Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:8]([C:28]([F:31])([F:30])[F:29])=[N:9][N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:21]=1.Cl[C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>O1CCCC1.O>[CH:22]1([N:10]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]4[O:20][CH2:19][CH2:18][CH2:17][C:16]=4[CH:21]=3)=[C:7]([C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:28]([F:31])([F:30])[F:29])=[N:9]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)C(=O)Cl
Reactant: FC(F)(F)c1nn(C2CCCCC2)c(-c2ccc3c(c2)CCCO3)c1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)c1c(C(F)(F)F)nn(C2CCCCC2)c1-c1ccc2c(c1)CCCO2
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 74.2 %

Procedure:
Under nitrogen, isopropyl magnesium chloride 2M in tetrahydrofuran (0.47 mL, 0.94 mmol) was dropwise added to a solution of 4-bromo-1-cyclohexyl-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (54b) (134 mg, 0.31 mmol) in anhydrous tetrahydrofuran (1.0 mL), previously cooled to −20° C. After 90 minutes stirring at the same temperature, ethyl chlorooxoacetate (70 μL, 0.62 mmol) was added dropwise. The mixture was stirred at −20° C. for 40 minutes before being poured in water (2 mL). The mixture was extracted with ethyl acetate (2×3 mL) and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 75/25) to provide the desired keto-ester (54c) (104 mg, 0.23 mmol, 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:31][CH2:30][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:32]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:32][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:31][CH2:30][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=4)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1
Reactant: CB(O)O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc(C(F)(F)F)nc4)c3C2)c(C#N)c1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
To a mixture of 5-bromo-2-(4-((6-(trifluoromethyl)pyridin-3-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (120 mg, 0.24 mmol), methylboronic acid (19 mg, 0.32 mmol), potassium phosphate (182 mg, 0.86 mmol), tricyclohexylphosphine (6.9 mg, 0.024 mmol), toluene (5 mL), and water (0.5 mL) under argon was added palladium acetate (2.8 mg, 0.012 mmol). The mixture was heated at 100° C. for 20 h and then cooled to rt. The mixture was filtered and concentrated. The residue was purified by semi-preparative HPLC to yield an off-white solid (75 mg, 71%).
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([N:18]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:19]([CH:24]([CH3:26])[CH3:25])[C:20]([NH:22][OH:23])=[O:21])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1)(=O)C.Cl>CO>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([N:18]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:19]([CH:24]([CH3:25])[CH3:26])[C:20]([NH:22][OH:23])=[O:21])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc2ccc(S(=O)(=O)N(CCC(C)C)C(C(=O)NO)C(C)C)cc2c1
Agent: Cl
Solvent: CO
Product: CC(C)CCN(C(C(=O)NO)C(C)C)S(=O)(=O)c1ccc2ccc(N)cc2c1

Procedure:
2-[(7-Acetylamino-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydroxy-3-methyl-butyramide (100 mg, 0.22 mmol) (example 61), 3 N hydrochloric acid (2 mL) and methanol (5 mL) are combined and stirred at reflux for 4 hours. The mixture is stirred at room for 60 hours. The solvent is partially removed in vacuo and a red precipitate forms. This precipitate is collected by filtration and air dried. LCMS (m/z): 408.2 (M+1), 406.3 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-])=O)[CH:5]=1)[CH3:2]>[Pd].C1COCC1.CCO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:8])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-ethoxy-2-nitroaniline (963 mg) and THF/EtOH (1/1, 10 mL) was added 10% Pd/C (281 mg), followed by stirring at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 4-ethoxybenzene-1,2-diamine.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 1c (2 g, 4.12 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 18 h, and concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 94%)
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.Br[C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[O:29][CH2:30][CH:31]([OH:40])[CH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>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.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:43]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][CH:31]([OH:40])[CH2:32][CH2:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[CH:41][CH:42]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: OC(CCc1cccnc1)COc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)c1
Temperature: 120 °C

Procedure:
Prepared according to the method as described in Example 33a) from toluene (8 ml), aqueous sodium carbonate (2 M, 2.47 ml), 3-methoxybenzeneboronic acid (0.413 g), ethanol (2 ml), (±)-1-(3-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.79 g, Example 56a) and tetrakis(triphenylphosphine)palladium(0) (0.071 g) with heating at 120° C. for 4 hours. After work up the residue was purified by column chromatography over silica with ethyl acetate to give the title compound as a white solid after trituration with ether:hexane (0.27 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14](=[S:16])[NH:13][C:12]3=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18]CN(C(C)C)C(C)C.CI.CCOC(C)=O>CN1C(=O)CCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14]([S:16][CH3:18])=[N:13][C:12]3=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN1CCCC1=O
Product: CSC1=NC(=O)C(=Cc2ccc3c(c2)OCO3)S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 g (7.54 mmol) of 5-Benzo[1,3]dioxol-5-ylmethylene-2-thioxo-thiazolidin-4-one and 1.5 ml (1.15 eq.) of DIEA were dissolved in 80 ml NMP. To this solution was added dropwise a freshly prepared solution of 2.43 ml (5 eq.) of Methyliodide in 10 ml NMP. The reaction mixture was stirred for two hours at RT. EtOAc was added and the organic layer was washed 5 times with brine and twice with water. The organic layer was reduced to 50% of volume, where upon 5-Benzo[1,3]dioxol-5-ylmethylene-2-methylsulfanyl-thiazol-4-one started to crystallize. Crystals were filtered off and washed with cold EtOAc.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:13][N:12]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: ON=C1CCc2ccccc21

