Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[CH3:2].[CH2:9]1[CH2:16][O:15][S:12](=[O:14])(=[O:13])[CH2:11][CH2:10]1>>[CH2:1]([N+:3]1([CH2:16][CH2:9][CH2:10][CH2:11][S:12]([O-:15])(=[O:14])=[O:13])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S1(=O)CCCCO1
Reactant: CCN1CCOCC1
Product: CC[N+]1(CCCCS(=O)(=O)[O-])CCOCC1

Procedure:
1.15 grams of N-ethylmorpholine was alkylated with 1,4-butanesultone in similar fashion to the previous example to give 1.09 grams of a white solid. The structure was confirmed by positive mode electrospray mass spectroscopy (M+H)=252.6 and (M+Na) 274.2 m/z and 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=4[CH3:31])[C:24]([O:26]C)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=4[CH3:31])[C:24]([OH:26])=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Temperature: 60 °C

Procedure:
To a mixture of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate (1 g, 2.4 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambient temperature was added 5 eq. of NaOH and heated to 60° C. for 5 h. The mixture was cooled to ambient temperature and then in an ice-water bath, quenched slowly with 1.5 N HCl and then concentrated. The mixture with white precipitates was diluted with water and filtered to get the solid. It is further washed with water and dried in vacuum. Yield: 0.850 g (90%). This acid was also prepared by the coupling of 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (Cs2CO3, (Ph3)4Pd, H2O/1,4-dioxane (1:5), 90° C.) in a similar manner as described. 1H NMR (400 MHz, DMSO-d6): δ 2.32 (s, 3H), 2.82-2.83 (d, 3H, J=4.6 Hz), 7.36-7.48 (m, 6H), 7.56-7.57 (d, 1H, J=1.44 Hz), 7.75-7.77 (d, 1H, J=8.48 Hz), 7.81-8.03 (m, 2H), 8.46-8.48 (d, 1H, J=4.7 Hz), 12.92 (s, 1H). LCMS: (ES+) m/z=404.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:18])[CH2:14][CH2:15][S:16][CH3:17])[C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:18])[CH2:14][CH2:15][S:16][CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCCC(=O)C1CCN(C(=O)OC(C)(C)C)C1=O
Solvent: C1CCOC1
Solvent: CSC
Product: CSCCC(O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.6 %

Procedure:
3-(3-Methylsulfanylpropionyl)-2-oxo-pyrrolidine-1-carboxylic acid t-butyl ester (188 mg, 654 μmol) was dissolved in THF (531 μL) under nitrogen. 2M BH3.Me2S in THF (981 μL) was added via syringe over 15 minutes. The mixture was stirred at room temperature for 1 hour, then heated at 65° C. for 1 hours, then cooled to room temperature. The mixture was cooled on an ice bath and the reaction was slowly quenched with cold MeOH (100 mL). The mixture was stirred overnight and then diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation to yield a yellow oil (300 mg), which was used without further purification. LCMS m/z: [M+H]+ calcd for C13H25NO3S, 275.40; found 276.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([CH:12]1[CH2:14][CH2:13]1)=[O:11].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:10]([CH:12]1[CH2:14][CH2:13]1)=[O:11]
Reactant: O=C(Cc1ccc(F)cc1F)C1CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(C1CC1)C(Br)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1-cyclopropylethanone (329 mg) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (360 mg) and 75% benzoyl peroxide with stirring at room temperature, and the resulting mixture was refluxed for 3.5 hours. After the reaction mixture was filtrated, 1N aqueous sodium hydroxide solution was added to the filtrate. The resulting mixture was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to afford the title compound (390 mg, yield: 84%) as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([O:19][C:18]([F:17])([F:27])[F:28])[CH:21]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1C[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of N-Boc-4-methylene-L-proline (1 g, 4.4 mmol) in CH2Cl2 (40 mL) was added 3-(trifluoromethoxy)aniline (0.71 mL, 5.28 mmol), HBTU (1.14 g, 6.6 mmol) and diisopropylethylamine (1.51 mL, 8.8 mmol). The reaction mixture was stirred at RT for 2 days. The mixture was successively washed with 30 mL of a saturated aqueous NaHCO3 solution and an HCl 1M solution. The organic layers were dried (phase separator) and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane/EtOAc:65/35) to give the title compound. TLC, Rf (c-hexane/EtOAc: 1:1)=0.55; MS (LC/MS): 287.0 [M-Boc]+, 385.0 [M−H]−.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:37]1([CH2:1][C:3]2[S:7][C:6]([C:8]3[CH:9]=[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=3)[NH:13][CH:12]=[C:11]4[CH:20]3[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:28])=[O:27])[CH2:22][CH2:21]3)=[CH:5][CH:4]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NC(=O)c1cc(-c2ccc(C=O)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(CN3CCCC3)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 5-(5-formyl-2-thienyl)-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (8.3 mg, 0.016 mmol) in methylene chloride (5 mL) was added pyrrolidine (0.001 mL, 0.016 mmol). The reaction mixture was stirred at room temperature for 1 hour before NaBH(OAc)3 (10.2 mg, 0.048 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (7 mg, 92%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33](=[O:49])[C@H:34]([CH:46]([CH3:48])[CH3:47])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:22][CH2:23][C:24]([O:26][CH2:27]Cl)=[O:25])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I-:50].[Na+]>C(#N)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33](=[O:49])[C@H:34]([CH:46]([CH3:48])[CH3:47])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:22][CH2:23][C:24]([O:26][CH2:27][I:50])=[O:25])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CCC(=O)OCCl)cc1OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CCC(=O)OCI)cc1OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 65 °C
Yield: 89.2 %

