Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]2=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([F:25])[CH:19]=3)[C:11]([C:13]([O:15]CC)=[O:14])=[CH:12][N:8]2[N:7]=[CH:6][N:5]=1.Cl>C1COCC1.C(O)C>[NH2:3][C:4]1[C:9]2=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([F:25])[CH:19]=3)[C:11]([C:13]([OH:15])=[O:14])=[CH:12][N:8]2[N:7]=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(-c2c(C(=O)O)cn3ncnc(N)c23)cc1F
Temperature: 65 °C
Yield: 99.5 %

Procedure:
1 N aqueous sodium hydroxide (253 mL, 253 mmol) was added to a suspension of ethyl 4-amino-5-(4-amino-3-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (40.0 g, 127 mmol) in THF (400 mL) and ethanol (400 mL). The reaction mixture was heated (65° C.) for 16 h and then cooled to rt. Hydrogen chloride (4 N in 1,4-dioxane, 70 mL, 280 mmol) was added and the volatiles were removed under reduced pressure. The residue was washed with water (200 mL) and then triturated with acetone and diethyl ether to give the desired product (36.3 g 99%) containing trace impurities. 1H NMR (300 MHz, DMSO-d6) δ 12.20-12.30 (br s, 1H), 8.03 (s, 1H), 7.94-8.05 (br s, 1H), 7.89 (s, 1H), 7.02 (dd, J=12.4, 2.0 Hz, 1H), 6.73-6.92 (m, 2H), 5.22-5.47 (br s, 1H), 5.12-5.25 (br s, 1H); ES-MS m/z 288.0 (MH)+; HPLC RT (Method A) 1.13 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[N:7]=[C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1>[C:14]([O:13][C:11]([NH:10][C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH2:18][C:19]([OH:21])=[O:20])[N:7]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cc(NC(=O)OC(C)(C)C)nn1CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C(=O)O)n(CC(=O)O)n1
Reaction time: 2 h
Yield: 122.1 %

Procedure:
To a solution of 5-tert-Butoxycarbonylamino-2-tert-butoxycarbonylmethyl-2H-pyrazole-3-carboxylic acid methyl ester (0.5 gm) dissolved in 25 ml of tetrahydrofuran was added 5 ml of 1M lithium hydroxide. After stirring the reaction mixture at 60 C for 2 hours, 1N hydrochloric acid was added and the product extracted with dichloromethane. The extract was dried over magnesium sulfate, filtered and evaporated to obtain 0.49 gm of title product. ESI M+1=286.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3C(C=O)=C(C)N=[C:10]3[CH2:9][N:8]=[C:7](C3C=CC=CC=3Cl)[C:6]=2[CH:25]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1C=CC=CC=1>[NH:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:25][C:6]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: Cc1nc2n(c1C=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C1=CNc2ccccc2C=N1

Procedure:
A mixture of 1.0 g. of 8-chloro-6-phenyl-2,4-dimethyl-4H-imidazo[1,2-a][1,4]benzodiazepine-1-carboxaldehyde (II) and 0.1 g. of tris(triphenylphosphine)rhodium chloride in 50 ml. of benzene is refluxed for about 6 hours. The mixture is then allowed to cool and filtered to remove the catalyst. The filtrate thus obtained is concentrated in vacuo to give 8-chloro-6-phenyl-2,4-dimethyl-4H-imidazo[1,2-a][1,4-benzodiazepine, which is further purified by chromatography and/or crystallization.
Reaction SMILES: [CH:1]1([C:5](Cl)=O)[CH2:4][CH2:3][CH2:2]1.[OH:8][C:9]1[CH:10]=[C:11]([C:15]23[CH2:22][CH:19]([NH:20][CH2:21]2)[CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.N>O1CCCC1.O.CN(C)C=O.C(N(CC)CC)C>[OH:8][C:9]1[CH:10]=[C:11]([C:15]23[CH2:22][CH:19]([N:20]([CH2:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:21]2)[CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Oc1cccc(C23CCCC(C2)NC3)c1
Agent: Cl
Agent: N
Agent: [Al+3]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Oc1cccc(C23CCCC(C2)N(CC2CCC2)C3)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.2 %

