Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:15]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-fluorobenzoic acid (3.0 g, 21.4 mmol) in methanol (71 mL) at 0° C. is treated dropwise with thionyl chloride (3.1 mL, 42.8 mmol). The solution is stirred for 15 min at 0° C., 2.5 h at room temperature, and 2 h at 50° C. The reaction is concentrated in vacuo and the residue dissolved in ethyl acetate (150 mL). The organic solution is washed with saturated aqueous sodium bicarbonate (2×100 mL), brine (100 mL), and dried over sodium sulfate. The solution is decanted and concentrated to yield the title compound, 2.61 g (79%), as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:22][C:23]#[N:24]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:22][C:23]#[N:24])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Yield: 999.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol), NaHCO3 (2.5 g, 3.0 mmol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH3CN (150 mol) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous solution was extracted with EtOAc. The EtOAc extract was washed with FI20, washed with brine, dried with MgSO4 and concentrated to yield 7.0 g of a tan solid. A 1.3 g sample was recrystallized from EtOAc to yield 0.65 g of a beige solid, m.p. 154°-156° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([NH:40][CH2:39][C:38]1[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=1[O:36][CH3:35])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: COc1ccccc1CN
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1COCCO1
Product: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-(t-butoxycarbonyl)tryptophan (46.4 g, 152.6 mmol) in 500 ml of dioxane was added carbonyl diimidazole (25.4 g, 156 mmol) in a portionwise manner. The resulting mixture was stirred for about 2.5 hours at room temperature and then stirred at 45° C for 30 minutes. Next, 2-methoxybenzylamine (20.7 ml, 158.7 mmol) was added and the reaction mixture was then stirred for 16 hours at room temperature.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([O:9]CC)=[O:8]>CO>[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)c1csnn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1csnn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
1N Aqueous solution of sodium hydroxide (6.7 ml.) was added to a solution of ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (syn isomer) (1.2 g.) in methanol (10 ml.) and the mixture was stirred for 1.5 hours at ambient temperature. Methanol was distilled off from the reaction mixture and water was added to the residue. The mixture was washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give prisms of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl) acetic acid (syn isomer) (0.7 g.), m.p. 110° to 113° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[C:9]1([O:18]O)[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1.S([O-])([O-])(=O)=O.[Mg+2]>S(=O)(=O)(O)O.C(O)C>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][CH:13]1[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9](=[O:18])[CH2:14]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O=C1CCCCC1
Solvent: CCO
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 0.17 h

Procedure:
To a stirred mixture of cyclohexanone (19.6 g) and ethanol (50 c.c.), kept at or below 0°C, was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g, 78% pure); solution was complete in ca. 10 min. To the solution was added conc. sulphuric acid (3 drops) and magnesium sulphate and the mixture was stored at 0°C for 3 days. The solid was filtered off, the filtrate washed with water, dried and distilled, to give cyclohexanone, dihydroisophorone and a fraction (11.5 g), b.p. 90°-100° at 0.02 mm Hg, peroxide equivalent 179. By mass spectroscopy the product was shown to contain the unsymmetrical peroxide ##SPC3##
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].N[C:7]1([O:16]O)[CH2:12][CH:11]([CH3:13])[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8]1>>[CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:13][CH:11]1[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7](=[O:16])[CH2:12]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Solvent: CCCC=O
Product: CC1CC(=O)CC(C)(C)C1

Procedure:
Butyraldehyde (28.8 g.) in petrol (100 c.c.) was cooled to below 0°C and with stirring treated with 1-amino-1-hydroperoxy-3,3,5-trimethylcyclohexane (33 g.; 93% pure). When the solid had dissolved the aqueous phase was removed and the petrol solution dried with magnesium sulphate overnight at 0°C. The working up as in Example 55 gave butyraldehyde, dihydroisophorone and the same peroxide (33.0 g.) b.p. 96° - 98°C/ 0.6 mm, as in Example 55.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.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>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OB(O)O)c(Cl)c1
Reactant: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nn2c(-c3ccc(OC)cc3Cl)cccc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
After dissolving 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (100 mg) in 1,2-dimethoxyethane (6 mL) and water (1 mL), 2-chloro-4-methoxyphenylboric acid (138 mg), tetrakis(triphenylphosphine)palladium (0) complex (86 mg) and barium hydroxide octahydrate (233 mg) were added and the mixture was heated and stirred at 80° C. for 3 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine, in that order. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as yellow crystals.
Reaction SMILES: [OH:1][OH:2].[CH3:3][C:4]1[CH2:9][CH2:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1>CO>[CH3:11][CH:10]([C:7]12[O:2][O:1][C:4]([CH3:3])([CH:9]=[CH:8]1)[CH2:5][CH2:6]2)[CH3:12]
Reactant: OO
Reactant: CC1=CC=C(C(C)C)CC1
Solvent: CO
Product: CC(C)C12C=CC(C)(CC1)OO2
Reaction time: 1.5 h

