Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1C=CN=[CH:2]1.[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N:21]=[N:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33])[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N:21]=[N:22][C:23]1[C:24]([N+:32]([O-:34])=[O:33])=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][C:28]=1[C:2]#[N:1])[N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])(=[O:8])[CH3:7]
Reactant: CCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: c1c[nH]cn1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1

Procedure:
A stirred mixture of 3-acetylamino-4-(2'-bromo-4',6'-dinitro phenylazo)-N,N-diethylaniline (4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.8 parts), imidazole (1.35 parts), and nitrobenzene (100 parts) was heated to 85° C. for 71/2 hours when thin layer chromatography showed reaction to be effectively complete. Isolation of the product by the method of Example 9 gave 3-acetylamino-4-(2'-cyano-4',6'-dinitrophneylazo)-N,N-diethylaniline (infra red spectrum identical with that of authenic material). When this experiment was repeated using 3.6 parts of imidazole in place of 1.8 parts a considerable amount of 3-acetylamino-4-(2',4'-dinitrophenylazo)-N,N-diethylaniline was produced in addition to the desired 3-acetylamino-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23]>CN(C=O)C.[Cu-]=O>[Cl:11][C:12]1[CH:17]=[C:16]([S:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:23])([F:25])[F:24]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 4-mercaptobenzoic acid (0.308 g), (R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (0.786 g) and copper (I) oxide (0.143 g) in DMF (5 ml) was stirred and heated under reflux for 1 hour. More 4-mercaptobenzoic acid (0.308 g) was added and heating was continued for a further 2 hours. The mixture was cooled, filtered, and the filter washed with DMF (5 ml). The filtrates were concentrated by evaporation and the residual solid was extracted with boiling ethyl acetate (2×60 ml). The extracts were absorbed onto deactivated silica (silica deactivated by treatment with 10% water) and purified by chromatography eluting with 5% methanol/ethyl acetate to give the title compound (0.803 g) as a solid. NMR: 1.63 (s, 3H), 7.31 (d, 2H), 7.5 (dd, 1H), 7.68 (d, 1H), 7.89 (d, 2H), 8.22 (d, 1H), 9.8 (brs, 1H); MS (ESP−): 418; EA: found: C, 48.2; H, 3.1; N. 3.2%; CH17H13NClF3O4S requires C, 48.6; H, 3.1; N, 3.3%.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:5][C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7].N1C=CC=CC=1.C(Br)(Br)(Br)[Br:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:34][CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:5][C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)NNC(=O)CC(CCO)c1cccc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)CC(CCBr)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
tert-Butyl N′-[5-hydroxy-3-(3-trifluoromethylphenyl)pentanoyl]hydrazinecarboxylate (2.0 g) was dissolved in methylene chloride (53 mL). Pyridine (1.29 mL), carbon tetrabromide (2.64 g) and triphenylphosphine (2.1 g) were added at room temperature, followed by stirring for 30 minutes. The reaction solution was partitioned with water and ethyl acetate. Then, the organic layer was washed with saturated ammonium chloride aqueous solution and a saturated sodium bicarbonate aqueous solution and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 50%) to obtain the title compound (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][N:17]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc(-c2nn([C@@H]3c4cc(Cl)cc(Cl)c4C[C@H]3O)c3c2CNCC3)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(Cl)cc(Cl)c3C[C@H]2O)C1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[1-((1R,2R)-4,6-Dichloro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (13e) (0.02 g, 0.047 mmol) in dry tetrahydrofuran at −70° C. was added slowly and portionwise 100 μl of a solution of methanesulfonyl chloride (100 μl in 10 ml dry tetrahydrofuran) and after 5 min triethylamine (21 mg, 0.208 mmol). The mixture was stirred at −70° C. for 15 min and then a second portion of the methanesulfonyl/tetrahydrofuran solution above was added (100 μl). The mixture was stirred at −70° C. for 15 min and then a third portion of the methanesulfonyl/tetrahydrofuran solution above was added (50 μl). The mixture was stirred at −70° C. for 3 min, quenched with aqueous NaHCO3 and extracted 3 times with CH2Cl2. The combined organic layers were evaporated to dryness and the residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 15 mg of 3-[1-((1R,2R)-4,6-Dichloro-2-hydroxy-indan-1-yl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (23a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]([OH:28])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]([O:28][C:41](=[O:43])[CH3:42])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1CC(O)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC(Cc1ccccc1C)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{4-[2-(2-methylphenyl)-1-hydroxyethyl]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g), acetic acid (5 ml) and acetic anhydride (3 ml) is added a drop of conc. sulfuric acid, and the mixture is stirred at room temperature for 12 hours, and subsequently stirred at a temperature from 60-70° C. for 6 hours. The reaction mixture is poured into ice-water, and thereto is added ethyl acetate (30 ml). The mixture is basified with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{4-[2-(2-methylphenyl)-1-acetyloxyethyl]-benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.36 g) as colorless amorphous.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:12]([C:25]2[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:11]=1)C)(C)(C)C.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.CC(O)C>[ClH:39].[F:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([C:13]2[N:12]([C:25]3[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[N:11]=[C:10]([CH2:9][NH:7][CH3:6])[CH:14]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CN(Cc1cc(S(=O)(=O)c2ccc(F)cc2)n(-c2cccnc2F)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(S(=O)(=O)c2ccc(F)cc2)n(-c2cccnc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
