Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][C@@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O.C1C=CC=CC=1>[CH2:18]([O:17][C:15]([NH:3][CH2:4][C@@H:5]([NH:13][C:15]([O:17][CH2:18][CH3:19])=[O:1])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:16])[CH3:19]
Reactant: NC[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)NC[C@H](Cc1ccccc1)NC(=O)OCC
Reaction time: 0.5 h

Procedure:
225 mmoles (9.00 grams) of NaOH were dissolved in 45 ml of water, cooled in an ice bath and treated with 49 mmoles (7.35 grams) of (S)-1,2-diamino-3-phenylpropane dissolved in about 45 ml of benzene. Within 30 minutes with stirring there was dropped in a solution of 108 mmoles (10.3 ml) of ethyl chloroformate in 45 ml of benzene and the mixture allowed to stir for 3 hours at room temperature. The organic phase was separated off and the aqueous solution shaken twice with 20 ml of benzene. The combined phases were dried over sodium sulfate and freed from solvent. There were obtained 40.33 mmoles (11.87 grams) of colorless, crystalline solid [(S)-1,2-bis(N-ethyloxycarbonylamino)-3-phenylpropane]. This was added in small portions to an ice cooled suspension of 370 mmoles (14.0 grams) of LiAlH4 in 300 ml of tetrahydrofuran. After heating for 24 hours under reflux by ice cooling the product was carefully hydrolyzed with 1.5 moles (27 ml) of water. The hydrolysis products were filtered off and the filtrate concentrated. The residue was extracted for 12 hours with 150 ml of tetrahydrofuran in a Soxhlet apparatus. The extract was combined with the filtrate and the solvent distilled off in a vacuum. The light brownish liquid was distilled in a high vacuum at 85° C. Colorless liquid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[C:18]([CH3:31])[C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:31][C:18]1[C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=[C:16]([O:12][C@H:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@@H:2]([NH2:1])[CH2:3][CH2:4]2)[CH:17]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Cc1cc(F)cn2c([C@@H]3CCCN3C)nnc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(O[C@@H]2CC[C@H](N)c3ccccc32)cn2c([C@@H]3CCCN3C)nnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.8 %

Procedure:
A mixture of Intermediate A (44 mg, 0.267 mmol) and sodium hydride (60% in mineral oil, 29 mg, 0.729 mmol) in anhydrous DMF (1 mL) was stirred at RT for 20 min under argon atmosphere. To the reaction mixture was added a solution of Intermediate 105d (57 mg, 0.243 mmol) in anhydrous DMF (2 mL) and stirring at 60° C. was continued for 2.5 h. After cooling to RT, the reaction mixture was diluted with EtOAc and poured into ice-water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by SCX cartridge by washing the cartridge with 10% MeOH in DCM and eluting the product with 10% (2M NH3 in MeOH) in DCM and then by FCC on silica, using 10% MeOH in DCM followed by 10% [2M NH3 in MeOH] in DCM, to give the title compound (53 mg, 58%). LCMS (Method 1): Rt 0.38, 1.54 min, m/z 378 [MH+].
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17](O)=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(C#N)(=O)(OCC)OCC.[NH2:30][C:31]1[CH:45]=[CH:44][C:34]([CH2:35][P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O.O>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([CH2:35][P:36]([O:37][CH2:38][CH3:39])([O:40][CH2:41][CH3:42])=[O:43])=[CH:44][CH:45]=4)=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)C1=Cc2cc(C3CCCCC3)ccc2CC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1ccc(NC(=O)C2=Cc3cc(C4CCCCC4)ccc3CC2)cc1)OCC
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
To a solution off 7-cyclohexyl-3,4-dihydronaphthalene-2-carboxylic acid (0.51 g) in N,N-dimethylformamide (DMF) (15 ml), diethyl phosphorocyanidate (DEPC) (0.36 g) was added under ice-cooling conditions, followed by stirring for 30 minutes. Diethyl 4-aminobenzylphosphonate (0.54 g) and triethylamine (0.22 g) were then added in this order, followed by stirring under ice-cooling conditions for 2 hours, after which the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to yield 7-cyclohexyl-N-(4-diethoxyphosphorylmethylphenyl)-3,4-dihydronaphthalene-2-carboxamide (0.43 g, 45%) as colorless prisms having a melting point of 137°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.BrCCCCCC[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=O.[C:27]([O-:30])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:4][CH2:3][CH2:2][CH2:8][CH2:7][CH2:17][C:18]23[CH:25]=[CH:24][CH:23]=[CH:22][CH:19]2[C:20]([NH:16][C:27]3=[O:30])=[O:21])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C2(CCCCCCNc3ccc(Cl)cc3)C=CC=CC12
Temperature: 90 °C
Reaction time: 25 h
Yield: 95 %

