Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:19])[C@:15]([NH2:18])([O:16][CH3:17])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:20]([S:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1)[CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:7])(C)(C)C.C(N(CC)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C>C(Cl)Cl>[C:15]([NH:18][C@:15]1([O:16][CH3:17])[C:14](=[O:19])[N:13]2[C:8]([C:6]([OH:5])=[O:7])=[C:9]([CH:20]([S:30][C:31]3[NH:32][N:33]=[N:34][N:35]=3)[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:10][S:11][C@H:12]12)(=[O:16])[C@@H:14]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[OH:19]
Reactant: CCN(CC)c1ccccc1
Reactant: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCC(=O)OC(C)(C)C)Sc3nnn[nH]3)CS[C@@H]21
Solvent: ClCCl
Product: CO[C@@]1(NC(=O)[C@H](O)c2ccccc2)C(=O)N2C(C(=O)O)=C(C(CCC(=O)O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.06 g. (2 mmol.) of 7β-amino-7α-methoxy-3-[1-(2-t-butoxycarbonylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.30 g. (2 mmol.) of N,N-diethylaniline in 100 ml. of dry methylene chloride is stirred at 0°-5° while 0.56 g. (2 mmol.) of D-O-dichloroacetylmandeloyl chloride in 10 ml. of methylene chloride is added dropwise over 10 minutes. The mixture is stirred in the cold for 30 minutes then warmed to room temperature and stirred for an additional 30 minutes. The solution is washed with 50 ml. of cold dilute hydrochloric acid and 50 ml. of cold 5% aqueous sodium bicarbonate, dried and evaporated to dryness. The residue is dissolved in a mixture of 10 ml. of trifluoroacetic acid and 2 ml. of m-dmethoxybenzene and stirred at ambient temperature for 2 hours. The excess trifluoroacetic acid is evaporated under vacuum and the residue is partitioned between 50 ml. of ether and 50 ml. of water and adjusted to pH 9.3-9.5 with 5% aqueous sodium carbonate. The organic phase is separated and discarded. The aqueous phase is stirred at pH 9.3-9.5 for 30 minutes, extracted with 50 ml. of ethyl acetate which is discarded, layered with fresh ethyl acetate and adjusted to pH 1.5 with dilute hydrochloric acid. The aqueous layer is extracted with three 50 ml. portions of ethyl acetate and the combined extracts are dried and evaporated to a small volume. Petroleum ether is added dropwise to precipitate the title compound which is collected by filtration and dried.
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)/[CH:8]([CH3:10])[CH3:9].[OH-].[Na+]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[C:7](/[CH:8]([CH3:10])[CH3:9])=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C\C=C\C(=O)O)C(C)C)cc1
Yield: 95.6 %

