Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:5]([N:8]2[C:13]([CH3:14])=[C:12]([Cl:15])[N:11]=[C:10](Cl)[C:9]2=[O:17])[CH2:6][CH3:7])[CH2:4][CH2:3][CH2:2]1.[ClH:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28](C)[CH:29]=1)[NH:26][CH2:25][CH2:24]2>>[Cl:15][C:12]1[N:11]=[C:10]([N:26]2[C:27]3[C:23](=[CH:22][C:21]([O:20][CH3:19])=[CH:29][C:28]=3[Cl:18])[CH2:24][CH2:25]2)[C:9](=[O:17])[N:8]([CH:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH2:6][CH3:7])[C:13]=1[CH3:14]
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CCC(C1CCC1)n1c(C)c(Cl)nc(Cl)c1=O
Reactant: Cl
Product: CCC(C1CCC1)n1c(C)c(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 536 using 1-(1-cyclobutylpropyl)-3,5-dichloro-6-methyl-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials to give a yellow amorphous solid; 1H NMR (300 MHz, CDCl3) δ 6.73 (s, 2H), 4.28 (t, J=8.4 Hz, 2H), 4.04–3.97 (m, 1H), 3.79 (s, 3H), 3.62–3.55 (m, 1H), 3.10 (t, J=7.7 Hz, 2H), 2.50 (s, 3H), 2.42–2.35 (m, 1H), 2.22–2.10 (m, 1H), 1.90–1.50 (m, 5H), 1.58–1.50 (m, 1H), 0.86 (t, J=7.3 Hz, 3H); HRMS (ESI) m/z 422.1420 [(M+H)+, calcd for C21H26N3O2Cl2 422.1402].
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].O.[NH2:14][C:15]1[C:16]([CH3:28])=[C:17]([C:22](SC#N)=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=O.[CH3:29]I>C(O)C>[NH2:14][C:15]1[C:16]([CH3:28])=[C:17]([C:22]([CH3:29])=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[S:10]
Reactant: [S-2]
Reactant: CI
Reactant: COC(=O)c1c(SC#N)ccc(N)c1C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=S)c1c(C)ccc(N)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.1 %

Procedure:
To a solution comprising 39.5 g of sodium sulfide nonahydrate and 110 ml of water, a solution comprising 32.9 g of methyl 3-amino-2-methyl-6-thiocyanobenzoate and 300 ml of ethanol, was dropwise added. The mixture was stirred at room temperature for 1.5 hours, and then 24 g of methyl iodide was dropwise added thereto under cooling with ice. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. A saturated sodium chloride aqueous solution was added thereto, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 30.1 g of the desired product. Oily substance.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.[ClH:37].CCOCC>O1CCOCC1>[ClH:37].[NH:27]1[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:14]4=[CH:15][C:16]5[O:20][CH2:19][O:18][C:17]=5[CH:21]=[C:13]4[O:12][CH2:11]3)[C:2]2=[O:1])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C1N(CCC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate (0.94 g, 1.91 mmol) in dioxane (5.00 mL) was added 4.0 M HCl in dioxane (2.00 mL, 8.00 mmol). The mixture was stirred at ambient temperature for 30 min followed by the addition of anhydrous ether (40.0 mL). The precipitated white solid was filtered, washed with ether and dried to give the title compound (0.75 g, 91%): 1H NMR (300 MHz, CD3OD) δ 7.37 (t, 1H), 7.20-7.07 (m, 3H), 6.52 (s, 1H), 6.10 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.67 (d, 1H), 3.97-3.75 (m, 2H), 3.45-3.33 (m, 2H), 3.01-2.85 (m, 2H), 2.15-2.01 (m, 2H), 1.82-1.37 (m, 5H); 13C NMR (75 MHz, CD3OD) δ 179.8, 157.6, 150.4, 143.7, 143.4, 133.6, 130.3, 124.9, 124.8, 120.8, 110.3, 103.7, 102.9, 94.3, 81.4, 59.8, 45.2, 38.5, 34.4, 32.6, 29.8, 29.7; MS (ES+) m/z 393 (M+1).
Reaction SMILES: [Cl-].[C:2]1([N+:8]2[C:13]([SH:14])=[CH:12][C:11]([NH2:15])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([Cl:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl-:23].[C:2]1([N+:8]2[C:13]([S:14][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:11]([NH2:15])=[CH:10][N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cn[n+](-c2ccccc2)c(S)c1
Reactant: ClCc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Nc1cn[n+](-c2ccccc2)c(SCc2ccccc2)c1
Yield: 90.2 %