Procedure:
Chloromethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate (1.9 g, 2.7 mmol) and sodium iodide (2 g, 13.3 mmol) were dissolved in acetonitrile (50 ml) and heated to 65° C. for 60 min. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane and filtrated. Removal of the solvent and purification by chromatography (ethyl acetate-hexane, 2:5) gave pure title product (1.9 g, 90%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C([O:12][C:13]([C:15]1[C:16]([OH:30])=[N:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=2)=O)C.C(Cl)Cl>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:13]([C:15]1[C:16]([OH:30])=[N:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:27])[F:28])[CH:19]=2)=[O:12]
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1O
Reactant: NCc1cccc(F)c1
Solvent: ClCCl
Solvent: CCO
Product: O=C(NCc1cccc(F)c1)c1c(O)nc2cc(C(F)(F)F)ccc2c1O
Temperature: 90 °C
Yield: 97.7 %

Procedure:
2.0 ml (17.3 mmol) 3-fluorobenzylamine was added to a suspension of 1.3 g (4.3 mmol) 2,4-dihydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in EtOH (50 ml) and the mixture was heated to 90° C. for 3 h. Concentration in a vacuum was subsequently carried out. After CC (DCM) of the residue, 1.6 g (4.2 mmol, 98%) N-(3-fluorobenzyl)-2,4-dihydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid amide was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=O)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[CH3:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:28])[CH:38]=[CH:39][C:40]=1[CH3:41]
Reactant: Cc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.451 g, 1 mmol), [(3-bromo-4-methylphenyl)methyl]amine (0.2 g, 1 mmol, HBTU (0.379 g, 1 mmol), and TEA (0.278 mL, 2 mmol) were combined in CH2Cl2 (25 mL). The mixture was stirred overnight at room temperature. Aqueous workup gave the crude product which was CombiFlashed on a 40 g column eluted with 0-10% MeOH/CH2Cl2 to give the title compound as a white solid. LC-MS m/z 633.8 (M+H)+, 1.85 min (ret time); mp 175-176° C.; analytical HPLC shows 97.5% purity, (ret time 13.568 min).
Reaction SMILES: [F:1][C:2](=[CH2:11])[C:3]([CH3:10])([CH3:9])[C:4]([O:6]CC)=[O:5].[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12]/[CH:11]=[C:2](\[F:1])/[C:3]([CH3:10])([CH3:9])[C:4]([OH:6])=[O:5]
Reactant: C=C(F)C(C)(C)C(=O)OCC
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C(=O)O)/C(F)=C/Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
Ethyl 3-fluoro-2,2-dimethyl-3-butenoate (14 g) and bromine (11 g) were dissolved in 50 mL of CCl4, and the solution heated at reflux for one hour. The solution was then cooled and concentrated in vacuo. The dibromo ester was taken up in 100 mL of dry THF and stirred at 0° C. while DBU (13 g) was added dropwise. Stirring was continued overnight, allowing the solution to warm to ambient temperature. The dark solution was then poured onto ice and excess 10N HCl, and the product was isolated by extraction into ether, washing with a saturated brine solution, drying and removal of the solvent. The bromovinyl ester (10.4 g) was then hydrolyzed by treatment with 7.3 g of potassium hydroxide in a solution of 10 mL of ethanol and 90 mL of water, at the reflux temperature for one hour. After the solution had cooled, it was diluted with 100 mL of water, acidified, extracted with ether (2×100 mL), and the combined organic layer washed with brine, dried and concentrated to yield 7.3 g of (Z) 4-bromo-3-fluoro-2,2-dimethyl-3-butenoic acid as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1N1CCOCC1
Yield: 98.9 %

