Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([O:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
This was prepared as follows:- A solution of benzyl bromide (10.26 g; 60 mmol) and 4chloro-3-nitrophenol (8.7 g; 50 mmol) in DMF (250 ml) was treated with Na2CO3 (10.6 g; 0.1 mol) and the mixture was stirred at room temperature for 3 days. The mixture was poured into water and extracted with Et2O. The organic phase was washed with brine and dried over MgSO4. The residue was purified by flash chromatography eluting with CH2Cl2 to give 5-benzyloxy-2-chloro-nitrobenzene as a pale yellow solid (12.32 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH2:25][CH:26](OCC)OCC.CN(C)C(=O)C>C(OCC)(=O)C>[CH3:20][N:11]([C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[NH:6][C:5]([C:21]1[S:23][CH:25]=[CH:26][N:22]=1)=[CH:4]2)[S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Reactant: CCOC(CBr)OCC
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3nccs3)cc12
Yield: 43 %

Procedure:
A mixed solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.20 g), 1-bromo-2,2-diethoxyethane (0.23 mL) and N,N-dimethylacetamide (10 ml) was stirred at 100° C. for 6 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75-35:65), and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (92 mg, yield 43%) as pale-yellow prism crystals. melting point 159-160° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:12]2[CH2:18][CH:17]([C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:23])=[C:6]([F:34])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=2[F:34])[CH:12]2[CH2:18][CH:17]([C:19]([F:21])([F:22])[F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:23])(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CN(C2CC(C(F)(F)F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NCCC(C(F)(F)F)CC1N(Cc1ccc(CO)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 3.5 h

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-5-trifluoromethyl-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester (0.05 g, 0.09 mmol) in THF (1 ml) was added dropwise to a cooled (ice-bath) suspension of LiAlH4 (0.02 g, 0.44 mmol) in THF (1 ml) under an argon atmosphere. The cold bath was removed and the reaction mixture was further stirred for 3.5 h. Ethyl acetate and a KHSO4/K2SO4 buffer was added to the reaction mixture. The organic fraction was further washed with a KHSO4/K2SO4 (2×), water, brine, dried (Na2 SO4), filtered, concentrated under reduced pressure and purified using preparative RP(C18) chromatography to give 4-chloro-N-(2-fluoro-4-hydroxymethyl-benzyl)-N-(2-oxo-5-trifluoromethyl-azepan-3-yl)-benzenesulfonamide as a lyophilisate: 13 mg; MS: m/e=509.4 (MH+).
Reaction SMILES: C([N:8]([CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39]CC2C=CC=CC=2)=[C:35]([NH:47][CH:48]=[O:49])[CH:34]=1)[OH:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]#[C:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1.[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]/[C:53]([OH:55])=[O:54]>C(O)C.[Pd].[OH-].[OH-].[Pd+2]>[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]/[C:53]([OH:55])=[O:54].[CH:48]([NH:47][C:35]1[CH:34]=[C:33]([C@@H:31]([OH:32])[CH2:30][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=2)[CH:38]=[CH:37][C:36]=1[OH:39])=[O:49]
Reactant: NS(=O)(=O)c1cccc(C#CCCOCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c(NC=O)c2)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(NC=O)c2)c1

Procedure:
A solution of 3-(4-{[6-(benzyl{(2R)-2-[4-(benzyloxy)-3-(formylamino)phenyl]-2-hydroxyethyl}amino)hexyl]oxy}but-1-ynyl)benzenesulfonamide (320 mg) in ethanol (15 ml) was hydrogenated in the presence of 10% palladium on carbon (50 mg) and palladium hydroxide on carbon (100 mg) at 100 p.s.i for 18 h. The catalyst was filtered off onto celite and the filtrate was evaporated to dryness. The residual oil was purified by chromatography on Biotage (8 g) cartridge eluting with dichloromethane/ethanol/0.88 ammonia (25:8:1). The residual oil (118 mg) was dissolved in methanol (20 ml) and treated with fumaric acid (0.5 equivalent) and evaporated to give the title compound (80 mg). LCMS RT=2.39 min, ES+ve 508 (MH)+.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])(C)(C)C.[C:15]([C@@H:18]([NH:51][C:52]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][C:70]([OH:72])=[O:71])=[O:53])[CH2:19][CH2:20][C:21](=[O:50])[NH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][C:30](=[O:49])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38]C(ON1C(=O)CCC1=O)=O)([OH:17])=[O:16].CCN(C(C)C)C(C)C>C1COCC1>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][NH:31][C:30]([CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][NH:22][C:21]([CH2:20][CH2:19][C@H:18]([NH:51][C:52]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][C:70]([OH:72])=[O:71])=[O:53])[C:15]([OH:17])=[O:16])=[O:50])=[O:49])=[O:7]
Reactant: O=C(O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCCN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NCCCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCCCC(=O)O)C(=O)O
Temperature: 25 °C
Yield: 55 %