tert-Butyl({5-[(4-fluorophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazol-3-yl}methyl)methylcarbamate (132 mg) was dissolved in ethyl acetate (2 ml) and 2-propanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and ethyl acetate to give the title compound as colorless crystals (yield 83 mg, yield 73%). melting point 211-214° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC1CCCCC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(Oc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, cyclohexanol and DBU in dioxane. EI-MS m/e (%): 339 (M{81Br}+, 15), 337 (M{79Br}+, 16), 257 ([M—C6H10]+, 97), 255 ([M—C6H]+, 100).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:35])[C:23](OC3C=CC([N+]([O-])=O)=CC=3)=[O:24])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].CN(C)C=O.[CH2:41]([NH2:46])[CH2:42][CH2:43][CH2:44][CH3:45]>O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:35])[C:23]([NH:46][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:24])[N:17]=2)=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)C(=O)OC
Reactant: CCCCCN
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)n1
Yield: 74.4 %

Procedure:
0.65 g (1.1 mmol) of methyl 2(S)-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)propanoate, 12 ml of dimethylformamide and 1 ml (8.8 mmol) of pentylamine are heated at 80° C. for 18 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 7/3 and then 6/4 heptane/ethyl acetate mixture. 0.35 g (76%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}propanoate is obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][C@@H:3]1[N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]1=[O:29].C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[C:37]([NH:1][C@@H:2]1[CH2:7][C@H:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][C@@H:3]1[N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]1=[O:29])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of benzyl (S)-1-((1S,2R,4R)-2-amino-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (22 mg, 0.055 mmol) in dichloromethane (2 mL) was charged sequentially with triethylamine (11.1 mg, 2 eq) and acetic anhydride (6.1 mg, 1.1 eq). The reaction was stirred for 1.5 h at room temperature, diluted with dichloromethane (50 mL) and washed with saturated NaHCO3 (20 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (22 mg, 90%). LC/MS found [M+H]=445.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:19][O:20][C:21](=[O:39])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31]CC2C=CC=CC=2)=[CH:27][CH:26]=1)[NH2:23]>>[CH3:19][O:20][C:21](=[O:39])[CH:22]([NH:23][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7](=[O:8])[C:6]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(C(=O)C2CCCCC2=O)cc1
Agent: Cl
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(OC)cc1
Yield: 28.5 %

Procedure:
The title compound (2.31 g) was prepared from 4.64 g (20 mmol) of 2-(4-methoxybenzoyl)-cyclohexanone (Howard, A. S. et. al. Tetrahedron Lett. 1979, (15), 1339-40) and 6.43 g (20 mmol) of O-benzyl-L-tyrosine methyl ester hydrochloride as a yellow solid as described for Intermediate 161: low resolution MS (Cl) m/e 406 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[C@@H:9]1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(=[O:3])[CH3:2].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:34]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:9]2[C@@H:8]([CH2:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:11](=[O:12])[N:10]2[C:13]2[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=2)=[CH:21][CH:22]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)O[C@@H](CC[C@H]1C(=O)N(c2ccc(I)cc2)[C@@H]1c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc([C@@H]2[C@@H](CC[C@H](OC(C)=O)c3ccc(F)cc3)C(=O)N2c2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1S)-1-(4-fluorophenyl)-3-[(2S,3R)-2-(4-hydroxyphenyl)-1-(4-iodophenyl)-4-oxoazetidin-3-yl]propyl acetate (1-7a) (2 g, 3.58 mmol) (prepared according to Burnett, D. S.; Caplen, M. A.; Domalski, M. S.; Browne, M. E.; Davis, H. R. Jr.; Clader, J. W. Bioorg. Med. Chem. Lett. (2002), 12, 311) in CH2Cl2 (25 mL) under nitrogen atmosphere was added acetic anhydride (0.4 mL, 4.30 mmol), triethylamine (0.75 mL, 5.38 mmol) and DMAP. The reaction mixture was stirred at RT for 1 hr and the solvent removed under vacuum. The residue was purified by MPLC (silica column) with stepwise gradient elution; (0-100% EtOAc/hexanes as eluent) to afford the title compound (i-8). m/z (ES) (M-OAc)+. 1HNMR (500 MHz, CDCl3) δ: 7.57 (d, J=8.6, 1H) 7.38-7.26 (m, 5H), 7.22 (br d, J=7.1 H, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.08-7.02 (m, 3H), 5.74 (t, J=6.7 Hz, 1H), 4.62 (d, J=2.3 Hz, 1H), 3.10 (dt, J=2.3, 7.8 Hz, 1H), 2.34 (s, 3H), 2.08 (s, 3H), 2.09-2.03 (m, 2H), 1.94-1.86 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>C(#N)C>[C:1]([CH:3]([C:19](=[O:22])[CH2:20][CH3:21])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C#N)C(=O)CC