Procedure:
0.52 g of cyclobutylcarbonyl chloride is added to a mixture of 0.43 g of 1-(3-hydroxyphenyl)-6-azabicyclo[3,2,1]octane, 0.51 g of triethylamine and 8 ml of dimethylformamide. The mixture is stirred at room temperature for 15 hours. Then, water is added to the mixture, and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is dissolved in 25 ml of tetrahydrofuran. 0.6 g of lithium aluminium hydride is added to the solution, and the solution is refluxed for 3 hours under heating. After cooling, water is added to the reaction solution to decompose lithium aluminium hydride. The reaction solution is acidified with hydrochloric acid. Then, the reaction solution is made alkaline with aqueous ammonia and extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. The residue is dissolved in 5 ml of chloroform. The chloroform solution is poured onto the column of 30 g of silica gel. Then, the column is eluted with a mixture of 500 ml of chloroform and 25 ml of methanol, and the effluent is evaporated to remove solvent. The residue thus obtained is distilled under reduced pressure, whereby 0.42 g of 1-(3-hydroxyphenyl)-6-cyclobutylmethyl-6-azabicyclo[3,2,1]octane is obtained as an viscous oil boiling at 240°C(bath temperature)/0.1 mmHg.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:11](Br)[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([S:26]([N:29]1[C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[NH2:41])(=[O:28])=[O:27])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH:23]([S:26]([N:29]1[C:33]2[CH:34]=[C:35]([C:11]3[N:10]=[C:9]([CH3:22])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[NH2:41])(=[O:27])=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Reactant: Cc1nc(Br)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)c(-c2ccc(F)cc2F)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 24.3 %

Procedure:
To a solution of 1-(benzyl)-4-(bromo)-5-(2,4-difluorophenyl)-2-(methyl)-imidazole (1.12 g, 3.08 mmol) in 8 mL DME, add 1-isopropylsulfonyl-2-amino-benzimidazole-6-boronic acid (2.62 g, 9.25 mmol). Add sodium carbonate (0.98 g, 9.25 mmol) dissolved in 1 mL of water and trans-dichlorobis(triphenylphosphine) palladium (II) (0.65 g, 0.93 mmol). Heat the mixture to 100° C. with stirring under nitrogen. After 3 hours, cool the solution and filter over a pad of Celite® and sodium sulfate. Purify the residue by radial chromatography eluting with 3% methanol in CH2Cl2 with a gradient to 10% methanol. Perform a second purification by radial chromatography eluting with 4% methanol in CH2Cl2 with a gradient to 6% methanol to yield 390 mg (24%) of the title compound as a yellow solid. MS(ES+): m/z=522.0 (M+H)+
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]3[C:25](Cl)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]3[C:25]([CH:28]4[CH2:30][CH2:29]4)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3(CC2)OCCO3)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCC3(CC2)OCCO3)cc1F
Temperature: 150 °C
Yield: 259.1 %

Procedure:
To a mixture of tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate (1.20 g, 3.00 mmol) in toluene (18 mL) was added cyclopropylboronic acid (1.55 g, 18.00 mmol), potassium phosphate tribasic (1.91 g, 9.00 mmol), tricyclohexyl- phosphine tetrafluoroborate (0.884 g, 2.40 mmol), palladium acetate (0.269 g, 1.20 mmol) and water (2 mL). The reaction mixture was thoroughly degassed by passing argon through it and then heated in a microwave at 150° C. for 30 minutes. The reaction was performed 4 times as described. After cooling to ambient temperature, the reaction mixtures were combined, diluted with ethyl acetate (200 mL) and filtered over anhydrous sodium sulfate. After removing all volatiles under reduced pressure, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate in hexanes as eluent to afford the title compound as a yellowish oil (3.16 g, 16%): 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J=8.4 Hz, 1H), 6.48 (d, J=12.7 Hz, 1H), 3.95-3.92 (m, 4H), 3.80 (d, J=6.1 Hz, 2H), 2.04-1.70 (m, 10H), 1.54 (s, 9H), 0.91-0.82 (m, 2H), 0.64-0.57 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:10]1[C:9](=[O:14])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:15]([F:16])([F:17])[F:18])[CH:4]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(C2CCCCC2=O)cc1C(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2CCCC(Br)C2=O)cc1C(F)(F)F
Temperature: 25 °C
Yield: 104.4 %

Procedure:
2-(4-Methyl-3-trifluoromethyl-phenyl)-cyclohexanone (50 mg, 0.20 mmol) was dissolved in chloroform (1 mL). To this solution bromine (32.7 mg, 0.21 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the title compound (70 mg) which was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:54])([C:50]([F:53])([F:52])[F:51])[CH2:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:33]2[CH:38]=[CH:37][C:36]([O:39][Si](C(C)C)(C(C)C)C(C)C)=[CH:35][CH:34]=2)=[C:24](\[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[CH2:25][CH3:26])=[CH:19][CH:18]=1>C(#N)C>[F:54][C:2]([F:1])([C:50]([F:51])([F:52])[F:53])[CH2:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[C:24](\[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH2:25][CH3:26])=[CH:19][CH:18]=1
Reactant: CC/C(=C(/c1ccc(OCCNCCCCCCSCCCC(F)(F)C(F)(F)F)cc1)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)c1ccccc1
Solvent: CC#N
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNCCCCCCSCCCC(F)(F)C(F)(F)F)cc1)c1ccccc1