Procedure:
A mixture of 1-indanone (100 g), hydroxylamine HCl (183 g), potassium carbonate (183 g), methanol (1700 ml) and water (170 ml) was heated at reflux for 18 hours, then cooled and poured into water. The title compound was filtered, washed with water and air-dried.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C@H:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].CCC(C)[BH-](C(C)CC)C(C)CC.[K+]>C1COCC1>[OH:8][C@@H:5]1[CH2:4][C@@H:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@H:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: CCOC(=O)[C@@H]1CC(=O)CC[C@H]1C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@@H](O)CC[C@H]1C

Procedure:
reacting said ethyl (1R,2R)-2-methylcyclohexane-5-one-1-carboxylate (11) with K-Selectride (potassium tri-sec-butylborohydride) in THF at −78° C. to produce ethyl (1R,2R,5S)-5-hydroxy-2-methylcyclohexane-1-carboxylate (12), and
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([N:21]=[C:22]=[S:23])[CH:20]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:22]([NH:21][C:19]1[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[CH3:24])=[S:23])[CH3:2]
Reactant: CCOC(=O)CNc1ccccc1
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C(=S)Nc1cc(Cl)ccc1C)c1ccccc1
Yield: 94.9 %

Procedure:
A mixture of N-phenyl glycine ethyl ester (8.95 g), 5-chloro-2-methylphenyl-isothiocyanate (9.18 g), and chloroform (200 mL) was heated at reflux for 24 hours. The solvent was evaporated. The residue was crystallized from ethyl acetate/hexane mixture. The solid was collected and dried to give 17.2 g of 2-[3-(5-chloro-2-methylphenyl)-1-phenyl-thioureido]-acetic acid ethyl ester as a white solid, m.p. 148°-1500° C. Anal. Calcd. for. C18H19Cl N2O2S: C, 59.58; H, 5.28; N, 7.72. Found: C, 59.79; H, 5.38; N, 7.65. Mass spectrum (EI, M.+) m/z 262/264.
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1>C(O)(C)C>[CH3:3][S:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1
Reactant: CSc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1ccc(CO)cc1
Yield: 98.7 %

Procedure:
Sodium borohydride (3.78 g) was added to isopropyl alcohol (50 ml) and the mixture was stirred under ice-cooling. Thereto was dropwise added 4-(methylthio)benzaldehyde (15 g) and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled away and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue obtained was recrystallized from hexane-ethyl acetate to give the subject compound (15 g) as white crystals. melting point=41-43° C.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:35][O:36][C:37]1[N:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[CH:39][C:38]=1[N:46]1[CH:50]=[C:49]([CH3:51])[N:48]=[CH:47]1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:35][O:36][C:37]1[N:42]=[C:41]([C:43]([NH:3][NH:2][C:1]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[O:44])[CH:40]=[CH:39][C:38]=1[N:46]1[CH:50]=[C:49]([CH3:51])[N:48]=[CH:47]1
Reactant: COc1nc(C(=O)O)ccc1-n1cnc(C)c1
Reactant: NNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(C(=O)NNC(=O)OCc2ccccc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzyl carbazate (27.8 g), 1-hydroxybenztriazole (24.8 g) and 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (35.4 g) were sequentially added to a solution of 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylic acid obtained in Preparation Example 1-5 (51.9 g) and IPEA (44 mL) in N,N-dimethylformamide (184 mL), and the mixture was stirred at room temperature for six hours and 30 minutes. Ethyl acetate, ice water and a saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then filtered through an NH silica gel pad. The resulting filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the powder was collected by filtration. The resulting powder was air-dried to obtain 28.4 g of the title compound.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:47])[NH:12][CH:13]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:14]([N:16]1[CH2:20][CH2:19][CH:18]2[N:21]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:22][CH:23]([C:24](=[O:36])[NH:25][CH:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28][CH2:27]3)[CH:17]12)=[O:15])[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:26]1([NH:25][C:24]([CH:23]2[CH2:22][N:21]([S:37]([CH3:40])(=[O:38])=[O:39])[CH:18]3[CH2:19][CH2:20][N:16]([C:14](=[O:15])[CH:13]([CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)[NH:12][C:11](=[O:47])[CH:9]([NH:7][CH3:6])[CH3:10])[CH:17]23)=[O:36])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2S(C)(=O)=O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2S(C)(=O)=O)C1CCCCC1
Reaction time: 1.5 h