Procedure:
N-tert-butoxycarbonyl cadaverine (24.3 mg; 0.12 mmol) was added to a solution of 17-((S)-1-Carboxy-3-{2-[2-({2-[2-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl methoxy)ethoxy]ethylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}propylcarbamoyl)-heptadecanoic acid (100 mg; 0.12 mmol) and DIPEA (46.68 mg; 0.36 mmol) in THF (2.0 ml). Reaction mixture was stirred over night at room temperature, and then concentrated in vacuo. The residue was dissolved in a mixture of water (5 ml) and THF (2 ml), and purified by preparative HPLC (RP18 column). Fractions containing the Boc-protected coupling product was pooled and taken to dryness. The residual was dissolved in 50% TFA-DCM (4 ml) and stirred for 1 h at room temperature, then concentrated in vacuo to provide 54 mg (55%) of the title material as its trifluoroacetic acid salt.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:20])[N:8]=[C:9]([C:12]2[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>CS(C)=O>[Cl:19][C:15]1[CH:16]=[C:17]([F:18])[C:12]([C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:20])[N:8]=2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1c(C)c(-c2ncc(Cl)cc2F)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1c(-c2ncc(Cl)cc2F)nn(C)c1C(=O)O
Temperature: 22 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
6.75 g of 5-(5-chloro-3-fluoropyridin-2-yl)-2,4-dimethyl-[2H]-pyrazole-3-carboxylic acid ethyl ester are suspended in 40 ml of dimethyl sulfoxide. With occasional cooling in an ice-bath (internal temperature <30° C.), 14.3 ml of a 2N sodium hydroxide solution are added dropwise. The thick, yellowish-brown suspension is stirred at 22° C. for 2 hours. The suspension is then introduced into ice-water and adjusted to pH 1 with 2N hydrochloric acid. The resulting slurry is filtered, washed well with cold water and then dried in vacuo at 60° C. 5.97 g of the desired title compound are obtained in the form of a beige solid having a melting point of 194-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (26.5 g, 142 mmol) in acetone (300 ml) at room temperature was treated with 3-bromo-propan-1-ol (14.5 ml, 156.2 mmol), potassium carbonate (50 g, 361.8 mmol) and potassium iodide (2.4 g, 14.2 mmol), and the mixture was heated at reflux for 18 h then allowed to cool to room temperature. The suspension was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (27.7 g, 80%).
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.Br[CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[Cl:17][C:18]1[CH:23]=[C:22](I)[CH:21]=[C:20]([Cl:25])[N:19]=1>CN(C)C(=O)C.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:18]1[CH:23]=[C:22]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:21]=[C:20]([Cl:25])[N:19]=1
Reactant: BrC1CCOCC1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Si](C)(C)Cl
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: Clc1cc(C2CCOCC2)cc(Cl)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a 100 mL round-bottomed flask containing zinc dust (2.03 g, 31.0 mmol, 1.70 equiv) in N,N-dimethylacetamide (20 mL) was added chlorotrimethylsilane (0.473 mL, 3.65 mmol, 0.200 equiv) and 1,2-dibromoethane (0.318 mL, 3.65 mmol, 0.200 equiv) over 10 min. A solution of 4-bromotetrahydro-2H-pyran (2.88 mL, 25.6 mmol, 1.40 equiv) in N,N-dimethylacetamide (15 mL) was then added to the mixture. After 30 min, the reaction mixture was filtered over Celite and added to a round-bottomed flask containing [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (745 mg, 0.913 mmol, 0.0500 equiv), cuprous iodide (348 mg, 1.83 mmol, 0.100 equiv), and 2,6-dichloro-4-iodo-pyridine (5.00 g, 18.3 mmol, 1.00 equiv). The reaction was then heated to 80° C. for 16 h. After cooling to room temperature, the reaction mixture was filtered over Celite washing with ethyl acetate (3×10 mL) and concentrated to dryness. Purification by flash column chromatography (30:70 ethyl acetate/heptane) furnished the product as a white solid (3.00 g, 71% yield). 1H NMR (CDCl3, 400 MHz), δ: 7.11 (s, 1H), 4.09 (dt, J=11.6, 3.3 Hz, 2H), 3.57-3.42 (m, 2H), 2.85-2.70 (m, 1H), 1.77 (tt, J=7.5, 3.7 Hz, 4H).
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH2:19][C:20]([NH:22][C@H:23]([C:27]([N:29]2[CH2:51][CH2:50][CH2:49][C@H:30]2[C:31]([NH:33][C@@H:34]([CH:46]([CH3:48])[CH3:47])[CH:35]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)[OH:36])=[O:32])=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:21])[C:13]1=[O:52])=[O:10])([CH3:7])([CH3:6])[CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(C)(C)C>[C:4]([O:8][C:9]([CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH2:19][C:20]([NH:22][C@H:23]([C:27]([N:29]2[CH2:51][CH2:50][CH2:49][C@H:30]2[C:31]([NH:33][C@@H:34]([CH:46]([CH3:47])[CH3:48])[C:35]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)=[O:36])=[O:32])=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:21])[C:13]1=[O:52])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)Cn1ccc(=O)n(CC(=O)OC(C)(C)C)c1=O)C(C)C)C(O)c1nc2ccccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)Cn1ccc(=O)n(CC(=O)OC(C)(C)C)c1=O)C(C)C)C(=O)c1nc2ccccc2o1
Yield: 80.2 %