Procedure:
As described in Example 99, (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid methyl ester (4.2 g) was saponified in a refluxing mixture of methanol (15 mL) and 2N NaOH (15 mL). After 2 hours reaction was worked up [n the usual way to afford 3.8 g of (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid. A sample was crystallized from cyclohexanehexane to give the analytical specimen, mp 131.5°-133° C.
Reaction SMILES: [CH2:1]([N:4]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2OS(C(F)(F)F)(=O)=O)[O:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])[CH:2]=[CH2:3].[Li+].[Cl-].C([C:32]1C=C(C)C=C(C(C)(C)C)[C:33]=1[OH:43])(C)(C)C.C[Sn](C)(C)C>CN(C=O)C.C1COCC1.CCCCCC.Cl[Pd]Cl>[C:33]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH2:17][CH:8]([N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][CH2:6][CH3:7])[CH2:9][O:10]2)(=[O:43])[CH3:32]
Reactant: C=CCN(CCC)C1COc2cccc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl[Pd]Cl
Agent: C[Sn](C)(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCN(CCC)C1COc2cccc(C(C)=O)c2C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
3 -(N-Allyl-N-n-propylamino)-5 -trifluoromethane sulfonyloxychroman (0.28 g, 0.74 mmol), LiCl (0.097 g, 2.3 mmol), PdCl2 (dppf) (0.031 g, 0.04 retool) and 2.6-di- t-butyl- 4-methylphenol (0,005 g) were dissolved in DMF (5.0 mL) in a three-necked round-bottom flask (50 mL) with a magnetic stirrer. The flask was evacuated, followed by inlet of CO (three times). Tetramethyltin (0.12 mL, 0.89 mmol) was added and then the mixture was stirred under an atmosphere of CO (1 arm) at 120° C. (oilbath temp) for 4 hours. The solvent was evaporated, the residue was partitioned between aqueous NH3 (2M) and CH2Cl2 (3×15 mL) and the organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Column chromatography on silica with THF-n-hexane (1:9) as eluent afforded 5-acetyl-3-(N-allyl-N-n-propylamino)chroman (0.078 g, 39% yield) as an oil. The base was precipitated from an ether solution by adding a slight excess of HCl (approx. 3M in ether). The crude salt was collected and dried in vacuo at 40° C. to give a white amorphous powder. Mp 125°-127° C. PdCl 2 (dppf)=dichloro[1,1'-bis(diphenylphosphino)-ferrocene] palladium (II).
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)(O)=[O:2]>O1CCCC1>[OH:2][CH2:1][CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(Sc1nc(CCO)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a suspension of 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin (10 g) synthesized in Example 461-4 in tetrahydrofuran (50 mL) was added 1 mol/L borane-tetrahydrofuran complex (25 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the reaction mixture, washed twice with tetrahydrofuran-methanol (1:1) solution, three times with tetrahydrofuran, twice with methanol, once with piperidine, once with tetrahydrofuran and once with methanol in this order, and vacuum dried. To this resin was added 1 mol/L borane-tetrahydrofuran complex (25 ml) again, and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the reaction mixture, washed once each with tetrahydrofuran, tetrahydrofuran-methanol (1:1) solution and tetrahydrofuran-piperidine (1:1) solution, then washed three times each with tetrahydrofuran and methanol, and vacuum dried to give the title pale-yellow resin (8.6 g).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:20][CH:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23](C(OCCCC)=O)[CH2:22]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl>O1CCOCC1>[NH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:21]([NH:20][C:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:2])=[O:3])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:22]1
Reactant: CCCCOC(=O)N1CCCCC(Nc2ncnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCNC4)ncnc32)cc1
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of test-butyl 3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)azepane-1-carboxylate (1.4 g, 2.9 mmol) in 1,4-dioxane (15 mL) was added 6 N HCl (2 mL) and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue was dissolved in EtOAc, washed with 10% NaHCO3. The EtOAc layer was separated, dried over Na2SO4 and concentrated in vacuo to afford the titled intermediate (910 mg, 88%), which was used in the next step without purification. LC-MS: m/z [M+1]=386.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:34])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:32]([NH2:33])=[N:31][O:30][N:29]=2)=[CH:13][CH:12]=1)(C)(C)C.[ClH:37].C(OC(C)C)(C)C>O1CCOCC1>[ClH:37].[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:34])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:32]([NH2:33])=[N:31][O:30][N:29]=2)=[CH:15][CH:16]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)cc1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: NCC(=O)Nc1ccc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 0.045 g of [(4-{2-[2-(4-amino-furazan-3-yl)-benzoimidazol-1-yl]-acetyl}-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (0.09 mmol; 1 eq.) in 0.5 mL of 1,4-dioxane are added dropwise 0.11 mL of a 4M HCl solution in 1,4-dioxane (0.44 mmol; 5 eq.) at room temperature. The reaction mixture is stirred for 2 h at room temperature. Then, 5 mL of diisopropylether are added and the resulting suspension is filtered, washed with diisopropylether (2×2 mL) and dried under reduced pressure to give 0.04 g of crude material. The crude solid is subjected to MCI gel column chromatography eluting with a mixture water/acetonitrile (85/15 to 70/30) containing 0.05% of HCl, to afford 0.014 g of the desired product as an orange powder.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][CH:9]=1>C1COCC1>[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:3])[CH:9]=1
Reactant: CI
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CCBr)cn2C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with NaH (145 mg, 3.62 mmol), MeI (0.45 mL, 7.24 mmol) and THF (1.7 mL). The resulting grey suspension was stirred at rt for 5 min, then a solution of 3-(2-bromo-ethyl)-5-methoxy-1H-indole (230 mg, 0.90 mmol) in THF (4.1 mL) was added dropwise. After stirring for 18 h at rt, the reaction mixture was concentrated and purification by FC (hex/EtOAc 2:1, Rf=0.5) yielded the title compound as an yellow solid. LC-MS conditions 08Z acidic tR=0.93 min, [M+H]+=no ionization.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[Cl-].[NH4+].O>O1CCCC1.C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[NH2:8]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1