Procedure:
4-Chloroaniline (2.55 g, 20 mmol), N-(6-bromohexyl)-phthalimide (6.20 g, 20 mmol) and K2CO3 (2.76 g, 20 mmol) were suspended in DMF (50 mL) under an atmosphere of argon and stirred at 90° C. for 25 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water (100 mL) and Et2O (100 mL). The aqueous layer was extracted with Et2O (2×50 mL), the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (EtOAc/hexane 1:6 to 1:3) to give the title compound (3.41 g), together with some 4-chloroaniline (≈2:1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([OH:25])[CH:27]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(O)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Hydroxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.10 (t, 1H), 6.66 (m, 2H), 6.45 (d, 1H), 5.39 (s, 2H), 3.74 (m, 4H), 3.33 (br, 2H), 3.24 (br, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=403.1, found 403.0.
Reaction SMILES: O=[C:2]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:10]([O:12]CC)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][N:25]2[C:10](=[O:12])[C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:2]=3[N:15]=[C:16]2[CH:17]=1)=[O:20]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CCOC(=O)C1CCCCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccn2c(=O)c3c(nc2c1)CCCCCC3
Temperature: 25 °C
Yield: 10.9 %

Procedure:
A solution of ethyl 2-oxocyclooctanecarboxylate (1 g, 5.05 mmol) and methyl 2-aminoisonicotinate (0.768 g, 5.05 mmol) in PPA (2.5 mL) and 1,2-dichloroethane (5 mL) was stirred at 85° C. for 18 hours. The reaction mixture was then cooled to ambient temperature. A chilled saturated sodium carbonate solution was added to adjust pH to 8. The resulting mixture was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel chromatography purification to afford 157 mg of desired product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1.Cl.[CH:17]([NH:19]N)=O.C([N:23](CC)CC)C>C(Cl)(Cl)Cl.CO.C(O)C>[F:1][C:2]([F:14])([F:15])[O:3][C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]2[N:19]=[CH:17][NH:23][N:11]=2)=[CH:6][CH:5]=1
Reactant: N#CC=Cc1ccc(OC(F)(F)F)cc1
Reactant: NNC=O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Oc1ccc(C=Cc2nc[nH]n2)cc1
Temperature: 0 °C
Reaction time: 96 h

Procedure:
4-Trifluoromethoxycinnamonitrile (16.9 g.) was dissolved in a mixture of dry chloroform (50 ml.) and dry methanol (18 ml.). After cooling the solution to 0° C., a stream of hydrogen chloride was passed through the solution until saturation was achieved, then the solution was kept at 0°-5° C. in a refrigerator for four days. Evaporation of the solvents gave a pale yellow solid which was dissolved in absolute ethanol (90 ml.) and treated with formohydrazide (9.01 g.) and triethylamine (23.0 g.). The solution was heated on a steam bath for three and a half hours, then the solvents were evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and dried over magnesium sulphate and the solvent was evaporated to give an orange oil, which was purified by column chromatography, using silica and chloroform/methanol (92:8 v/v) as the element, to give 3-(4-trifluoromethoxystyryl)-1,2,4-triazole, m.p. 125°-127° C.
Reaction SMILES: ClC12[O:8]C1CCC(Cl)(F)C2.[CH2:11]([C:14]1(O)[C:19]([Cl:21])([Cl:20])[CH2:18][CH2:17][CH2:16][C:15]1([Cl:23])Cl)[CH:12]=[CH2:13].[OH-].[Na+]>O>[CH2:11]([CH:14]1[C:19]([Cl:21])([Cl:20])[CH2:18][CH2:17][CH:16]2[C:15]1([Cl:23])[O:8]2)[CH:12]=[CH2:13]
Reactant: C=CCC1(O)C(Cl)(Cl)CCCC1(Cl)Cl
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCC1C(Cl)(Cl)CCC2OC21Cl
Reaction time: 0.25 h
Yield: 92 %

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 1.12 g (4.03 mmol) of crude alcohol 1l, 5.5 cm3 of distilled water and 0.6 g (12.5 mmol) of sodium hydroxide; reaction time was 1 h 15 min followed by ether extraction; the crude product was employed as such (crude yld=90.5%) or purified by flash chromatography on silica (eluent: ether/petroleum ether=3/97): 0.89 g of epoxide 2j were obtained, that was a 92% yield (macrobore GC purity>98.6%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]([CH3:34])[CH3:33]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CC(C)CBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)C)c1OCC1CC1
Temperature: 70 °C
Yield: 21.4 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and isobutylbromide (101 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 21%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:9]=1[O:10][C:11]1[N:16]=[C:15]2[N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:18]=[C:19](I)[C:14]2=[CH:13][N:12]=1.[C:34]1([CH3:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[F:7][C:8]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:9]=1[O:10][C:11]1[N:16]=[C:15]2[N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:18]=[C:19]([CH:1]=[CH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:14]2=[CH:13][N:12]=1
Reactant: Cc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cnc(Oc3ccc(F)cc3F)nc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2cnc(Oc3ccc(F)cc3F)nc21
Temperature: 65 °C
Reaction time: 16 h