Procedure:
At 35° C., 45 μl of H2O2 (50%) were added to a solution of 325 μl of α-terpinene and 48.5 mg of Na2MoO4.2H2O in 4 ml of methanol. Five further 45 μl portions of H2O2 (50%) were added to this mixture as soon as the red-colored reaction mixture turned yellow again. After 1.5 hours, the reaction mixture was analyzed by means of HPLC. Analysis gave a quantitative formation of ascaridol.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)CCCCC1.[C:14]([O:17]CC)(=[O:16])[CH3:15]>>[C:14]([O:17][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:16])[CH3:15]
Reactant: CCOC(C)=O
Reactant: c1ccccc1
Solvent: OC1CCCCC1
Product: CC(=O)OC1CCCCC1
Reaction time: 28 h

Procedure:
When a benzene solution containing 15 mmols of cyclohexanol, 5 mmols of ethyl acetate and 0.05 mmols of complex 1 was refluxed under argon atmosphere, GC analysis after 28 hrs showed that all of the ethyl acetate disappeared and cyclohexyl acetate was formed as a single product (Table 30, entry 1). 1H NMR and GC-MS of the isolated product were identical to cyclohexyl acetate prepared by refluxing neat acetic anhydride with cyclohexanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=1)[CH2:32][N:33]1[CH2:37][C@H:36]2[C@H:38]([NH2:41])[CH2:39][CH2:40][C@H:35]2[CH2:34]1.CC[N+](CCCN(C)C)=C=N>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:41][C@H:38]1[C@H:36]2[C@H:35]([CH2:34][N:33]([CH2:32][C:31]3[CH:42]=[CH:43][CH:44]=[C:29]([C:28]([F:46])([F:27])[F:45])[CH:30]=3)[CH2:37]2)[CH2:40][CH2:39]1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC[N+](=C=N)CCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-L-leucine (180 mg, 0.778 mmol), hydroxybenzotriazole (119 mg, 0.778 mmol), and (3aS,4R,6aR)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine (201 mg, 0.707 mmol) from Example 154 Step A were combined in dichloromethane (1 mL). After 20 minutes, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.138 mL, 0.778 mmol) was added and the reaction stirred at room temperature for 24 hours. The reaction was quenched with water, and the layers were separated. The aqueous layer extracted with 1 mL of dichloromethane. The combined organic layers were applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) and eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give N2-(tert-butyloxycarbonyl)-N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.66 (d, J=7.1, 1H), 7.97 (d, J=8.5, 1H), 7.73 (s, 1H), 7.56 (s, 2H), 7.44 (t, J=7.7, 1H), 4.70 (dd, J=5.9, 11.0, 1H), 4.40 (br s, 1H), 3.56 (d, J=13.5, 1H), 3.41 (d, J=13.5, 1H), 2.74 (d, J=8.9, 1H), 2.48 (s, 2H), 2.37-2.31 (m, 1H), 2.27 (d, J=8.4, 1H), 2.24-2.19 (m, 1H), 2.12 (dq, J=6.0, 12.0, 1H), 1.91-1.81 (m, 4H), 1.66 (td, J=7.4, 14.7, 1H), 1.50 (s, 9H), 1.43-1.35 (m, 1H), 0.87 (d, J=5.9, 3H), 0.84 (d, J=5.6, 3H); MS (ESI+) m/z 498 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(C)=O.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Solvent: CO
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (100 g) in acetone (1000 ml) a solution of (1R)-10-camphorsulfonic acid (47 g) in methanol (500 ml) was added at rt, then slurry was heated under stirring to almost reflux for ca. 30 min, then cooled slowly to rt, seeded with the pure enantiomeric salt and stirred over night. The solid was collected by filtration, washed with methanol/acetone mixture, dried under reduced pressure. The residue was taken up with a solvent mixture of methylenechloride/water and after addition of saturated aqueous sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated, the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 39 g (39% yield, 92% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][S:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][S:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CSCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCOc1ccc(N)c([N+](=O)[O-])c1