Procedure:
A mixture of Example 1D (22.5 g, 68.2 mmol), iron powder (19.0 g, 341 mmol), and ammonium chloride (7.30 g, 136 mmol) in tetrahydrofuran (117 mL), ethanol (117 mL), and water (39 mL) was refluxed at 100° C. for 2 hours. The mixture was cooled just below reflux, and filtered through Celite. The filter cake was washed with warm methanol (3×50 mL). The solution was concentrated under reduced pressure, neutralized to a pH of about 8 with saturated NaHCO3 (150 mL), and extracted with ethyl acetate (3×100 mL). The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered, concentrated, and purified by flash chromatography (silica gel, 0-15% ethyl acetatehexane gradient) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][O:35][C:34]4=[O:39])=[CH:28][CH:27]=3)[S:25][C:18]=12.O>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][O:35][C:34]5=[O:39])=[CH:28][CH:27]=4)[S:25][C:18]=23)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=C1OCCCN1Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCOC5=O)cn4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 117.4 %

Procedure:
To a solution of 4-amino-2-fluorophenol (70.7 mg, 0.556 mmol) in DMSO (5 mL) was added sodium tert-butoxide (53.4 mg, 0.556 mmol) and the reaction mixture was stirred for 30 min. Chloride 199 (100 mg, 0.278 mmol) was added and the reaction mixture was heated at 100° C. overnight. The mixture was then cooled to RT and poured into water (20 mL) and the precipitated product was collected by filtration and purified by Biotage (MeOH/EtOAc 0-50%, SNAP 25 g cartridge) to give title compound 200 (147 mg, 33% yield) as a beige solid. MS: 451 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[C@H:9]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:14][C@H:12]1[CH2:13][NH:8][C@H:9]([C:19]([OH:21])=[O:20])[C@@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]1
Reactant: [H][H]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](O)CN[C@@H]1C(=O)O

Procedure:
A mixture of 2-benzyl 3-methyl(2S,3S,5R)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (1.00 g, 0.00261 mol) in 10 mL of methanol was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, for 3 h. After filtered off the catalyst, the filtration was concentrated to dry in vacuo and used directly in next step. MS (ESI): (M+H)+=204.0.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][C:10]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=[O:11].O>CN(C)C=O>[CH3:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[C:13]=1[NH:12][C:10](=[O:11])[CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)Cn1ccnc1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of 6.0 g of a 60% oil dispersion of sodium hydride in 90 ml of dimethylformamide was stirred and heated at 50° C. during the portionwise addition of 10.32 g of imidazole. After stirring for 20 minutes, 15.0 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added and heating was continued for an additional 30 minutes. Water was added and the reaction mixture was evaporated to dryness. The residue was dissolved in 2N hydrochloric acid, washed with ether, made strongly basic with excess sodium hydroxide and the product was extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and evaporated to give 14 g of N-(2,6-dimethylphenyl)-1H-imidazole-1-acetamide, mp 160°-162° C.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:10])=[C:7]([OH:22])[CH:6]=1.Cl[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>CN(C=O)C>[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[O:10])=[C:7]([O:22][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH:6]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
To a stirred suspension of sodium hydride (320 mg of 60%, 8 mmoles, washed with n-pentane) in DMF (15 ml) was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.289 g, 4 mmoles) and the mixture stirred for 20 minutes followed by addition of chloroacetophenone (619 mg, 4 mmoles). The mixture was stirred 4 hours, poured into ice-cold water (50 ml) whereupon a solid separated out. This was isolated by filtration, dried and recrystallized from methanol to give 810 mg (50%) of the title compound as white solid mp 153°-4°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.64 (bs, 1H); 8.2 (s, 1H); 8 (m, 2H); 7.6 (m, 3H); 6.22 (s, 1H); 5.36 (s, 2H); 4.4 (s, 2H); 3.52 (m, 2H); 2.64 (m, 6H); 1.01 (m, 6H).
Reaction SMILES: [CH:1]([O:8]CC)([O:5][CH2:6][CH3:7])OCC.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=O)#[N:12]>C(OC(=O)C)(=O)C>[C:11]([C:13](=[CH:14][O:16][CH2:17][CH3:18])[C:1]([O:5][CH2:6][CH3:7])=[O:8])#[N:12]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(=O)OCC
Temperature: 155 °C
Yield: 84.2 %