Procedure:
4-Fluoronitrobenzene (5 g) and morpholine (7.2 g) were dissolved in ethanol (50 ml) and refluxed for 2 hr, before the ethanol was removed in vacuo. The resulting slurry was dissolved in ethyl acetate (30 ml) and washed with water (20 ml), dried over magnesium sulphate (2 g), and the solvent removed in vacuo to yield the title compound as an orange solid (7.3 g).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.Cl.[NH2:13][OH:14].C(N(CC)CC)C>CO>[C:9]1(=[N:13][OH:14])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH2:11]1
Reactant: NO
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: ON=C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.7 %

Procedure:
To a solution of α-tetralone (10 g, 68.5 mmol) in anhydrous MeOH (175 mL), hydroxylamine hydrochloride (7.6 g, 109.6 mmol) and triethylamine (15.3 mL, 109.6 mmol) were added. The mixture was stirred at room temperature for 16 hrs, followed by removal of the solvent in vacuo. The residue was dissolved in DCM, washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to yield crude 3,4-dihydro-2H-naphthalen-1-one oxime (12 g). MS [M+H]+: 162.1; tR=2.03 min. (method 1)
Reaction SMILES: [Na].[C:2]([S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=O)[CH3:3].[N+:13](CCOC(=O)C)([O-:15])=[O:14]>C(O)C>[N+:13]([CH2:3][CH2:2][S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)([O-:15])=[O:14]
Reactant: CC(=O)SC1CCCCCC1
Reactant: CC(=O)OCC[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])CCSC1C=CCCCC1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To 40 ml of absolute ethanol was added 1.38 g (.060 gram atom) metallic sodium. When the reaction was completed 10.2 g ( b .060 mole) of 3-acetylmercaptocycloheptane in 20 ml of absolute ethanol was added and the reaction mixture was brought up to reflux for 15 minutes. The solution was then cooled to 0° and 7.98 g (.060 mole) of 1-nitro-2-acetoxyethane in 20 ml absolute ethanol was added. The reaction was allowed to proceed for 3.0 hours at 0° and then was partitioned between lN HC1 and methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic phases were pooled, dried over sodium sulfate, and evaporated to afford 12 g (99%) of pure 3-[2-nitroethylthio]cycloheptene as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:14][CH:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([OH:18])=O)([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])=[O:5])[CH3:2].[CH3:23][NH:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH2:27]>ClCCl.O1CCCC1>[CH2:1]([O:3][P:4]([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])([CH2:14][CH:15]([C:16](=[O:18])[NH:27][C@H:26]([C:25](=[O:32])[NH:24][CH3:23])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)CNC1=O
Reactant: CNC(=O)[C@@H](N)CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)CNC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.1 %

