Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29].C(OC(=O)C)C>CN(C)C=O.O>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:28][CH3:29])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CCI
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (1.3 g, 5 mmol) in dimethylformamide (25 ml) was added potassium carbonate (1 g, 7.5 mmol), and iodoethane (0.4 ml, 5.1 mmol), and the mixture was stirred at room temperature for 3 hours. Ethylacetate and water were added, the ethylacetate layer was separated, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from ethylacetate/hexane to afford the title compound, m.p. 200-202° C. (0.4 g, 27%); 1H-NMR (DMSO-d6) δ 1.25 (t, J=7.2 Hz, 3H), 1.64 (s, 6H), 4.07 (q, J=7.2 Hz, 2H), 6.29 (d, J=4.1 Hz, 1H), 7.0 (d, J=8 Hz, 1H), 7.05 (d, J=4.1 Hz, 1H), 7.34 (m, 2H), 10.42 (s, 1H). MS (ESI (−)) m/z 294 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].C(O)(=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:19][N+:16]([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
28.0 g of 2,3-dichlorobenzaldehyde, 13.9 g of ammonium acetate, 13.9 ml of nitromethane and 120 ml of glacial acetic acid are refluxed for 2 hours. After cooling, the reaction mixture is poured onto ice and stirred for 30 minutes. The formed precipitate is then filtered off, washed with water and dried in vacuo to thus obtain the product in the form of slightly yellowish crystals, m.p. 89°-91° C. IR (CHCl3) in cm-1 : 1650 (C=C); 1530 and 1350 (NO2). NMR (CDCl3) in ppm: 7.2-7.7 (m, 4H); 8.50 (d, J=15 Hz, 1H).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:11]=[C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][C:14]([C:22]2[N:27]=[C:26]([CH2:28]S([O-])(=O)=O)[CH:25]=[CH:24][CH:23]=2)=[N:13]1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:1]([S:8][CH2:28][C:26]1[N:27]=[C:22]([C:14]2[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:12](=[O:11])[N:13]=2)[CH:23]=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1nc(-c2cccc(CSCc3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.9 %

Procedure:
Benzyl mercaptan (0.41 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.18 g, 16%) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12]>[Pt].[Br-].[Br-].[Zn+2].CO>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12])[NH2:8]
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1Br
Agent: [Pt]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Product: CC(C)c1ccc(N)cc1Br
Yield: 101 %

Procedure:
2-Bromo-1-isopropyl-4-nitrobenzene (XI) (20 g, 79.1 mmol, 96.5 GC % by area), methanol 400 ml), platinum on carbon (1% of platinum, 2% of vanadium, moist with water) (1.0 g, 0.018 mmol) and zinc dibromide (90 mg, 0.40 mmol) were placed in a 600 ml autoclave. The autoclave was subsequently flushed with nitrogen and pressurized to 5 bar with hydrogen at room temperature. The contents of the autoclave were filtered through Celite, washed with methanol and the solvent was distilled off under reduced pressure. 3-Bromo-4-isopropylaniline (17.1 g, 93 LC-% by area, 98.3 GC-% by area, 98% of theory) was obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>>[Cl:1][C:2]1[C:3]([CH:8]([NH:22][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 108.3 %

Procedure:
In a 10 mL flask were added C-(3-chloropyrazin-2-yl)-C-(4-phenoxyphenyl)-methylamine (110 mg, 0.35 mmol), cyclohexanecarboxylic acid (0.090 g, 0.00070 mol), DIEA (0.55 mL, 0.0032 mol), TBTU (0.17 g, 0.00053 mol) and DMF (5 mL, 0.07 mol) and the reaction mixture is stirred at rt for 10 min. Reaction mixture was stirred at rt over weekend. The reaction mixture was concentrated in vacuo dissolved in DCM and washed with sat. aq NaHCO3 followed by brine. The organics were collected and concentrated in vacuo to give 160 mg of the compound as a yellow solid. Purification by prep TLC in 60% EtOAc:hexanes afforded 110 mg of the title compound as a light yellow solid. Compound was carried on to the next step. MS(ES+): m/z 422.15 (100)[MH+]. HPLC: tR=3.97 min (Open Lynx, polar—5 min).
Reaction SMILES: [C:1]([N:4]1[CH2:20][CH2:19][CH2:18][C:7]2=[N:8][C:9]3[CH:10]=[CH:11][C:12]([OH:17])=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[Br:21]Br>C(O)(=O)C.O>[C:1]([N:4]1[CH2:20][CH2:19][CH2:18][C:7]2=[N:8][C:9]3[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([Br:21])[C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)N1CCCc2nc3ccc(O)cc3c(C)c2C1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCCc2nc3ccc(O)c(Br)c3c(C)c2C1