Procedure:
5 parts of 1-phenyl-4-amino-6-mercaptopyridazinium chloride in 100 parts of toluene is stirred with 2.5 parts of benzyl chloride for 1 hour at 110° C. 6.2 parts (90.2% of theory) of 1-phenyl-4-amino-6-benzylmercaptopyridazinium chloride is obtained; C17H16N3SCl, melting point 226° to 228° C after having been recrystallized from alcohol. The perchlorate melts at 170° to 171° C.
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][C:7]2=3)CCCC1.[F:29]C(F)(F)C1C=C(F)C=CC=1C(Cl)=O.[CH2:43]([Mg]Br)[CH:44]([CH3:46])C>>[F:29][C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:7]3[CH:6]([CH2:1][CH:44]([CH3:46])[CH3:43])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[O:28])=[C:19]([C:24]([F:25])([F:26])[F:27])[CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Reactant: CC(C)C[Mg]Br
Product: CC(C)CC1OB(O)c2cc(NC(=O)c3ccc(F)cc3C(F)(F)F)ccc21

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with 2-trifluoromethyl-4-fluorobenzoyl chloride replacing 2-trifluoromethylbenzoyl chloride, and with isobutyl magnesium bromide replacing cyclopentyl magnesium bromide. Data: LCMS (M/Z): 396 (M+H); 1H NMR (DMSO-d6) δ: 10.54 (s, 1H), 9.13 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.73-7.81 (m, 2H), 7.58-7.68 (m, 2H), 7.31 (d, J=8.2 Hz, 1H), 5.10 (dd, J=9.8, 3.1 Hz, 1H), 1.60-1.69 (m, 1H), 1.21-1.31 (m, 1H), 0.98 (d, J=6.5 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H), 0.85 (t, J=7.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([OH:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[F:20][C:21]([F:27])([F:26])[S:22](O)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][S:22]([C:21]([F:27])([F:26])[F:20])(=[O:24])=[O:23])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)c1c(O)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(Cl)cc(Cl)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
A solution of the above ester (4.64 g, 20.99 mmol) and pyridine (1.87 mL, 23.09 mmol) in 100 mL CH2Cl2 was cooled to 0° C. Trifluoromethanesulfonic acid (4.94 mL, 29.39 mmol) was added, and the solution was stirred for 2 h. The reaction mixture was washed with aqueous sodium bicarbonate, aqueous copper sulfate and brine, dried over Na2SO4, filtered and concentrated to provide methyl 2,4-dichloro-6-{[(trifluoromethyl)sulfonyl]oxy}benzoate that gave proton NMR spectra consistent with theory.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:9])[CH2:4][O:5][CH:6]([CH3:8])[CH3:7].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(N(C(C)C)CC)(C)C.CN(C=O)C>C1COCC1>[OH:9][CH:3]([CH2:4][O:5][CH:6]([CH3:8])[CH3:7])[CH2:2][NH:1][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)OCC(O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)OCC(O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1 g of rac-1-amino-3-isopropoxypropan-2-ol (7.5 mmol, 1 equivalent) were initially charged in 25 ml of THF, and 1.16 ml of benzyl chloroformate (8.3 mmol, 1.1 equivalents), 3.9 ml of diisopropylethylamine (22.5 mmol, 3 equivalents) and 183 mg of N,N-dimethylaminopyridine (1.5 mmol, 0.2 equivalents) were added. The reaction mixture was stirred at RT, and after about 30 min 5 ml of DMF were added. After a further 2.5 h at RT, the mixture was concentrated to dryness. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was used without further purification for the next reaction.
Reaction SMILES: F[C:2]1C=CC(N2C(C(N(OC)C)=O)=CN=C2SCC2C(F)=CC=C(F)C=2F)=C[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[C:41]([C:42]([OH:44])=[O:43])=[CH:40][N:39]=[C:38]2[S:45][C:46](C2C=CC=CC=2)(C2C=CC=CC=2)[C:47]2C=CC=CC=2)=[CH:33][CH:32]=1.CS(OCC[C:72]1[C:77]([F:78])=[CH:76][CH:75]=[CH:74][C:73]=1[Cl:79])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:79][C:73]1[CH:74]=[CH:75][CH:76]=[C:77]([F:78])[C:72]=1[CH2:47][CH2:46][S:45][C:38]1[N:37]([C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=2)[C:41]([C:42]([O:44][CH2:2][CH3:3])=[O:43])=[CH:40][N:39]=1
Reactant: CS(=O)(=O)OCCc1c(F)cccc1Cl
Reactant: O=C(O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Reactant: CON(C)C(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SCCc2c(F)cccc2Cl)n1-c1ccc(F)cc1