Procedure:
5.7 G. of 1-acetamido-4-methylthiomethoxy-2-nitrobenzene is added to a mixture of 12 ml. 5N NaOH and 60 ml. methanol and the mixture heated for 15 minutes on a steam bath. The mixture is poured into 500 ml. water and is extracted with methylene chloride. The methylene chloride layer is separated, dried over sodium sulfate, and evaporated leaving 1-amino-4-methylthiomethoxy-2-nitrobenzene as a gum. This gum is dissolved in a mixture of 5 ml. acetic acid and 95 ml. methanol. 8 G. of iron powder is added and the mixture is heated at reflux for two hours. The methanol and acetic acid are evaporated and the residue is extracted with 200 ml. hot tetrahydrofuran. This solution is filtered and the tetrahydrofuran evaporated to yield 1,2-diamino-4-methylthiomethoxybenzene as a gum. This is purified by column chromatography.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[C:5]1(=[O:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[OH-].[Na+]>CS(O)(=O)=O>[NH:1]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6][C:5]1=[O:15]
Reactant: O=C1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCCc2ccccc2N1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
Sodium azide (1.95 g, 30 mmol) was added in small portions to a solution of 3,4-dihydro-1(2H)-naphthalenone (2.92 g, 20 mmol) in CH3SO3H (50 mL) at 0° C. The mixture was stirred at 0° C. for 15 min, hr at room temperature, poured into ice (400 mL), basified until pH>8 with 1N NaOH at 0° C. and extracted with ether (3×100 mL). The combined organic layer was dried (MgSO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:1) gave 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.71 g, 85%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ2.18-2.32 (m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (td, J=7.6, 1.5 Hz, 1H), 7.22 (d, J=7.0 Hz, 2H), 8.10 (br, 1H) ppm.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH:20](=O)[CH:21]=[O:22]>C1COCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:20]/[CH:21]=[O:22])=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=CC=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C/C=N/Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of 4-fluorophenylhydrazine hydrochloride (1 g, 6 mmol) in THF (20 mL) is treated with DIPEA (3 mL, 18 mmol). Then oxalaldehyde (40% in water, 0.89 g, 6.0 mmol) in THF (10 mL) is added dropwise in an ice-bath. After the addition, the mixture is stirred at RT for 30 min, quenched with water, and extracted with EtOAc. The organic phase is washed with saturated aqueous sodium chloride, dried over Na2SO4 and concentrated to afford the crude title compound (0.97 g, 97% yield). MS (m/z): 167 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[N:6])[CH3:2].[CH3:10][O-:11].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5](=[NH:6])[O:11][CH3:10])[CH3:2]
Reactant: C[O-]
Reactant: CCOC(C#N)OCC
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a stirred solution of diethoxyacetonitrile (5 g, 38.75 mmol) in dry methanol (80 mL) was added 1 mL of a 20% solution of sodium methoxide. After the addition, the reaction mixture was stirred at RT for 24 h, quenched with solid CO2, and then concentrated. The resulting residue was diluted with water and extracted with chloroform. The organic layer was washed with brine and dried over Na2SO4 to yield methyl 2,2-diethoxyacetimidate (6 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.95 (s, 1H),), 4.82 (s, 1H), 3.66 (s, 3H), 3.49 (q, 4H, J=7.2 Hz); 1.16-1.13 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C:9](=[O:12])[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C(O)C>[CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@H:9]([OH:12])[CH2:10][Cl:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Yield: 90.3 %

Procedure:
33.06 g of lithium aluminum tri-tert.-butoxyhydride were added portionwise at -15° C. to a suspension of 25.57 g of methyl (S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate in 280 ml of ethanol and the mixture was subsequently hydrolyzed at 0° C. with 140 ml of 3N hydrochloric acid and 170 ml of water. The suspension was concentrated to 370 ml, filtered and the residue was washed with water/ethanol (4:1) and dried, there being obtained 23.27 g (90%) of isomerically-pure methyl (1S,2S)-(1-benzyl-3-chloro-2-hydroxypropyl)-carbamate, m.p. 163°-164.5° C. IR (KBr): 3323s, br. (NH, OH), 1689 (C=O), 1546s (amide II).
Reaction SMILES: Cl[O-].[F:3][C:4]([F:16])([F:15])[CH2:5][N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][C:9](=[O:14])[CH2:10]2.Cl.[C-:18]#[N:19].[K+]>O.C(OCC)C>[C:18]([C:9]1([OH:14])[CH2:8][CH:7]2[N:6]([CH2:5][C:4]([F:3])([F:15])[F:16])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1)#[N:19]
Reactant: [C-]#N
Reactant: O=C1CC2CCC(C1)N2CC(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOCC
Product: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.5 %

