pd]>[CH3:26][C:25]1([CH3:27])[O:24][C:23]([NH:28][C:29]23[CH2:36][CH:35]4[CH2:37][C:31]([C:38]([NH2:39])=[O:40])([CH2:32][CH:33]2[CH2:34]4)[CH2:30]3)=[N:22][S:21](=[O:41])(=[O:42])[C@@H:20]1[C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: CCCCOC(=O)N1CC=C(c2ccc([C@@H]3C(C)(C)OC(NC45CC6CC4CC(C(N)=O)(C6)C5)=NS3(=O)=O)cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-{4-[(R)-2-(2-carbamoylhexahydro-2,5-methanopentalen-3a-ylamino)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid butyl ester (100 mg) in methanol (10 mL) was admixed with palladium on carbon (10%, 100 mg) and the mixture was stirred in a hydrogen atmosphere for 1.5 h. The mixture was filtered and concentrated. The residue was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. After stirring at room temperature for 1 h, the solvent was removed under reduced pressure and TFA ester formed was cleaved by treatment with 1 N HCl. Extraction with ethyl acetate gave the crude product, which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Triethylamine 0.7 ml (5.0 mmol) was added to a solution of 500 mg (2.5 mmol) of 2-(4-bromophenyl)ethanamine in tetrahydrofuran (5 ml). 2-Nitrobenzenesulfonyl chloride (664.6 mg, 3.0 mmol) was then added thereto, and the mixture was stirred at room temperature for one hr. Thereafter, a saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 915 mg (yield 95%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=O>>[F:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(F)cc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 65 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-fluoro-5-(trifluoromethyl)benzoic acid: MS (ESI): m/z 455 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:13]1[O:15][CH2:14]1.B(F)(F)F.CCOCC>ClCCl.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1
Reactant: C1CO1
Reactant: COC(=O)c1ccc(CO)cc1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc(COCCO)cc1
Temperature: 25 °C
Yield: 17 %

Procedure:
To a two-neck round bottom flask, which was equipped with a Dewar condenser, a solution of 4-hydroxymethylbenzoic acid methyl ester (2.50 g, 0.015 mol) in anhydrous dichloromethane (30 mL) was cooled to −10° C. in a salt/ice bath. Ethylene oxide (1.10 mL) was added to the cooled stirring solution dropwise followed by the addition of boron trifluoride etherate (0.51 ml). The reaction mixture was stirred for 45 minutes and then warmed to room temperature for 30 minutes to boil off any excess of ethylene oxide from the reaction mixture. The reaction mixture was then diluted with brine. The aqueous layer was extracted with dichloromethane (3 times). All of the organic layers were combined, dried over Na2SO4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to provide the desired product (537 mg, 2.56 mmol) in 17% yield. 1H (CDCl3 8.36, 600 MHz): δ (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.5 Hz), 4.62 (3H, s), 3.92 (2H, s), 3.78 (m, 2H), 3.63 (2H, m); 13C(CDCl3 167.1, 143.5, 130.0, 129.8, 127.5, 72.9, 72.0, 150 MHz): δ 62.1, 52.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:20]=2[CH3:21])=[O:15])[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:32])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:20]=2[CH3:21])=[O:15])[CH2:9][C:10]([Cl:32])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)NC(CC(=O)O)c2cccc(Br)c2)cnn1-c1ccc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: Cc1c(C(=O)NC(CC(=O)Cl)c2cccc(Br)c2)cnn1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 3-(3-bromo-phenyl)-3-{[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid (870 mg, 1.8 mmol) in thionyl chloride (40 mL) is heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture is concentrated in vacuo to afford 3-(3-bromo-phenyl)-3-{[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-propionyl chloride as an off-white solid (880 mg, 98%) which is used without further purification.