Procedure:
(E)-6-(4,4,5,5,5-pentafluoropentylthio)-N-(2-(4-(2-phenyl-1-(4-(triisopropylsilyloxy)phenyl)but-1-enyl)phenoxy)ethyl)hexan-1-amine from reaction 6 is dissolved in acetonitrile. To this solution is added HF/pyridine complex. The mixture is stirred until the reaction is complete (TLC). When the reaction is complete, the mixture is washed with dilute hydrochloric acid, dilute sodium bicarbonate and water. The aqueous layers are extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (Z)-4-(1-(4-(2-(6-(4,4,5,5,5-pentafluoropentylthio)hexylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenol among other products.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]([OH:9])=[CH:4][C:5]([O:7][CH3:8])=[O:6]>CO>[F:1][CH:2]([F:10])[C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C=C(O)C(F)F
Solvent: CO
Product: COC(=O)CC(=O)C(F)F

Procedure:
The procedure of Example 4 was repeated using methanol instead of ethanol. After distillation the methyl ester was obtained as a colorless liquid. According to the 1H NMR data the product was a tautomeric mixture of ca. 60% keto form and ca. 40% enol form (methyl 4,4-difluoro-3-hydroxybut-2-enoate).
Reaction SMILES: [C:1]1([C:7](=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:18].[Na+].OO.[Cl-].[Na+]>CO>[C:1]1([C:7]2([O:18][CH:11]2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:8](=[O:10])[CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C(=Cc1ccncc1)c1ccccc1
Reactant: [OH-]
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)C1(c2ccccc2)OC1c1ccncc1
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a stirred solution of 3-phenyl-4-(4-pyridyl)-3-butene-2-one (step 1) (500 mg, 2.24 mmol) in methanol (10 ml) at room temperature was added an aqueous solution (9 ml) of sodium hydroxide (100 mg, 2.24 mmol) and hydrogen peroxide (0.5 ml of 30% aqueous solution, 4.4 mmol). After stirring for 2 hours, sodium chloride was added and the reaction was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the crude 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (385 mg, 65%) as an oil. This was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[C:14]([C:19](O)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:12][C:13]1[C:14]([C:19]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][N:3]=2)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccn1)c1ncccc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A mixture of 0.81 g of 2-amino-4-trifluoromethylpyridine, 0.78 g of 3-chloropicolinic acid, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 70° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.33 g of 3-chloro-N-(4-trifluoromethylpyridin-2-yl)picolinamide.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)C(O)C(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)C(O)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4R)-4-amino-2-methyl-hexan-3-ol (42 mg, 3.0 eq, 0.32 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSo4) and evaporated in vacuo. The residue was purified-by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 7.8 mg (19%). 50% de 4R,3S: 50% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.91-1.04 (m, 9H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.66-1.94 (m, 4H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.22-3.34 (m, 1H, —NHCH(CH2CH3) CH(CH (CH3)2)OH), 3.79-3.93 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.57-4.71 (m, 1H, —CH(CH3)2), 4.85-4.97 (m, 2H, —HNCH2-Pyr), 5.13-5.24 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 6.65-6.79 (m, 1H, —HNCH2-Pyr), 7.13-7.24 (m, 1H, Pyr-H), 7.32-7.42 (m, 1H, Pyr-H), 7.56 (s, 1H, —N═CH—N—), 7.58-7.73 (m, 1H, Pyr-H), 8.60 (d, 1H, J=4.42 Hz, Pyr-H). FABMS m/z (relative intensity): 398 ([M+H]+, 100), 324 (50). Accurate Mass (M+H): Actual: 398.2668, Measured: 398.2654.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][N:7]([C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:22])[CH3:20])[CH2:13][CH2:12]1)=[O:10])[CH3:8])C.[Li+].[OH-]>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:21]([N:19]([CH3:20])[CH2:18][CH2:17][C@H:14]2[CH2:13][CH2:12][C@H:11]([C:9]([N:7]([CH3:8])[CH2:6][CH2:5][C:4]([OH:31])=[O:3])=[O:10])[CH2:16][CH2:15]2)=[O:22])=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCN(C)C(=O)[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(CC[C@H]1CC[C@H](C(=O)N(C)CCC(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a cooled (0° C.) and stirred solution of 0.39 g (0.87 mmol) of trans-3-[(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarbonyl)-methyl-amino]-propionic acid ethyl ester in 2.6 mL of THF was added within 5 min 2.6 mL (2.6 mmol, 3 eq) of aqueous 1M LiOH and the solution was stirred at RT for 2.5 h. The reaction was partitioned between Et2O (×3)/aqueous 10% KHSO4. The organic phase was washed with 10% NaCl, dried over Na2SO4 and evaporated to yield 0.38 g (quantitative) of trans-3-[(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarbonyl)-methyl-amino]-propionic acid, MS: 425 (MH+, 1Cl).
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH2:8][C@:7]([CH:26]([CH3:28])[CH3:27])([C:10]([N:12]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)=[O:11])[CH2:6]1)(=O)C.O[Li].O>O.[Cl-].[Na+].O>[CH:26]([C@:7]1([C:10]([N:12]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]([F:24])([F:25])[F:23])[CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)=[O:11])[CH2:8][CH2:9][CH:5]([OH:4])[CH2:6]1)([CH3:28])[CH3:27]
Reactant: CC(=O)OC1CC[C@@](C(=O)N2COc3ccc(C(F)(F)F)cc3C2)(C(C)C)C1
Agent: [Cl-]
Agent: [Li]O
Agent: [Na+]
Solvent: O
Product: CC(C)[C@]1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CCC(O)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of (3S)-3-isopropyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentyl acetate (935 mg, 2.34 mmol) was treated with a solution of LiOH H2O (491 mg, 11.7 mmol) in deionized water (5 mL). The resulting reaction mixture was stirred at rt for 40 min, then was diluted with brine and extracted with ether. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated to give (3S)-3-isopropyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentanol (a mixture of two isomers), which was used as is.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1.O[C:16]([C:19](O)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[CH3:17][C:16]1([CH3:18])[C:19]([CH3:21])([CH3:20])[O:12][B:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:13])[F:14])[CH:5]=2)[O:11]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: CC1(C)OB(c2cccc(OC(F)(F)F)c2)OC1(C)C
Yield: 25 %