Procedure:
A 50 ml 3-necked round bottom flask was equipped with a magnetic stirrer, thermometer and hypochiorite scrubber. 8-(2,2,2-Trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (1.06 g, 5 mmol) was charged to the reaction flask followed by hydrochloric acid (5M, 10 ml) and the mixture was cooled to 0° C. Diethyl ether (7 g) was added and the mixture stirred for 5 minutes. Potassium cyanide (3.69 g, 55 mmol) was added portionwise to the stirred, cooled reaction mixture over 0.25 hour. After complete addition the resultant pink mixture was stirred for 3 hours at 5° C. Water (10 ml) was added, the organic layer separated and the aqueous phase extracted with diethyl ether (2×10 ml). The combined ether extracts were dried (Na2SO4), filtered and concentrated in vacuo (without heat) to give 3-cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (1.13 g) as a dark red oil which solidified on standing and this was used directly in Step 2.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][OH:20])[CH2:3]1.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O.CCCCCC>N1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CC[C@@H](O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reaction time: 48 h
Yield: 86.4 %

Procedure:
A sample of benzyl (1S,2R,4R)-4-hydroxy-2-(hydroxymethyl)cyclohexylcarbamate (20.5 g, 73.4 mmol) was dissolved in anhydrous pyridine (140 mL) at room temperature prior to the addition of trityl chloride (20.46 g, 73.4 mmol) in one portion. The reaction mixture was stirred for two days. Pyridine was evaporated and the residue was dissolved in EtOAc. The solution was washed with water (2×) followed by brine. The combined aqueous layer was re-extracted with EtOAc. This organic layer was washed with brine. The combined organic layer was then dried over anhydrous Na2SO4 and evaporated to get an oily residue which yielded white crystalline product from EtOAc and hexane. The mother liquor was chromatographed (400 g silica gel eluted with 20% EtOAc/hexane followed by 40% and finally 70%). The desired regioisomer, benzyl (1S,2R,4R)-4-hydroxy-2-(trityloxymethyl)cyclohexylcarbamate (33.08 g, 63.4 mmol, 86% yield) was obtained as a white solid. MS found [M−H]−=520.2 (AP/CI). 1H-NMR (400 MHz, CDCl3) δ, ppm 7.4 (d, J=7.12 Hz, 6H), 7.19-7.34 (m, 15H), 5.25-5.31 (m, 1H), 4.98-5.09 (m, 2H), 3.92 (s, 1H), 3.66 (bs, 1H), 3.14-3.24 (m, 1H), 2.97 (dd, J=9.41, 4.83 Hz, 1H), 1.98-2.08 (m, 1H), 1.91 (d, J=11.9 Hz, 2H), 1.76-1.84 (m, 1H), 1.36-1.49 (m, 2H), 1.39-1.43 (m, 1H), 1.19-1.30 (m, 1H). A small amount of the undesired isomer, benzyl (1S,2R,4R)-2-(hydroxymethyl)-4-(trityloxy)cyclohexyl carbamate (1.17 g, 2.243 mmol, 3.06% yield) was also obtained. MS found [M−H]−=520.2 (AP/CI). 1H-NMR (400 MHz, CDCl3) δ, ppm 7.48 (d, J=7.12 Hz, 6H), 7.32-7.40 (m, 5H), 7.21-7.32 (m, 10H), 5.05-5.14 (m, 2H), 4.96 (d, J=8.65 Hz, 1H), 3.89 (dd, J=8.39, 2.8 Hz, 1H), 3.84 (dd, J=10.7, 4.58 Hz, 1H), 3.46 (ddd, J=14.5, 9.92, 4.07 Hz, 1H), 3.07 (ddd, J=15.26, 10.43, 4.3 Hz, 1H), 1.66 (dd, J=14.24, 3.05 Hz), 1.43-1.51 (m, 1H), 1.30-1.40 (m, 2H), 1.14-1.23 (m, 1H), 0.79-0.91 (m, 1H), 0.72-0.79 (m, 1H).
Reaction SMILES: O=[C:2]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO.O>[C:16]1([N:22]2[C:4]([NH2:5])=[CH:3][C:2]([C:6]3([C:9]([F:10])([F:11])[F:12])[CH2:8][CH2:7]3)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1
Temperature: 90 °C
Yield: 43.1 %

Procedure:
To 3-oxo-3-(1-(trifluoromethyl)cyclopropyl) propanenitrile (230 mg, 1.3 mmol) in EtOH (5 mL, 200 proof) was added H2O (3.7 mL), 1N NaOH(aq) (1.3 mL), and phenylhydrazine hydrochloride (188 mg, 1.3 mmol) and the mixture heated at 90° C. overnight. After cooling to room temperature, the mixture was diluted with H2O, extracted with EtOAc, the org layer concentrated in vacuo, and purified by column chromatography (5-25% EtOAc/hexanes) to give 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (150 mg, 0.56 mmol, 43%). LC-MS (ESI) m/z 268 (M+H)+.