Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:19])[CH2:13][S:14]([O:16]CC)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:19])[CH2:13][S:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOS(=O)CC(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(CS(=O)O)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
In ethanol (7 ml) was dissolved 2.2 g (7.4 mmol) of ethyl 2-(benzyloxycarbonylamino)propane-1-sulfinate, and 3.2 g (8 mmol) of 10% aqueous sodium hydroxide solution was slowly dropped thereinto under ice-cooling. The reaction was carried out at room temperature for 1 hour, after which the ethanol was distilled off and water was added to the residue, followed by two runs of extraction with methyl t-butyl ether. The aqueous layer was acidified with concentrated hydrochloric acid, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the crude crystals thus obtained were washed twice with a solvent (hexane:ethyl acetate=4:1) to obtain 1.73 g (yield 91%) of 2-(benzyloxycarbonylamino)propane-1-sulfinic acid.
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:6])(=O)C.S(=O)(=O)(O)O.CC(C)=O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=[O:4])[CH3:6]
Reactant: CC(=O)OC(C)c1ccc2ccccc2c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
2-Acetylnaphthalene is prepared by treating 2-(1-bromoethyl)naphthalene, prepared as described above, with sodium acetate in acetic acid to afford 2-(1-acetoxyethyl)naphthalene which upon base hydrolysis furnishes the 2-(1-hydroxyethyl)naphthalene. The latter is oxidized with an equivalent of chromium trioxide in glacial acetic acid, or 8N sulfuric acid and acetone to furnish 2-acetylnaphthalene. 2-Carboxynaphthalene is prepared from 2-acetylnaphthalene by treating the latter with aqueous sodium hypochlorite. The 2-carboxynaphthalene is treated with diborane in an ether, such as diglyme (diethyleneglycol dimethyl ether), to yield 2-hydroxymethylnaphthalene.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[C:11]([C:15]4[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=4)=[N:12][NH:13][CH:14]=3)=[C:4]2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:29]1([NH:35][C:36]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:11]3[C:10]([C:9]4[CH:8]=[CH:7][N:6]=[C:5]5[NH:1][CH:2]=[CH:3][C:4]=45)=[CH:14][NH:13][N:12]=3)=[CH:16][CH:17]=2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccc(-c2n[nH]cc2-c2ccnc3[nH]ccc23)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1ccc(-c2n[nH]cc2-c2ccnc3[nH]ccc23)cc1
Reaction time: 14 h

Procedure:
To a solution of 4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.13 mmol) and triethylamine (0.20 mmol) in tetrahydrofuran (1.5 mL) was added phenyl isocyanate (0.13 mmol). After 14 h, the reaction mixture was concentrated in vacuo and the residue was purified by Gilson reverse phase HPLC to provide the title compound. ESMS [M+H]+: 395.2
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:39]=[CH:38][C:12]([C:13]([NH:15][CH:16]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:17]([CH3:31])([CH3:30])[C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O-:29])=[O:28])[CH2:22][CH2:21]3)=[O:19])=[O:14])=[CH:11][CH:10]=2)=[NH:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C>CO.[C].[Pd]>[N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][CH:16]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:17]([CH3:31])([CH3:30])[C:18]([N:20]3[CH2:21][CH2:22][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][CH2:25]3)=[O:19])=[O:14])=[CH:38][CH:39]=2)=[NH:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C(=O)N1CCC(CC(=O)[O-])CC1)C(NC(=O)c1ccc(C(=N)N2CCOCC2)cc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C(=O)N1CCC(CC(=O)O)CC1)C(NC(=O)c1ccc(C(=N)N2CCOCC2)cc1)c1ccccc1
Reaction time: 8 h
Yield: 69.6 %

Procedure:
The compound of Example 69, i.e. benzyl-N-(N-(4-(4-morpholinoimidoyl)benzoyl-β-phenyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (54 mg, 0.086 mmol) was dissolved in a 80% aqueous methanol solution (10 ml) containing 2% acetic acid. To the resulting solution was added 5% palladium carbon (10 mg) and the mixture was stirred overnight under a hydrogen atmosphere. After the solvent was distilled off, the residue was dissolved in a 1N aqueous solution of acetic acid and purified by HPLC in the same manner as in Example 44 to yield the titled compound (32 mg, 69%).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:14][C:15]([O:17]C)=[O:16])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH2:6]1)=[O:4].[ClH:19]>>[ClH:19].[C:3]([C:5]1([CH2:14][C:15]([OH:17])=[O:16])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH2:6]1)([OH:4])=[O:2]
Reactant: COC(=O)CC1(C(=O)OC)CN=C2C=CC=CN21
Agent: Cl
Product: O=C(O)CC1(C(=O)O)CN=C2C=CC=CN21
Yield: 51 %