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A solution of ethyl cyanoacetate (17.0 g, 150 mmol), magnesium chloride (14.4 g, 151 mmol) and triethylamine (42 mL, 301 mmol) in acetonitrile (150 mL) was stirred at 0° C. for 15 minutes. To the solution, propionyl chloride (13.8 g, 150 mmol) was added dropwise over 15 minutes at the same temperature, and subsequently the solution was allowed to warm to room temperature and stirred for 24 hours. After addition of 30% hydrochloric acid (100 mL), the organic matter was extracted with diethylether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude ethyl 2-cyano-3-oxopentanoate (24.6 g, 97% yield). The compound (25.4 g, 150 mmol) was dissolved in a mixed solvent of dimethylsulfoxide (50 mL) and water (5 mL), and the solution was stirred at 120° C. for 1.5 hours. The solution was allowed to cool to room temperature and poured into saturated brine, and the organic matter was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure to give the title compound (14.6 g, quantitative).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>O1CCOCC1.C(OCC)(=O)C>[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: Nc1cncc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1cncc(OCc2ccccc2)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a stirred solution of benzyl alcohol (432 μL; 4.0 mmol) in dioxane (2 mL) was added sodium hydride (96 mg; 4.0 mmol). After stirring for 30 minutes, 2-amino-6-chloropyrazine (258 mg; 2.0 mmol) was added and the reaction was heated to 90° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), and brine (30 mL), then dried (MgSO4). and filtered. The crude product was purified using the biotage 12i cartridge eluting with hexane and ethyl acetate (3:1) to yield a white solid (33% yield).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[C@H:24]1[C@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:28]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:27]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:26]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:25]1)(=O)=O.[C:63]([CH2:67]O[Na])([F:66])([F:65])[F:64]>C(CO)(F)(F)F>[CH2:47]([O:46][C@H:27]1[C@H:28]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]([C:9]2[CH:10]=[C:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=3)[C:12]([Cl:14])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5][CH2:67][C:63]([F:66])([F:65])[F:64])[O:25][C@@H:26]1[CH2:54][O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: FC(F)(F)CO[Na]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CCOS(C)(=O)=O)cc2Cl)cc1
Solvent: OCC(F)(F)F
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CCOCC(F)(F)F)cc2Cl)cc1
Reaction time: 9 h

Procedure:
The solution of 5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenethyl methanesulfonate (58 mg, 0.066 mmol) in 0.8 mL of 1.5 M CF3CH2ONa in CF3CH2OH was stirred at 60° C. under argon. After it was stirred for about 9 h, an additional 0.6 mL of 1.5 M of CF3CH2ONa in CF3CH2OH was added and the mixture was stirred for another 15 h at 60° C. After removal of the volatiles with a rotary evaporator under vacuum, the residue was partitioned between water and EtOAC. The organic layer was separated, washed with brine and dried over Na2SO4. Concentration gave the crude product, which was purified by preparative TLC to yield 30 mg of title compound. MS ESI (m/z) 896 (M+NH4)+, calc. 878.
Reaction SMILES: C([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[OH-].[K+]>O1CCOCC1.O>[OH:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 3β-acetoxy-5α-pregn-16-ene-11,20-dione (25.7 g.) in dioxan (500 ml.) was treated with potassium hydroxide (10 g.) and water (250 ml.) and the mixture allowed to stand at room temperature for 1 hour. After a further 1 hour at 40° the mixture was diluted with water and the product filtered off. The crude material was dissolved in chloroform and filtered through a column of grade III neutral alumina. Crystallisation from acetone-petrol gave pure 3β-hydroxy-5α-pregn-16-ene-11,20-dione (17.65 g.) as small plates m.p. 217.5°, [α]D + 82.9°. (c 1.1)
Reaction SMILES: [CH3:1][CH:2]([CH3:44])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34]OS(C)(=O)=O)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1.[NH:45]1[CH:49]=[CH:48][CH:47]=[N:46]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:44][CH:2]([CH3:1])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34][N:45]2[CH:49]=[CH:48][CH:47]=[N:46]2)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1
Reactant: c1cn[nH]c1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCOS(C)(=O)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCn1cccn1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 72 h
Yield: 59.3 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-{(2-methylpropyl) [(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-benzimidazol-2-yl)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (127 mg) and pyrazole (41 mg) in N,N-dimethylacetamide (3 ml) was added cesium carbonate (326 mg), and the mixture was stirred at 60° C. for 3 days. The to reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (72 mg).