Procedure:
The mixture of triethyl orthoformate (33.3 mL, 0.2 mol) and ethyl cyanoacetate (21.3 mL, 0.2 mol) in acetic anhydride (80 mL) was heated at 150-160° C. for 5 h. After cooling to room temperature, the solvent was removed under reduced pressure to give ethyl 2-cyano-3-ethoxyacrylate as a yellow solid (28.5 g, 84%).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:17])[N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=1.[CH3:18][N:19]([CH3:24])[C:20](=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[CH3:18][N:19]([CH3:24])[C:20](=[O:23])/[CH:21]=[CH:22]/[C:2]1[N:3]=[C:4]([CH3:17])[N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)nc2C)cc1
Reactant: C=CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(/C=C/C(=O)N(C)C)nc2C)cc1
Yield: 90 %

Procedure:
A mixture of 4-iodo-2-methyl-1-(4-methylbenzenesulphonyl)-1H-imidazole (3.62 g), N,N-dimethylacrylamide (1.05 g), palladium (II) acetate (125 mg) and triethylamine (2 ml) in acetonitrile (3 ml) was heated at 120° under nitrogen for 2.5 h. The cooled mixture waspartitioned between chloroform (3×50 ml) and 2N sodium carbonate (75 ml), and the combined organic layers were dried and evaporated in vacuo to leave a solid (ca. 3.0 g). This solid was purified by FCC eluting with chloroform to give the crystalline title compound (1.55 g), m.p. 162°-163°.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:36]#[N:37])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18][CH:17]([C:25]([OH:27])=O)[CH:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])=[C:11]([F:38])[CH:10]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:25]([CH:17]1[CH:16]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[F:38])([C:36]#[N:37])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:22])[CH3:23])[NH:18]1)=[O:27]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(F)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(F)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 58.2 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 62c (0.47 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 58%).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl>C(OCC)C>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:23]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C(CC(=O)C(F)F)c1ccc(Cl)cc1
Yield: 99.5 %

Procedure:
Ethyl difluoroacetate (24.82 g, 200 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in diethyl ether (200 mL). To the stirred solution was added 25% sodium methoxide in methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute period. Next, 4′-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether (50 mL), and added to the reaction dropwise over 5 minutes. After stirring overnight (18 hours), 1N HCl (250 mL) and ether (250 mL) were added. The organic layer was collected, washed with brine (250 mL), dried over MgSO4, Altered, and concentrated in vacuo to give 46.3 g of a yellow solid. The solid was recrystallized from methylene chloride and iso-octane to give 31.96 g (69%) of the dione: mp 65-66.5° C.
Reaction SMILES: C([O:9][CH2:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:37]=[C:36]([C:38]([O:40]CC)=[O:39])[NH:35][N:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)(=O)C1C=CC=CC=1.O.O.[OH-].[Li+]>O1CCOCC1>[OH:9][CH2:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:31])([CH3:32])[C:20]([C:33]2[CH:37]=[C:36]([C:38]([OH:40])=[O:39])[NH:35][N:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)OCC)[nH]n6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)O)[nH]n6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 49.5 %

Procedure:
To a solution of ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(benzoyloxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1H-pyrazole-5-carboxylate (0.07 g, 0.105 mmol) in 1,4-Dioxane (4 mL) was added Water (1 mL) and lithium hydroxide monohydrate (0.085 g, 2.026 mmol). The mixture was heated to 75° C. for 18.25 h, was cooled to rt, and was quenched with 1N HCl (7 mL). The mixture was extracted with dichloromethane (4×7 mL) and the combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. Purification was accomplished by crystallization from dioxane and water to give 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1H-pyrazole-5-carboxylic acid (0.03 g, 0.052 mmol, 49.2% yield) as a white solid. LCMS: m/e 533.60 (M−H)−, 1.24 min (method 1). 1H NMR (500 MHz, Pyr) δ ppm 0.86 (t, J=7.48 Hz, 3H), 0.95 (s, 3H), 1.06 (s, 6H), 1.06-1.99 (m, 22H), 1.80 (s, 3H), 2.14-2.24 (m, 2H), 2.40-2.51 (m, 2H), 2.65 (dt, J=10.99, 5.49 Hz, 1H), 3.69 (d, J=10.68 Hz, 1H), 4.12 (d, J=10.68 Hz, 1H), 4.79 (s, 1H), 4.93 (d, J=2.14 Hz, 1H), 6.13 (br. s., 1H), 7.33 (s, 1H).