Procedure:
2.5 gm (9.3 millimols) of 2-acetyl-9-hydroxy-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline were dissolved in 60 ml of glacial acetic acid and 12 ml of water, and the solution was brominated at room temperature with a solution of 1.48 gm (9.3 millimols) of bromine in 10 ml of glacial acetic acid. After distilling off the solvent, the residue was dissolved in water, and the solution was adjusted to a pH-value of 7.5 with 2 N sodium hydroxide, whereupon the reaction product crystallized out.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1[S:7][C:8](=[C:11]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:12]([O-:14])=[O:13])[S:9][CH:10]=1.[CH:21]1[CH:26]=CC=C[CH:22]=1.C(N(CC)CC)C>O>[S:9]1[CH:10]=[CH:6][S:7][C:8]1=[C:11]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:12]([O:14][CH:21]([CH3:26])[CH3:22])=[O:13]
Reactant: c1ccccc1
Reactant: CC(C)S(=O)(=O)C(C(=O)[O-])=C1SC=C(O)S1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(C)OC(=O)C(=C1SC=CS1)S(=O)(=O)C(C)C

Procedure:
After dropwise addition of 13.5 g of thionyl chloride to a mixture of 32.7 g of 4-hydroxy-1,3-dithiol-2-ylidene-isopropylsulfonylacetate and 100 ml of benzene, the reaction mixture was refluxed for 30 minutes. Subsequent to its cooling, 13.0 g of triethylamine was added to the reaction solution, followed by further reflux for 3 hours. The resultant reaction mixture was cooled. Water was added to the reaction mixture and the resulting organic layer was separated. Upon removal of the solvent by distillation under reduced pressure, 28.3 g of the title compound was obtained as pale brown crystals. Upon recrystallization from a mixed solvent of benzene and n-hexane, they turned to white crystals. Melting point: 124.5°-125° C.
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13][CH2:12]2)(=[O:7])[CH3:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:10]1[C:11]2[CH2:12][CH2:13][CH:14]=[CH:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:8][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCC=C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
Sodium borohydride (931 mg, 24.6 mmol) was added to a methanol solution (60 ml) of 6-acetamido-1-tetralone (5.00 g, 24.6 mmol) under ice-cooling, which was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then, the solvent was distilled out under reduced pressure. p-Toluenesulfonic acid (468 mg, 2.46 mmol) and toluene (120 ml) were added to the obtained alcohol form (5.05 g, 24.6 mmol), which was stirred at 100° C. for 1 hour. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:1), and powdered with hexane to give N-(7,8-dihydro-2-naphthalenyl)acetamide (3.17 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=3)[C:12]([CH2:22][C:23]([OH:25])=[O:24])=[CH:11][C:10]2=[O:26])=[CH:6][CH:5]=1.Cl>C(O)(=O)C>[NH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]([CH2:8][C:7]1[CH:27]=[CH:28][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:10](=[O:26])[CH:11]=[C:12]2[CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)c(CC(=O)O)cc(=O)n2Cc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1.17 h
Yield: 52 %

Procedure:
Iron powder (18g.) was added over 40 minutes to a stirred solution of 1-(4-chlorobenzyl)-1,2-dihydro-6-nitro-2-oxoquinol-4-ylacetic acid (13g.) in 50% v/v aqueous acetic acid (200 ml.) at 90° C. When the addition was completed, the mixture was stirred a further 70 minutes at 90° C. and then poured into an ice-water mixture (700 ml.). The mixture was adjusted to pH 1 with hydrochloric acid, and then filtered. The filtrate was adjusted to pH 6 with ammonium hydroxide solution, and the resulting mixture filtered. The solid residue (13g.) was dissolved as far as possible in 2N-sodium hydroxide solution, and the mixture was filtered. The filtrate was adjusted to pH 6 with glacial acetic acid, and the precipitated solid was filtered off, stirred with hot water (85° C., 200 ml.) and filtered while hot to give 6-amino-1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetic acid, m.p. 196-9° C., (decomposition) in 52% yield.
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([C:29]3([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=4)[CH:18]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CO>[ClH:1].[ClH:1].[N:3]1([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C@@H:16]([C:29]3([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=4)[CH:18]=3)[CH2:13][CH2:14]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc2cc(C(CN3CCC(N4CCCCC4)CC3)C3(O)CCCCC3)ccc2c1
Agent: Cl
Solvent: CO
Product: COc1ccc2cc([C@@H](CN3CCC(N4CCCCC4)CC3)C3(O)CCCCC3)ccc2c1