Procedure:
The imidazopyridine ester product of Example 2 (0.057 g, 0.23 mmol) was dissolved in 4N HCl (4 mL) and heated to reflux for 14 h. All solvent was removed in vacuo and the residue triturated with diethyl ether to yield clean title compound (0.021 g, 51%). Anal. Calcd for C11H8N2O4.1.1 HCl.0.9 H2O: C, 43.44; H, 3.97; N, 10.13; Cl, 14.10. Found: C, 43.32; H, 3.60; N, 10.18; Cl, 14.22. 1H NMR (300 MHz, DMSO): 4.5 (2H, s), 7.5 (1H, t, J=6.25 Hz), 7.95 (2H, m), 9 (1H, d, J=12.5 Hz).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([S-:20])[CH3:19].[Na+]>C(S)C>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([S:20][CH2:18][CH3:19])=[NH:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[S-]
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: [Na+]
Solvent: CCS
Product: CCSC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium ethanethiolate in ethanethiol there is obtained ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-thiocarboximidate and therefrom with hydrochloric acid in alcohol there is obtained the hydrochloride, m.p. 220° C. (with decomposition);
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35])[CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=2)[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cccc(F)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(F)c1
Yield: 97 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.25 g, 0.69 mmol) prepared in example 4b was reacted with 1-(3-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 11a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.35 g, 97%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]=2)[CH:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+]>CS(C)=O>[CH:31]([C:28]1[CH:29]=[CH:30][C:25]([N:19]([CH:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])[S:16]([C:13]2[CH:12]=[CH:11][C:10]([O:8][CH2:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:15][CH:14]=2)(=[O:17])=[O:18])=[N:26][CH:27]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1ccc(N(C(C)C(C)C)S(=O)(=O)c2ccc(F)cc2)nc1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1ccc(N(C(C)C(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (10.20 mg, 0.088 mmol) and 4-fluoro-N-(5-isopropylpyridin-2-yl)-N-(3-methylbutan-2-yl)benzenesulfonamide (32 mg, 0.088 mmol) in dimethyl sulfoxide (DMSO) (1 mL) stirred in air at room temperature was added sodium hydride (3.51 mg, 0.088 mmol, 60% wt in mineral oil). The reaction mixture was stirred at 20° C. for 2 hours. Additional (tetrahydro-2H-pyran-4-yl)methanol (10.20 mg, 0.088 mmol) and sodium hydride (3.51 mg, 0.088 mmol, 60% wt in mineral oil) were added and the reaction mixture stirred overnight. The reaction was carefully quenched with isopropanol (1 mL) and water (1 mL). The solvent was evaporated in vacuo and the residue partitioned between water (5 mL) and dichloromethane (2×5 mL), then separated using a hydrophobic frit. The solvent was removed in vacuo and the crude was purified by mass directed autoprep (formic acid modifier) to give the title product (32 mg). LCMS (2 min, formic) Rt 1.41 min, m/z (ES+) 461 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=O.C([Li])CCC.Cl>C1COCC1.CCCCCC>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:7]=[C:2]2[C:3]([CH2:12][CH2:13][C:14]2=[O:16])=[CH:4][CH:5]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCc2ccc(C(F)(F)F)cc21
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
To a solution of 3-[2-bromo-4-(trifluoromethyl)phenyl]propanoic acid (6.40 g, 21.5 mmol) in THF (300 mL) and hexane (80 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexane (19 mL). After being stirred for 15 min, the mixture was poured into a 2 N HCl solution (150 mL). The two layers were separated and the water layer was extracted by ether. The combined organic layers were washed with NaHCO3 solution, water, brine, dried over MgSO4 and concentrated. Column chromatography on silica (10-20% EtOAC in hexane) provided the title compound (2.2 g, 51%) as an oil. MS calculated for C10H7F3O: (M+H)+201; found 201.0.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(Br)[C:13]1[CH:18]=[CH:17][CH:16]=CC=1>O1CCCC1>[CH2:8]([C:1]([CH2:13][CH2:18][CH2:17][CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9])[CH2:1][CH2:2][CH3:3]
Reactant: BrCc1ccccc1
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(C#N)(CCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flame dried 500 ml three neck round bottomed flask, equipped with a dry argon inlet, magnetic stir bar, and thermometer, is added benzyl cyanide ((1), 5.0 gm.; 0.043 mol) and tetrahydrofuran (100 ml). To the reaction is slowly added sodium hydride (60% in oil) (7.2 gm, 0.1075 mol) over one hour. Once addition is complete the reaction is stirred at room temperature for 1 hour. To the reaction is added benzyl bromide (18.4 gm; 0.043 mol) and the reaction is stirred at 50° C. for 18 hours. The reaction is evaporated to dryness, residue dissolved in toluene and washed with 1N HCl. Organic phase is dried with Na2SO4, filtered and evaporated to yield α,α-dibutyl-benzeneacetonitrile (2), wt=7.7 gm (65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][N:7]=2)[CH:3]=1)=[O:25]
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Product: O=C(CCCCl)Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1