Procedure:
A solution of 22 (222 mg, 0.3 mmol) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 1.5 h, the solution was concentrated, diluted with EtOAc, washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was diluted with ACN/H2O containing 0.1% HOAc and purified by reverse-phase HPLC (2″ Dynamax® C18, 10-100% ACN/H2O containing 0.1% HOAc). The product-containing fractions were frozen and lyophilized to afford 23 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1([S:17]([NH:20][C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:14]2[CH2:15][CH2:16][N:11]([S:17]([NH:20][C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[CH2:12][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)N1CCNCC1
Solvent: CCOCC
Product: COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(C(=O)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 4-chlorophenylisocyanate (0.33 g, 2.14 mmol) in diethyl ether (30 ml) was added methyl 2-(R)-[(piperazine-1-sulfonyl)amino]propionate (0.42 g, 1.8 mmol) [prepared as described in Step 1 above]. The reaction was stirred at RT for 2 h and filtered. The solid was washed with additional ether and the solid was collected to give methyl 2-(R)-{[4-(4-chlorophenylamino-carbonyl)piperazine-1-sulfonyl]amino}propionate (55%). This material was converted to N-hydroxy-2-(R)-{[4-(4-chlorophenylaminocarbonyl)piperazine-1-sulfonyl]amino}propionamide by following Example 13.
Reaction SMILES: COC(CCC/C=[C:9]1/[C:10](=[O:17])[CH:11]2[CH:15]([CH2:16]/1)[CH2:14][CH2:13][CH2:12]2)=O.[OH-].[Li+].O>CO>[CH:11]12[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:9][C:10]2=[O:17]
Reactant: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CCC2CCCC12
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A stirred solution of 6-[(E)-3-cyclohexyl-(mixture of 3α and 3β)-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (20 mg), prepared as described in Example 8 and predominantly in the 6β-configuration, otherwise known as (±)-methyl(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoate, in methanol (3.2 ml) was treated with lithium hydroxide (33.8 mg) and water (1.1 ml) at 20° C. and stirred for 2 hours. The mixture was then concentrated in vacuo. The resulting residue was diluted with water (5 ml) and then acidified to pH 3 by treatment with dilute hydrochloric acid (2N). The aqueous layer was then extracted with ethyl acetate (5×5 ml). The combined organic extracts were dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting residue was subjected to chromatography on a silica gel column, using a mixture of ethyl acetate, hexane and formic acid (50:50:1 by volume) as eluant, to give 3-[(E)-4-carboxybutylidene]-6-[(E)-3-cyclohexyl-(mixture of 3α and 3β)-hydroxyprop-1-enyl]bicyclo[3,3,0]octan-2-one (10 mg), predominantly in the 6β-configuration, otherwise known as (±)-(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoic acid [NMR in deuterochloroform: multiplets at 6.5, 5.5, 4.2-3.5, 3.0-0.7 p.p.m⟧
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][O:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[CH2:5][CH:6]=[CH2:7]>C(O)C.[Pd]>[CH3:1][NH:2][CH2:3][CH:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][O:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[CH2:5][CH2:6][CH3:7]
Reactant: C=CCC(CNC)C1c2ccccc2COc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCCC(CNC)C1c2ccccc2COc2ccccc21
Reaction time: 16 h
Yield: 70 %

Procedure:
Dissolved N-methyl-2-[6,11-dihydro-dibenzo[b,e]oxepin-11-yl]-pent-4-en-1-amine (0.50 g, 2.08 mmol) in 15 mL of absolute ethanol. Added 10 mg of 10% palladium on carbon catalyst, and stirred under atmospheric hydrogen balloon for 16 hours. Filtered through Celite, and washed with ethanol. Evaporated filtrate. Purified crude product by flash chromatography on silica gel eluting with 5% MeOH--CH2Cl2. Combined appropriate fractions, and evaporated to give 0.43 g (86% yield) of N-methyl-2-[6,11-dihydro-dibenzo[b,e]oxepin-11-yl]-pentanamine. Dissolved free base in ethyl acetate, and added one equivalent of maleic acid dissolved in absolute ethanol. Evaporated to foamy glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1
Reactant: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: COc1ccc2c(c1/C=C\CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.2 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperidine-1-carboxylate (0.0902 g, 0.226 mmol) synthesized in Example B61, Step 3 in ethanol (5 mL) was added with Lindlar's catalyst (0.100 g), and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and then the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-enyl]piperidine-1-carboxylate (0.0265 g, 29%).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[CH:17][N:16]([CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]=3[CH:32]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[CH:17][N:16]([CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]=3[CH:32]=2)=[O:9])=[CH:33][CH:34]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc(N)cc3)cc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{6-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (241 mg, 526 μmol) in a mixture of ethanol and water (6:1, 14 mL) was added palladium on carbon (48 mg, 10% w/w Pd) and ammonium formate (200 mg, 3.18 mmol). The suspension was heated to reflux for 2 hours, and was then cooled to room temperature, and filtered through a pad of Celite®. The filtrate was evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=4.61 min, MH+ 429].