Procedure:
Racemic 1-[2-(1,4′-bipiperidin-1′-yl)-1-(6-methoxy-2-naphthyl)ethyl]cyclohexanol (see Example 346) was dissolved in methanol at a concentration of approximately 50 mg/mL. The resulting solution was injected onto the Supercritical Fluid Chromatography instrument. The baseline resolved enantiomers, using the conditions described below, were collected. The enantiomeric purity of each enantiomer was determined under the same Supercritical Fluid Chromatography conditions using a Chiralcel OJ-H 5u, 250 mm×4.6 mm ID column at 2.0 mL/min flow rate using Analytical Supercritical Fluid Chromatography (Berger Instruments, Inc. Newark, Del. USA).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11](O)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].CC([O-])=O.[Na+].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1.CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:11]=[O:12])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(I)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=CC1(c2ccc(I)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Part A. 1-(4-Iodophenyl)cyclopropane carboxylic acid (0.64 g, 2.25 mmol) was stirred in THF (10 mL) at 0° C. under N2. Et3N (0.47 mL, 3.37 mmol) was added, followed by dropwise addition of ClCO2Et (0.28 mL, 2.93 mmol). The reaction mixture was then stirred at 0° C. for 30 min. TLC showed the completion of the reaction. The mixture was filtered through a filter funnel and rinsed with anhydrous THF. The THF filtrate (ca.15 mL) was stirred at 0° C. under N2. NaBH4 (0.41 g, 10.8 mmol) was added, followed by addition of MeOH (3 mL). The resulting mixture was stirred at 0° C. for 30 min. Analytical LC-MS showed completion of the reaction. Sat'd Na2SO4 was then added. The mixture was extracted with EtOAc (2×). The organic layer was washed with H2O (2×) and brine (2×), dried over Na2SO4, filtered, and concentrated to dryness. The resulting alcohol was stirred in anhydrous CH2Cl2 (10 mL) at RT under N2. NaOAc (0.42 g, 5.12 mmol) and molecular sieves (4 Å, 0.75 g) were added, followed by the addition of PCC (0.83 g, 3.84 mmol). The resulting slurry was stirred at RT for 1.5 h. Analytical LC-MS showed completion of the reaction. The mixture was filtered through Celite, and rinsed with CH2Cl2. The filtrate was washed with H2O (2×) and brine (2×), dried over Na2SO4, filtered, and concentrated in vacuo to give almost pure 4-iodophenylcyclopropanecarbaldehyde. This aldehyde and pyrrolidine (0.37 mmol) were stirred in dichloroethane (6 mL) at RT under N2. NaBH(OAc)3 (1.37 mg, mmol) was added, followed by addition of several drops of HOAc. The reaction mixture was stirred at RT for 20 min. Analytical LC-MS showed completion of the reaction. H2O was added. The mixture was extracted with EtOAc; and the organic extracts were washed with H2O (2×) and brine (2×), dried over Na2SO4, filtered, and concentrated to dryness to give almost pure 1-{[1-(4-iodophenyl)cyclopropyl]methyl}pyrrolidine (0.41 g, yield % for 3 steps). LC/MS (ESI+) 328.2 (M+H)+. (10–90% CH3CN/H2O in a 4-min run, tR=1.77 min).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1.[CH2:15]([S-:17])[CH3:16].[Li+]>>[CH2:15]([S:17][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1)[CH3:16]
Reactant: CC[S-]
Reactant: O=C1NCC[C@H]1Oc1ccc(Br)nc1
Agent: [Li+]
Product: CCSc1ccc(O[C@@H]2CCNC2=O)cn1