Procedure:
To methylene chloride (30 ml) containing 2-(3-tert-butoxy-carbonylmethyl-2,4-dioxo-1-pyrimidinyl)acetyl-L-valyl-N-[(1S)-2-(2-benzoxazolyl)-1-isopropyl-2-hydroxyethyl]-L-prolinamide (1.5 g) obtained in Example 9 are added t-butyl alcohol (0.16 g) and a Dess-Martin reagent (1.9 g), and the mixture is stirred at room temperature for one hour. The reaction solution is poured into a saturated aqueous sodium thiosulfate solution, and the mixture is extracted with ethyl acetate. The extract is washed successively with a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure to give the desired 2-(3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl)acetyl-L-valyl-N-[(1S)-2-(2-benzoxazolyl)-1-isopropyl-2-oxoethyl]-L-prolinamide (1.2 g) as powders.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:13](O)([CH3:16])([CH3:15])[CH3:14].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 4-acetylbenzoic acid (3.9 g) in anhydrous methylene chloride (120 ml) are added 4-dimethylaminopyridine (1.5 g), t-butyl alcohol (4.6 ml), N-methylmorpholine (3.4 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.0 g) under ice cooling. The mixture is stirred under ice cooling for six hours and under water cooling overnight. The reaction mixture is concentrated under reduced pressure, water is added to the concentrate, and the whole is extracted with ether. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 3.13 g (59%) of t-butyl 4-acetylbenzoate as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]I)=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:26]2[N:27]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:28](=[O:30])[NH:29][C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:20][C:21]1[C:26]2[N:27]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:11][CH2:10][CH2:9][CH:8]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:33][CH2:32]3)[C:28](=[O:30])[NH:29][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]c2cccc(Cl)c2n1C1CCNCC1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2cccc(Cl)c2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 7.4 parts of 1,1-bis(-4-fluorophenyl)-4-iodobutane, 5 parts of 7-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5 parts of sodium carbonate and 56 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, the reaction mixture is poured onto water. The organic layer is separated, dried, filtered and concentrated to half its volume. From the residue, the product is allowed to crystallize. The product is filtered off and recrystallized from a mixture of 4-methyl-2-pentanone and 2-propanol, yielding 7-chloro-1-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 215.4° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[C:14]([S:24](Cl)(=[O:26])=[O:25])=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=2.Cl>O.O1CCOCC1>[Cl:12][C:13]1[C:14]([S:24]([NH:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:26])=[O:25])=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=2
Reactant: NCC(=O)O
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNS(=O)(=O)c1cc2ccc(Cl)cc2cc1Cl
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a solution of potassium carbonate (11.7 g) and glycine (6.4 g) in water (140 ml) were added 3,6-dichloronaphthalen-2-ylsulfonyl chloride (20.8 g) and dioxane (50 ml) at room temperature, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, the resultant solution was acidified with 2 N hydrochloric acid to a pH in the range of 1 to 2, and extracted with ethyl acetate. The organic layer was washed with water, then with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Ethyl acetate was removed in vacuo to give 19.0 g of the objective compound.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[C:6]([CH3:15])[CH:7]=[CH:8][C:9]=2[CH3:14])[N:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[C:6]([CH3:15])[CH:7]=[CH:8][C:9]=3[CH3:14])[N:4]=2)=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(C)c2c(C)cc(NN)nc12
Product: Cc1ccc(C)c2c(C)cc(NNC(=O)Nc3cc(Cl)cc(Cl)c3)nc12