Procedure:
Ethyl 2-((2-chloro-6-fluorophenethyl)thio)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (53) was prepared in a similar manner as that described for the synthesis of compound 9 using ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (6) (700 mg, 2.62 mmol), 2-chloro-6-fluorophenethyl methanesulfonate (813 mg, 3.144 mmol), potassium carbonate (1.1 g, 7.86 mmol) in DMF (20 mL).
Reaction SMILES: FF.[F:3][C:4]([F:16])([F:15])[CH:5]([C:11]([F:14])([F:13])[F:12])[C:6](OCCl)=O>>[F:3][C:4]([F:16])([F:15])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH2:6]
Reactant: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Agent: FF
Product: C=C(C(F)(F)F)C(F)(F)F

Procedure:
Among the thus produced fluorine-containing compounds (I), monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate is reacted with an amine to give 2-trifluoromethyl-3,3,3-trifluoropropene in a high yield.
Reaction SMILES: O.O.[Sn](Cl)Cl.[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13](=[NH:42])[C:14]2[CH:15]=[C:16]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=4)(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:8]1>C(O)(=O)C.CO>[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:21]([NH:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([N:10]4[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]4)=[NH:42])[CH:15]=3)=[O:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])=[CH:34][CH:35]=1
Reactant: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)cc2)c1)N1CCC(O)CC1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)c3ccc(N)cc3)cc2)c1)N1CCC(O)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A suspension of tin(II) chloride dihydrate (3 equivalents) in concentrated acetic acid was treated with a 3 M solution of chloridric acid in methanol for 30 minutes. The resulting suspension was added portionwise to a solution of 1-(3-((4-hydroxypiperidin-1-yl) (imino)methyl)phenyl)-3-(4-(4-nitrophenyl sulfonyl)phenyl)urea (10) in acetic acid. The resulting solution was stirred 2 hours at 85° C. The reaction mixture was quenched with a 5% NaOH aqueous solution, and extracted with ethyl acetate. The title compound was obtained after preparative HPLC.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.C(OP([CH:18]([CH3:24])[C:19]([CH:21]1[CH2:23][CH2:22]1)=O)(=O)OCC)C.O.[NH2:26][NH2:27]>>[CH:21]1([C:19]2[C:18]([CH3:24])=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:27][N:26]=2)[CH2:23][CH2:22]1
Reactant: O=C1C(=O)C2CCC1C2
Reactant: CCOP(=O)(OCC)C(C)C(=O)C1CC1
Reactant: NN
Solvent: O
Product: Cc1c(C2CC2)nnc2c1C1CCC2C1