Procedure:
A solution of EXAMPLE 89 (150 mg, 0.59 mmol) and 4-chlorobutanoyl chloride (83 mg, 0.59 mmol) in dichloromethane (5 mL) was stirred at room temperature for 16 hours, and was concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated to provide the title compound. MS (DCI/NH3) m/z 360 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 1.66-1.73 (m, 4H), 2.07-2.15 (m, 2H), 2.40-2.46 (m, 2H), 2.48-2.51 (m, 2H), 2.50-2.56 (m, 2H), 3.63 (t, J=6.44 Hz, 2H), 3.96 (s, 2H), 6.93 (d, J=7.67 Hz, 1H), 7.21-7.26 (m, 1H), 7.36 (s, 1H), 7.38-7.46 (m, 1H).
Reaction SMILES: [CH:1]1([C:7]([N:9]([CH2:31][C:32]2[C:33](=[O:43])[N:34]([CH3:42])[C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:10][CH:11]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:42][N:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[C:32]([CH2:31][N:9]([CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:8])[C:33]1=[O:43]
Reactant: Cn1c(=O)c(CN(CC(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C2CCCCC2)cc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1c(=O)c(CN(CC(c2ccccc2)C2CCNCC2)C(=O)C2CCCCC2)cc2ccccc21
Reaction time: 1.5 h

Procedure:
tert-butyl 4-(2-{(cyclohexylcarbonyl) [(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)piperidine-1-carboxylate (1.63 g, 2.78 mmol) in CH2Cl2 (5 ml) was added to 4 M HCl in dioxane (20 mL, 80 mmol) at 0° C. and the reaction stirred for 1.5 hours before being poured into satd. bicarb. The mixture was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. 1.35 g, 100%.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]=O)=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[OH:1][C:2]1[C:3]([CH2:12][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1cc2c(cc1O)CCCO2
Solvent: CO
Product: Oc1cc2c(cc1CNc1ccccc1)OCCC2
Yield: 45 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-7-carboxaldehyde (429 mg, 2.41 mmol) and aniline (224 mg, 2.42 mmol) in methanol (30 mL) was warmed and the methanol, which distilled over, was collected. When 10 mL of methanol had been collected, the mixture was allowed to cool and the intermediate Schiff's base crystallized out. This material was collected and redissolved in fresh methanol (30 mL). Sodium borohydride (1 molar equiv.) was added in portions and the color immediately discharged. The mixture was concentrated to 50% of its original volume, then poured into an excess of water (100 mL). The aqueous solution was rendered acidic with 2N HCl, filtered to remove any insoluble material, then basified with 7%, NaHCO3. The product, which precipitated, was collected by filtration and dried to afford 6-hydroxy-7-phenylaminomethyl-3,4-dihydrobenzopyran (277 mg, 49%), m.p. 135°-137° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[S:26](Cl)([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl>[CH3:29][S:26]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)C[C@H]1CCCOC1
Temperature: 25 °C
Yield: 111.6 %