Procedure:
Tris(dibenzylidine acetone)dipalladium CHCl3 (5.0 mg, 0.004 mmol), and potassium carbonate (26 mg, 0.19 mmol) were suspended in 1 mL of toluene under argon. A solution of 6-(2,4-Difluoro-phenoxy)-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (48 mg, 0.09 mmol) in 2 mL toluene was added, and the reaction mixture was stirred at 65° C. for 16 hours, then stirred at 110° C. for four hours. The reaction mixture was cooled, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (23 mm×14 cm silica with hexanes/EtOAc 20:1 to 4:1) to yield 42 mg of 6-(2,4-Difluoro-phenoxy)-3-styryl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([CH2:9][OH:10])[CH2:7][OH:8].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1.C(=O)([O-])O.[Na+]>CC(C)=O.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]1[CH2:7][O:8][C:15]([CH3:20])([CH3:16])[O:10][CH2:9]1
Reactant: OCC(CO)Cc1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)OCC(Cc2cccc(Br)c2)CO1
Reaction time: 1 h
Yield: 1400.7 %

Procedure:
2-(3-Bromobenzyl)-1,3-propanediol (1.85 g) was dissolved in a mixture of 8 ml of acetone/18 ml of benzene, and 70 mg of p-toluenesulfonic acid monohydrate was added. The solution was subjected to azeotropic dehydration with Dean-Stark apparatus for 1 hour. After addition of saturated sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 1.47 g of the objective compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:4][C:3]=1[NH:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.[CH3:30][C:31]1([CH3:39])[C@@H:36]2[C@H:32]1[C:33](=[O:38])[O:34][C:35]2=O.CC(O)=O>C(#N)C>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[N:11]=4)=[CH:7][C:2]=3[N:1]=[C:35]2[CH:36]2[CH:32]([C:33]([OH:38])=[O:34])[C:31]2([CH3:39])[CH3:30])=[CH:29][CH:28]=1)#[N:27]
Reactant: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2N)cc1
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Solvent: CC(=O)O
Solvent: CC#N
Product: CC1(C)C(C(=O)O)C1c1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a solution of 4-(((2-amino-4-(quinolin-2-ylmethoxy)phenyl)amino)methyl)benzonitrile (124 mg, 0.33 mmol) in acetonitrile (3 mL) was added cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione (49 mg, 0.33 mmol) and the solution heated to 80° C. for 4 h. AcOH (1 mL) was then added and the heating continued at 80° C. for an additional 16 h. The resulting mixture was cooled to RT and the mixture was concentrated to dryness. The residue purified using FCC to provide 81.4 mg of the title compound. MS (ESI): mass calcd. for C31H26N4O3, 502.20; m/z found, 503.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=8.6 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.78-7.73 (m, 1H), 7.70-7.65 (m, 3H), 7.59-7.54 (m, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.19-7.09 (m, 4H), 5.49-5.39 (m, 4H), 2.32 (d, J=8.3 Hz, 1H), 1.99 (d, J=8.3 Hz, 1H), 1.20 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: C(Br)C.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:29][C:30]1[C:40]2[N:39](CC)[C:38](=[O:43])[C:37]([CH3:45])([CH3:44])[N:36]=[C:35]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[F:52])[C:34]=2[CH:33]=[C:32]([N+:53]([O-:55])=[O:54])[CH:31]=1>CCOCC.CCCCCC>[Cl:29][C:30]1[C:40]2[NH:39][C:38](=[O:43])[C:37]([CH3:45])([CH3:44])[N:36]=[C:35]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[F:52])[C:34]=2[CH:33]=[C:32]([N+:53]([O-:55])=[O:54])[CH:31]=1
Reactant: CCN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCOCC
Solvent: CCBr
Solvent: CCCCCC
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O

Procedure:
From 10 g (0.028 mol) of 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and ethyl bromide there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 8 days and chromatography of the crude product on silica gel (elution agent: methylene chloride), 9-chloro-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 117°-120° (ether/n-hexane).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[C:12](OCC(C)C)=[O:13])[CH3:9])[CH2:4][CH2:5][CH3:6].CO.O>C1(C)C=CC=CC=1>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[CH2:12][OH:13])[CH3:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOC(C)O[C@H](C)C(=O)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCOC(C)O[C@H](C)CO
Yield: 91.4 %