Procedure:
off-white crystalline solid. MS (EI): 200.2 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, (2-Cyclopropyl-1-methyl-2-oxo-ethyl)-phosphonic acid diethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([O:13][CH2:14][C@H:15]([CH2:17][OH:18])[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:19]1([C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)Cl)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O1CCCC1.C(#N)C>C(N(CC)CC)C>[CH2:1]([O:13][CH2:14][C@H:15]([CH2:17][O:18][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOC[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
19.83 grams of (S)-1-dodecyl-glycerol and 21.0 grams of triphenylchloromethane were added to a mixture of 250 ml dry tetrahydrofuran (THF) and 60 ml dry acetonitrile. 22 ml of dry triethylamine was added and the reaction mixture was refluxed for 17 hours under nitrogen. The reaction mixture was then cooled to room temperature, and 5 ml triethylamine and 10 grams of ice were added. The mixture was transferred to a separatory funnel and extracted with 100 ml MTBE. The organic phase was washed consecutively with 150 ml water, 150 ml of dilute (1.5%) H2SO4, 150 ml water, 150 ml of concentrated aqueous sodium bicarbonate, and again with 150 ml water. The solution was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The residue, 40.63 grams of a brown oil, was dissolved in 200 ml ethyl acetate and cooled to −20° C. for a couple of days. The mixture was centrifuged at a temperature of −10° C. and the mother liquid was poured off. The solid melted at room temperature and was purified by chromatography on a silica gel column (195 grams). 18.57 grams of pure (R)-1-dodecyl-3-trityl-glycerol was eluted by mixtures of chloroform and hexane followed by a mixture of 9:1 (v/v) chloroform:ethyl acetate. The yield was 48.5%.
Reaction SMILES: [Na].C1C2C(=CC=CC=2)C=CC=1.CC1C=CC(S([N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][S:31][C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]2=3)(=O)=O)=CC=1>COCCOC>[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][S:31][C:30]2[CH:39]=[CH:40][CH:41]=[CH:42][C:29]1=2
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Agent: [Na]
Solvent: c1ccc2ccccc2c1
Solvent: COCCOC
Product: c1ccc2c(c1)CSc1ccccc1N2C[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
Sodium (55 mg) was added to a solution of naphthalene (340 mg) in DME (6 ml) and the mixture stirred at room temperature for one hour, treated with a solution of (S)-5,11-dihydro-5-(1-[4-methylphenylsulphonyl]-2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine (see Preparations 15 and 16) (200 mg) in DME (4 ml), stirred with ice-cooling for one hour, quenched with water and extracted with ethyl acetate. The organic extract was worked-up and purified as described in Preparation 13 to give the title compound as a colourless oil, (16 mg, 12%).
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.[OH-].[K+].I[CH3:24]>CC(C)=O.O>[CH3:24][O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1
Reactant: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CON=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of 0.2 g (0.75 mmol) of 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide in 2 mL of acetone cooled to 0° C. was added a solution of 0.065 g (1.16 mmol) of potassium hydroxide in 1 mL of water followed by 0.164 g (1.16 mmol) of iodomethane. The resulting mixture was stirred at room temperature overnight then 10 mL of water was added. The mixture was extracted with ether and the organic layer was washed with water and brine, then dried by sodium sulphate and filtered. The solvent was removed by evaporation under reduced pressure and the residue chromatographed on silica gel with a 3% methanol-dichloromethane mixture. Chromatographically homogenous fractions were pooled, the solvents were removed under reduced pressure and the residue was crystallised from toluene to give the product as off-white crystals of m.p. 157.9°-159.4° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:44])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:43])[CH2:9][CH2:10][C@@:11]3([C:27]([N:29]4[CH2:34][CH2:33][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:35]#[N:36])[CH2:31][CH2:30]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:46])[CH3:45].N1C=CC=CC=1.[CH3:53][C:54]1([CH3:61])[CH2:58][C:57](=[O:59])[O:56][C:55]1=[O:60]>C(OCC)(=O)C>[C:35]([C:32]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:34][N:29]([C:27]([C@:11]23[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]2[C@@H:13]2[C@@:8]([CH3:43])([CH2:9][CH2:10]3)[C@@:7]3([CH3:44])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:46])([CH3:45])[C@@H:2]([O:1][C:57](=[O:59])[CH2:58][C:54]([CH3:61])([CH3:53])[C:55]([OH:60])=[O:56])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:28])[CH2:30][CH2:31]1)#[N:36]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)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
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)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

Procedure:
To a stirred solution of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)-4-phenylpiperidine-4-carbonitrile (Example 76, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) was added then 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) was added and the contents were refluxed for about 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 753 (100%), [M+1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([F:15])=[CH:4][C:3]=1[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(OC(=O)C)(=O)C.C(OCC)(OCC)OCC>[CH2:18]([O:20][CH:21]=[C:17]([C:16](=[O:23])[C:3]1[CH:4]=[C:5]([F:15])[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[CH:7][C:2]=1[F:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:17]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2CCN(C)CC2)cc1F
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCN(C)CC2)cc1F