Procedure:
A solution of 2-hydrazinyl-4,5,8-trimethylquinoline (100 mg, 0.50 mmol) and 93.53 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.43 (s, 3 H) 2.73 (s, 3 H) 2.77 (s, 3 H) 6.69 (s, 1 H) 6.92 (d, J=7.03 Hz, 1 H) 7.09 (t, J=1.90 Hz, 1 H) 7.23 (d, J=7.62 Hz, 1 H) 7.68 (br. s., 2 H) 8.35 (s, 1 H) 8.53 (s, 1 H) 9.24 (br. s., 1 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCC1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 100.1 %

Procedure:
To methyl 2-oxocyclopentanecarboxylate (5 g, 35.1 mmol) in H2O (7.5 mL), NaOH (1.5 g) was added. The reaction mixture was stirred at room temperature for 40 h, then cooled to 0° C. and conc. HCl (3 mL) was added, then stirred for an additional 30 min. at 0° C. to give 2-oxocyclopentanecarboxylic acid (4.5 g, crude). In another set up, 3,4-dichloroaniline (5.5 g, 33.9 mmol) was dissolved in H2O (22 mL), cooled to 0° C. and conc. HCl (8.3 mL) was added and stirred for 20 min. while maintaining the temperature at 0° C. NaNO2 (2.3 g, 33.9 mmol) in water was added to the reaction mixture and stirred at 0° C. for another 30 min. The reaction mixture was filtered and to the filtrate 2-oxocyclopentanecarboxylic acid (4.5 g, crude) (prepared above) was added slowly. The reaction mixture was slowly warmed to room temperature and stirred for 1 h during which time a solid precipitated out which was filtered to provide the title compound as a yellow solid (5 g, 58%). 1H NMR (200 MHz, CDCl3, δ in ppm) 7.59 (bs, 1H), 7.40-7.30 (m, 2H), 7.09-6.94 (m, 1H), 2.80 (t, J=7.4 Hz, 1H), 2.68 (t, J=7.4 Hz, 1H), 2.55-2.45 (m, 2H), 2.24-2.06 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]1.N1C=CC=CC=1.[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.C(OCC)(=O)C>[C:20]1([CH2:19][O:26][C:27]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]2)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C1CCNN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 3-pyrazolidinecarboxylic acid, 1,1-dimethylethyl ester (10.935 g., 63.5 mmol.) in dry acetonitrile (90 ml.) was cooled to 0° C. (ice-salt bath) and treated with dry pyridine (11.0 ml.) followed by a solution of benzylchloroformate (12.54 g., 10.5 ml., 69.9 mmol.) in dry acetonitrile (25 ml.). The reaction was stirred at 0° C. for 3 hours, evaporated to dryness and the syrup obtained was redissolved in ethyl acetate (250 ml.). The solution was washed with 5% sodium bicarbonate (2×25 ml.) and brine (25 ml.), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude product mixture was chromatographed on a silica gel column (Merck), eluting the column with ethyl acetate:hexane mixtures (1:4; 1:2) to give 11.144 g. of title product as a syrup.
Reaction SMILES: C([O:9][CH2:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[O:37][N:36]=[C:35]([C:38]([O:40]CC)=[O:39])[CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)(=O)C1C=CC=CC=1.O.O.[OH-].[Li+]>O1CCOCC1.Cl>[OH:9][CH2:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:31])([CH3:32])[C:20]([C:33]2[O:37][N:36]=[C:35]([C:38]([OH:40])=[O:39])[CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)OCC)no6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)O)no6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 32590.9 %

Procedure:
To a solution of ethyl 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(benzoyloxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)isoxazole-3-carboxylate (0.015 g, 0.022 mmol) in 1,4-Dioxane (2 mL) was added Water (0.5 mL) and Lithium hydroxide monohydrate (0.17 g, 4.05 mmol). The mixture was heated to 75° C. After 3.5 h the mixture was cooled to rt and was diluted with 1N HCl (7 mL) then was extracted with dichloromethane (4×7 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by crystallization using dioxane, water, and methanol. The expected product, 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)isoxazole-3-carboxylic acid (4 mg, 7.17 mmol, 31.9% yield), was isolated as a white solid. LCMS: m/e 536.35 (M+H)+, 2.03 min (method 7). 1H NMR (500 MHz, Pyr) δ ppm 0.87 (s, 3H), 0.96-1.88 (m, 20H), 1.04 (s, 3H), 1.05 (s, 3H), 1.17 (s, 3H), 1.21 (s, 3H), 1.81 (s, 3H), 2.14-2.27 (m, 1H), 2.39-2.53 (m, 1H), 2.59-2.74 (m, 1H), 3.70 (d, J=10.99 Hz, 1H), 4.12 (d, J=10.99 Hz, 1H), 4.80 (br. s., 1H), 4.94 (s, 1H), 6.40 (d, J=6.41 Hz, 1H), 7.08 (s, 1H).