Procedure:
To a solution of tert-butyl (S)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (6.2 g, 23.9 mmol) and triethylamine (7.25 g, 71.8 mmol) in CH2Cl2 at 0° C. was added mesyl chloride (5.5 g, 47.8 mmol) dropwise. The reaction mixture was stirred at rt until the starting material disappeared. The reaction was quenched with ice-cold water and extracted with CH2Cl2 (3×100 ml). The combined organic layers were washed with water (3×50 ml), dried over Na2SO4, and concentrated under vacuo to give the (S)-2-(tert-butoxycarbonylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propyl methanesulfonate (9 g), which was used for the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>ClCCl>[N:11]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ncccn3)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cnc(-c2ccc(N3CCNCC3)cc2)nc1
Reaction time: 2 h

Procedure:
4-(4-Pyrimidin-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 5.03 gm was dissolved in 25 ml dichloromethane and 10 ml of 4N HCl dioxane added. After stirring for 2 hrs, the mixture was then evaporated to obtain the title product.
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([O:19][P:20]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Product: CCOP(=O)(Cc1ccc(C(=O)c2ccccc2)cc1)OCC
Temperature: 125 °C

Procedure:
A mixture of 4.8 g of 4-benzoylbenzyl bromide and triethylphosphite was heated at 125° C. for 0.5 hours and cooled to room temperature. The resulting oil was purified by flash chromatography (70% ethyl acetate/hexanes) to afford 3.2 g of diethyl 4-benzoylbenzylphosphonic acid, as an oil. A mixture of 3.2 g (9.6 mmol) of diethyl 4-benzoylbenzylphosphonic acid and 40 ml of concentrated hydrochloric acid was refluxed for 7 hours and cooled to room temperature. The two phase mixture was partitioned between 125 ml of water and 400 ml of EtOAc, the EtOAc layer was dried over Na2SO4, filtered and evaporated to give 0.7 g of product; m.p. 172°-175° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH2:22][O:23][CH3:24])=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:3])[CH3:2].[N:27]1([C:32]2[CH:33]=[C:34]([C:38]3[O:43]C(C)(C)[O:41][C:40](=O)[CH:39]=3)[CH:35]=[CH:36][CH:37]=2)[CH:31]=[CH:30][N:29]=[CH:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH2:22][O:23][CH3:24])=[CH:10][C:9]=1[NH:25][C:40](=[O:41])[CH2:39][C:38]([C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH:33]=1)=[O:43])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Product: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-2′-methoxymethoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G42) (181 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (135 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (221 mg).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:22])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:22]
Reactant: CC=CCC1Cc2ccc(OCC(C)C)cc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)COc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 1.5 h
Yield: 48 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 5.1 g of (RS)-2-(2-buten-1-yl)-6-isobutoxy-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.16 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 170 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 2.3 g (48%) of (RS)-2-(2-oxoethyl)-6-isobutoxy-1-indanone were obtained as a red-brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16].[CH3:48][C:49]1([CH3:56])[CH2:54][C:53](=[O:55])[O:52][C:50]1=[O:51]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:37])([CH3:38])[C@@H:26]([O:39][C:53](=[O:55])[CH2:54][C:49]([CH3:56])([CH3:48])[C:50]([OH:52])=[O:51])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 61 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1S,3R)-2,2-dimethyl-3-(piperidine-1-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 11, 0.110 g, 1.697 mmol) 2,2-Dimethylsuccinic anhydride (0.2 ml, 1.697 mmol) and DMAP (0.044 g, 0.338 mmol) in pyridine (5 ml) were added at room temperature then the reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, 1N HCl, water, brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.080 g: Yield: 61%; 1H NMR (300 MHz, CDCl3): δ 6.01 (d, 1H, J=8.4 Hz), 4.72 (s, 1H), 4.58 (s, 1H), 4.53-4.43 (m, 1H), 4.16-4.08 (m, 1H), 3.71-3.62 (m, 2H), 3.54-3.35 (m, 3H), 3.18-3.06 (m, 1H), 2.93-2.87 (m, 1H), 2.66 (d, 1H, J=15.9 Hz), 2.56 (d, 1H, J=15.9 Hz), 2.50-2.27 (m, 2H), 1.99-1.88 (m, 2H), 1.80-1.00 (m, 46H), 0.94, 0.92, 0.83 (s, 12H); Mass: [M+1]+ 777 (100%), [M+Na]+ 799 (80%); IR (KBr, cm−1): 3411, 2944, 2867, 1733, 1730, 1625, 1467, 1445, 1368, 1253, 1220, 1192, 1022, 977, 884, 767; M.R: 139.5° C.-141.5° C.; HPLC: 96.7%.