Procedure:
A solution of 3.25 g (10 mmoles) of ethyl 2,5-difluoro4-(1-methyl-4-piperidinyl)-β-oxobenzenepropionate in 20 ml of acetic anhydride and 2.5 ml of triethyl orthoformate was refluxed 11/4 hours and evaporated under vacuum to give the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[CH3:16])=O.[C:19]([C:24]1C=CC=CC=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:16])=[C:5]2[C:3]([C:2]([F:18])([F:17])[F:1])=[CH:24][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COc1ccc2[nH]c(C)c(C(=O)C(F)(F)F)c2c1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(c1c(C)[nH]c2ccc(OC)cc12)C(F)(F)F
Temperature: 120 °C
Yield: 98.4 %

Procedure:
A suspension of the indole from Step 1 (18.3 g, 71.4 mmol) and carbethoxy-methylenetriphenylphosphorane (49.7 g, 142.8 mmol) in 100 mL of toluene was pressurized to 900 psi nitrogen in a stainless steel, high pressure Parr reactor and was heated to 120° C. for 39 h. The reaction mixture was cooled, concentrated and purified by flash chromatography (30% ethyl acetate/hexanes) to give 23 g of the title compound as a mixture of E- and Z- isomers.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C=O.[CH3:12][O:13][CH:14](OC)[O:15][CH3:16].Cl>O1CCOCC1.C(=O)(O)[O-].[Na+].CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:14]([O:15][CH3:16])[O:13][CH3:12]
Reactant: COC(OC)OC
Reactant: O=CCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(CCCCCCCCBr)OC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a 100 mL round-bottomed flask was added 9-bromononanal (7.2 g, 32.5 mmol), methanol (30 mL) and trimethylorthoformate (4 mL, 36.5 mmol). A solution of 4 N hydrochloric acid in dioxane (0.2 mL, 0.8 mmol) was added and the resulting mixture was refluxed for 3 h. The reaction mixture was then cooled to room temperature and solid sodium bicarbonate (100 mg, 1.2 mmol) was added. The resulting mixture was concentrated to one-fourth its original volume under reduced pressure and then ethyl acetate (50 mL) was added. The organic layer was washed with water (2×40 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (8.44 g, (97% yield)) as a liquid, which as used in the next step without further purification.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)=[N+:2]=[N-:3].[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[CH:26])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O.[CH3:41][C:42](O)([CH3:44])[CH3:43]>O>[C:42]([O:11][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([N:1]2[CH:26]=[C:25]([CH2:24][O:23][C:20]3[CH:21]=[CH:22][C:17]([S:14]([CH3:13])(=[O:15])=[O:16])=[CH:18][CH:19]=3)[N:3]=[N:2]2)[CH2:9][CH2:8]1)=[O:12])([CH3:44])([CH3:43])[CH3:41]
Reactant: C#CCOc1ccc(S(C)(=O)=O)cc1
Reactant: [N-]=[N+]=NC1CCN(C(=O)O)CC1
Reactant: CC(C)(C)O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(COc3ccc(S(C)(=O)=O)cc3)nn2)CC1
Reaction time: 8 h

Procedure:
4-Azido-piperidine-1-carboxylic acid text-butyl ester (1 eq) and 1-methanesulfonyl-4-prop-2-ynyloxy-benzene (1 eq) were suspended in H2O/t-BuOH (1:1). Sodium ascorbate (0.1 eq) was added followed by CuSO4.5H2O (0.01 eq). The mixture was stirred vigorously overnight. The mixture was diluted with water and a precipitate formed. The precipitate was collected by filtration and purified on silica gel to give the desired product. 1H NMR (CDCl3): δ 7.88 (2H, d), 7.67 (1H, s), 7.14 (2H, d), 5.29 (2H, s), 4.64 (1H, m), 4.28 92H, m), 3.05 (3H, s), 2.94 (2H, m), 2.2 (2H, m), 1.96 (2H, m), 1.48 (9H, s).