Procedure:
The title compound (25%, oil) was prepared from 3-trifluoromethoxyphenylboronic acid and pinacol.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]#[N:27])=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Yield: 42.4 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a white solid (151 mg, 42%). MS (ISP) 357.0 [(M+H)+]; mp 192° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1>C(O)C.C1COCC1.[Ni]>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(S(=O)(=O)C2CC2)cc1
Yield: 92 %

Procedure:
A solution of 1.60 g (7.0 mmol) of 1-cyclopropanesulphonyl-4-nitrobenzene in 50 ml of ethanol and 50 ml of THF was admixed with 3.2 g of Raney nickel (50% moisture) and hydrogenated for 1.5 hours under atmospheric pressure at 0° C. The mixture was filtered and concentrated by evaporation. This gave 1.28 g (6.5 mmol; yield: 92%) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl.[C:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1)(=[O:28])[CH3:27].Cl>C(Cl)Cl>[C:26]([N:29]1[CH2:30][CH2:31][CH:32]([C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])[CH2:33][CH2:34]1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1cc(-c2cccc(N)c2)on1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2cccc(NC(=O)C3CCN(C(C)=O)CC3)c2)on1
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To ethyl 5-(3-aminophenyl)isoxazole-3-carboxylate (0.224 mmole) and triethylamine (0.896 mmole) in methylenechloride (3 mL) was added 1-acetyl-piperidine-4-carbonyl chloride HCl salt (0.314 mmole) via syringe at ambient temperature. After two hours, 1N HCl was added and the mixture was extracted with methylene chloride (3×40 mL). The combined organics were washed with aqueous Na2CO3, dried with anhydrous Na2SO4, filtered, concentrated under vacuo and purified by flash chromatography (10–15% ethyl acetate/Hexane) to provide (68 mg) of the titled compound.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6]([OH:8])=[O:7])(=O)[CH3:2]>CCO>[CH3:2][C:1]1[C:4]2[C:5](=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[O:8][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CC(=O)c1cccc(C)c1C(=O)O
Solvent: CCO
Product: Cc1c(C(=O)O)oc(=O)c2c(C)cccc12

Procedure:
4, 8- Dimethylisocoumarin -3-carboxylic acid, mp. (EtOH- dilute HCl) 237°-9°, (Found: C, 66.33; H, 4.77. C12H10O4 requires C, 66.05; H, 4.62) was prepared from 2- acetyl -6- methylbenzoic acid by an analgous procedure to that described in Example 2.