Procedure:
0.22 g (0.64 mmol) of 2(RS)-[[(RS)-(ethoxy)[(2,5-dioxo-1-imidazolidinyl)methyl]phosphinyl]methyl]-4-methylvaleric acid and 0.116 g (0.81 mmol) of L-leucine methylamide were taken up in 5 ml of dichloromethane and 2.5 ml of tetrahydrofuran. The solution was treated at -8° C. with 0.3 g (1.2 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline. The mixture was stirred at room temperature for 24 hours and was then left to stand at 0° C. for 48 hours. The solvent was removed by evaporation. The residue was taken up in 50 ml of chloroform. The solution was washed in sequence with 5% citric acid solution, 5% sodium hydrogen carbonate solution and sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give a gum. This gum was chromatographed on silica gel using chloroform/methanol (19:1) for the elution to give 0.08 g of [(2,5-dioxo-1-imidazolidinyl)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester as a gum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:21][CH3:22])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=2)[CH:8]=1
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Yield: 97 %

Procedure:
A solution of 8-chloro-4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-quinoline (2.0 g, 5.97 mmol) in POCl3 (10 mL) was heated at 85° C. during 30 min. Then, the reaction mixture was concentrated under reduced pressure. The residue was poured into ice-cooled water (20 mL), the pH was adjusted to 10 with 50% NaOH, and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to give 2.05 g (97%) of the title compound 92 as a yellow solid: m/z=353 (M+H)+.
Reaction SMILES: COC[O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][C@H:24]([O:31]COC)[C@@:23]2([CH3:35])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[OH:19])[CH2:6]1>C1COCC1>[OH:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][C@H:24]([OH:31])[C@@:23]2([CH3:35])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[OH:19])[CH2:6]1
Reactant: COCO[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](OCOC)[C@]2(C)[C@@H]([C@H](C)CCC(C)(C)O)CC[C@@H]32)C1
Solvent: C1CCOC1
Product: C[C@H](CCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
A solution of the crude alcohol in 60 mL of THF and 18 mL of 2 M liCl was refluxed for 24 h. After the solution was concentrated to about 20 mL and diluted with about 50 mL of ether, it was washed with 50 mL of water, 50 mL of saturated NaCHO3 2 and 50 mL of brine respectively. The solution was dried over anhydrous MgSO4 and concentrated to afford crude 3α,12α-dihydroxy-24,24-dimethyl-5α-cholan-24-ol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[C:17]1([N:16]2[C:8](=[O:10])[C:7]3=[C:2]([Cl:1])[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]3[C:11]2=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: C1COCCO1
Product: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1c1ccccc1
Yield: 90 %

Procedure:
In 1.2 l of dioxane was dissolved 286 g (1 mol) of tetrachlorophthalic anhydride, and while refluxing the solution, 93 g (1 mol) of aniline was added dropwise to the solution. Thereafter, the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool, whereby tabular crystals were precipitated. The crystals were collected by filtration, washed with dioxane, and dried to provide 325 g of N-phenyltetrachlorophthalimide having a melting point of 251° C. to 253° C. (yield 90%).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>ClCCl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([CH:3]([N:4]3[CH:8]=[N:7][CH:6]=[N:5]3)[CH:2]([CH3:19])[CH3:1])=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])=[O:35])=[CH:29][CH:28]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1cncn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(c1ccc(NC(=O)Cc2ccc(Cl)cc2)c([N+](=O)[O-])c1)n1cncn1
Yield: 69.9 %

Procedure:
To a stirred and cooled (5° C.) solution of 10 parts of 4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrobenzenamine and 6.7 parts of pyridine in 195 parts of dichloromethane was added a solution of 14.4 parts of 4-chlorobenzeneacetyl chloride in 39 parts of dichloromethane under nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (99:1 by volume) as eluent. The eluent of the desired fraction was evaporated, yielding 11 parts (69.9%) of 4-chloro-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrophenyl]benzeneacetamide (interm. 112).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 20, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.