Procedure:
8.4 g (0.204 mole) of sodium borohydride was suspended at room temperature in a solution of 44.1 g (0.17 mole) of the isobutyl (R)-(+)-2-(1-n-butoxyethoxy)propionate (obtained in Reference Example 6) dissolved in 170 ml of toluene. Thereto was dropwise added slowly 41.3 ml (1.02 mole) of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature for 5 hours to give rise to a reaction. To the reaction mixture was added 50 ml of water, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to extraction with 50 ml of toluene. The two organic layers were combined and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 27.4 g (yield: 91.3%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[C:40]3[C:32](=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]([C:41]([N:43]3[C:54]5[C:46](=[C:47]6[C:51](=[CH:52][CH:53]=5)[NH:50][CH:49]([C:55]([N:57]5[C:68]7[C:60](=[C:61]8[C:65](=[CH:66][CH:67]=7)[NH:64][CH:63]([C:69]([O:71]C)=[O:70])[CH2:62]8)[CH:59]=[CH:58]5)=[O:56])[CH2:48]6)[CH:45]=[CH:44]3)=[O:42])[CH2:34]4)[CH:31]=[CH:30]2)=[O:28])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[CH2:13])=[CH:5][CH:4]=1.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[C:40]3[C:32](=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]([C:41]([N:43]3[C:54]5[C:46](=[C:47]6[C:51](=[CH:52][CH:53]=5)[NH:50][CH:49]([C:55]([N:57]5[C:68]7[C:60](=[C:61]8[C:65](=[CH:66][CH:67]=7)[NH:64][CH:63]([C:69]([OH:71])=[O:70])[CH2:62]8)[CH:59]=[CH:58]5)=[O:56])[CH2:48]6)[CH:45]=[CH:44]3)=[O:42])[CH2:34]4)[CH:31]=[CH:30]2)=[O:28])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[CH2:13])=[CH:5][CH:4]=1
Reactant: C=C/C=C(\C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)n1ccc2c4c(ccc21)NC(C(=O)n1ccc2c5c(ccc21)NC(C(=O)OC)C5)C4)C3)(c1ccccc1)c1ccc(OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C/C=C(\C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)n1ccc2c4c(ccc21)NC(C(=O)n1ccc2c5c(ccc21)NC(C(=O)O)C5)C4)C3)(c1ccccc1)c1ccc(OC)cc1
Temperature: 55 °C
Reaction time: 30 h
Yield: 60.4 %

Procedure:
A suspension of 10 (270 mg, 0.28 mmol) in a mixture of THF (6 ml), MeOH (4 ml) and 4M LiOH (2 ml) was stirred at 55° C. for 30 h. The reaction was cooled and neutralized to pH 6 with cold 10% citric acid. Insoluble material was collected by filtration and washed with water, MeOH and ether. Drying under vacuum afforded 160 mg (60%) of the title compound 11. By HPLC analysis this product contained ˜5% of unreacted 10. The crude acid was used in the next step without additional purification.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C@@H:38]([OH:41])[CH2:39][OH:40])[N:33]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:22])[F:23])[C:12]2=[O:24])[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C@@H:38]([OH:41])[CH2:39][OH:40])[N:33]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: Nc1ccn(C[C@@H](O)CO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (5 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 200 μL, 0.40 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (5 mL) and then added dropwise to a separate reaction flask containing a mixture of (R)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (prepared as in US 20080021032, Example 35, 70 mg, 0.45 mmol) and 2,6-lutidine (250 μL) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was then stirred room temperature for 2 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride. The organic layer was then washed with a 1 N aqueous hydrochloric acid solution. The organic layer was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 100% ethyl acetate to 10% methanol/ethyl acetate) to afford (S)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (98 mg, 69%) as a white foam: [α]29D=+12.0°, (c=0.15, methanol); HR-ES(+) m/e calcd for C23H27N4O4F3 [M+H]+ 481.2057, observed 481.2055; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (s, 1H), 7.94-8.05 (m, 2H), 7.71-7.79 (m, 1H), 7.53 (d, J=2.34 Hz, 1H), 6.40 (d, J=2.13 Hz, 1H), 4.99-5.11 (m, 2H), 4.93 (d, J=5.33 Hz, 1H), 4.67-4.76 (m, 2H), 4.09 (dd, J=3.84, 13.85 Hz, 1H), 3.81-3.91 (m, 1H), 3.76 (br. s., 1H), 3.23-3.31 (m, 2H), 1.05-2.13 (m, 11H).