Procedure:
Typical Procedure 8 was followed. Reaction of (R)-3-(6-bromo-pyridin-3-yloxy)-pyrrolidin-2-one with lithium ethanethiolate provided the title compound. MS ESI+: m/z=239 [M+H]+.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]43[O:37][C@H:17]4[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.O>CC(C)=O>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 26 °C
Reaction time: 3 h
Yield: 103.2 %

Procedure:
A stirred mixture of 28.4 kg (3β,5α,15α)-14,15-epoxycholest-7-en-3-ol benzoate (3) (Example 2) in 280 liters of acetone, under nitrogen, in a 200gallon reactor, at 22° C. was treated with 100 ml of 70% perchloric acid. The mild exothermic reaction raised the reaction mixture temperature to 26° C. in about a 5 minute period The mixture was cooled to 21° C. and an additional 180 ml of 70% perchloric acid was added. The reaction mixture temperature was kept at 22±1° C. and the mixture was stirred for 3 hours to complete the reaction. The mixture was cooled and treated with 140 liters of water at 19° C. for 30 minutes, then stirred 20 minutes more. The solid was collected by filtration, washed with a large quantity of water and dried in vacuo at 40°-60° C. to give 29.3 kg of the desired crude product (6).
Reaction SMILES: [CH3:1][C:2]12[CH2:22][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]2.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C=O)C>[CH2:27]([N:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]([N:7]2[CH2:8][C:2]3([CH3:1])[CH2:22][CH:6]2[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]3)=[O:10])=[CH:12][CH:13]=1)[S:18]([CH3:21])(=[O:19])=[O:20])[CH3:28]
Reactant: CCI
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NS(C)(=O)=O)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1)S(C)(=O)=O
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-methanesulfonamide (300 mg, 0.86 mmol) in dry DMF (25 ml) was added sodium hydride (42 mg, 1.73 mmol in 60% mineral oil) and the mixture was stirred for 1 hr. Ethyl iodide (83 μl, 1.03 mmol) was added and the stirring was continued for an additional 16 hrs. The reaction was quenched by addition of water (25 ml) and extracted with diethyl ether (2×50 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel) using EtOAc-Heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness affording a slowly crystallizing oil which was suspended in diethyl ether and the solid filtered off affording 140 mg (43%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH2:13])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: COc1cc2ncnc(N)c2cc1[N+](=O)[O-]
Reactant: Brc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: COc1cc2ncnc(Nc3ccccn3)c2cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
7-methoxy-6-nitroquinazolin-4-ylamine (300 mg, 1.36 mmol) in <Step 6> of Example 23, 2-bromopyridine (0.2 mL, 2.04 mmol), palladium acetate (31 mg, 0.136 mmol), Xantphos (158 mg, 0.273 mmol) and cesium carbonate (888 mg, 2.73 mmol) were placed under 6.5 mL of 1,4-dioxane in a closed container, degassed, and the mixture was stirred at 120° C. for 2 hours. The mixture was cooled to room temperature, 50 mL water was added thereto, and the mixture was washed with a solution of chloroform/isopropanol (4:1). The mixture was dried over sodium sulfate and filtered and distilled under reduced pressure. The resulting oil was purified by column chromatography to obtain the title compound (78.5 mg, 20%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([Cl:21])=[O:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of m-phenoxyphenylacetic acid (110) (1.14 g, 5.0 mmol) in 15 mL of dichloromethane was added 1.27 g (0.87 mL) of oxalyl chloride. The resulting solution was allowed to stir at room temperature for 24 hr. Solvent was evaporated to give an oil (1.233 g, 97%), which was used in next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:11][C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1COCO[CH2:36]1>ClCCl.S(=O)(=O)(O)O>[CH2:15]([N:14]1[C:12](=[O:13])[CH2:11][C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:34])[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:36]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1OCOCO1
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(=O)NCc2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To the solution of N-benzyl-2(R)-[(4-methoxyphenyl)sulfonylamino]-succinamic acid benzyl ester as an oil (2.10 g, 4.4 mmol) in 200 mL of dichloromethane is added, with stirring, 1.3,5-trioxane (1.57 g, 17.4 mmol) followed by two drops of sulfuric acid. The reaction is heated at reflux for 3 hours at which time mass spectrometry (ES) indicates the reaction to be complete. The reaction is allowed to cool to room temperature, diluted with dichloromethane (250 mL), and washed with water (2×). The product is purified by flash silica gel chromatography (1:1 hexanes-ethyl acetate), to give benzyl 1-benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)-carboxylate.