Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH3:18][O:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:21]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]([O:19][CH3:18])=[O:21])=[CH:30][CH:29]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2c2ccc(OC)c(OC)c2)cc1
Reaction time: 1 h

Procedure:
2.6 g of (+/−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene are dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. At RT, a solution of 2.4 g of 4-methoxycarbonylbenzoyl chloride in 30 ml of methylene chloride is added dropwise over a period of 3 h, and the mixture is stirred for 1 h and then extracted with 50 ml each of water, 2 N hydrochloric acid, sat. sodium bicarbonate solution and once more with water. The organic phase is dried with sodium sulfate, concentrated and crystallized from ethyl acetate. This gives 2.0 g (45.5% of Th.) of the title compound of m.p. 139-143° C.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]>C(O)CCC>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCCC1
Temperature: 100 °C

Procedure:
Add cyclopentanamine (32 mL) to a solution of 2,4-dibromo-1-nitro-benzene (20 g) in 1-butanol (160 mL). Heat the mixture at 100° C. overnight. Remove the solvent under vacuum, add water and extract with EA. Wash the organic layer sequentially with an aqueous saturated solution of sodium bicarbonate and then water. Dry over magnesium sulfate and remove the solvent under vacuum to afford 22 g of the title compound. MS (ES+): m/z=286 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(S[C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>COCCOC.FC(F)(F)C([O-])=O.[Ag+]>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18]
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)SC(C)(C)C
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: COCCOC
Product: CC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)Nc1cc(O)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
Silver trifluoroacetate (1.5 g) was added, over a period of 1 hour, to a stirred solution of 3-amino-4-chlorophenol (0.67 g) and 3-oxo-2-(4-pyrazol-1-ylbenzyl)thiobutyric acid S-tert-butyl ester (1.7 g) in 1,2-dimethoxyethane (10 mL) at room temperature, and the resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 3:1 by volume) to afford title compound as a brown solid (1.1 g).
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>N1C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([NH:5][NH:6][C:7](=[NH:9])[NH2:8])=[O:17])[CH3:16]
Reactant: N=C(N)NN
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C(O)O
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)NNC(=N)N
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.7 %

Procedure:
To a solution of 1-aminoguanidine carbonic acid salt (12 g, 88 mmol) in pyridine (50 ml) was added ethyl 2-chloro-2-oxoacetate (10 g, 73.24 mmol). The resulting solution was stirred for 12 h at room temperature. The resulting solution was diluted with PE (200 ml). The solids were collected by filtration and then dissolved in water (50 ml), the pH was adjusted to 8 with NaOH (aq., 10N). The product precipitated and was filtered to afford ethyl 2-(2-carbamimidoylhydraziny)-2-oxoacetic acid as a white solid (2 g, 19%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:10][C:9](=[O:11])[CH:8]2[CH2:12][CH:5]1[CH2:6][CH2:7]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>CCCCCC.O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:10]2[C:4](=[O:3])[CH:5]3[CH2:12][CH:8]([CH2:7][CH2:6]3)[C:9]2=[O:11])=[O:22])=[CH:16][C:15]=1[C:23]([F:24])([F:25])[F:26]
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.064 g, 1.59 mmol) was washed with dry hexane under a nitrogen atmosphere to remove mineral oil. It was then suspended in dry tetrahydrofuran (3 mL). To the suspension was added a solution of 2,4-dioxobicyclo[3.2.1]octane (0.20 g, 1.45 mmol) in dry tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. It was then treated with 4-fluoro-3-(trifluoromethyl)phenyl isocynate (0.31 mL, 2.17 mmol) via syringe. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture was then concentrated on a rotary evaporator and the residue was partitioned between dichloromethane (150 mL) and 1N aqueous HCl (100 mL). The aqueous layer was extracted twice with additional portions of dichloromethane ((25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatrography on silica gel (2% methanol/dichloromethane) to yield the title compound as a light yellow solid (0.36 g, 73% yield), mp=97–100° C.; MS (−) ESI m/z=342 (M−H)−.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[OH:14][CH2:15][C:16](O)=O.C(=O)(O)[O-].[Na+]>>[CH3:1][N:2]1[C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[C:12]=2[N:13]=[C:16]1[CH2:15][OH:14]
Reactant: O=C(O)CO
Reactant: CNc1ccc2cccnc2c1N
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(CO)nc2c3ncccc3ccc21
Temperature: 115 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A mixture of N7-methylquinoline-7,8-diamine (1.0 g, 5.8 mmol) and 2-hydroxy acetic acid (2.2 g, 29 mmol) was stirred at 115° C. for 2 h. Then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc. The organic layer was concentrated to give a residue which was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 30:1) to give (3-methyl-3H-imidazo-[4,5-h]quinolin-2-yl)methanol as a yellow solid (1.0 g, yield 83%). ESI MS: m/z 214 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:14][O:15][CH3:16])[C:8]=1[O:9][C:10](=[O:13])[NH:11][CH3:12])[NH2:5].C(N(CC)C1C=CC=CC=1)C.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:29](=[O:30])[O:31][CH:32]([CH3:34])[CH3:33])[CH:6]=[C:7]([CH2:14][O:15][CH3:16])[C:8]=1[O:9][C:10](=[O:13])[NH:11][CH3:12]
Reactant: CNC(=O)Oc1c(Cl)cc(N)cc1COC
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CNC(=O)Oc1c(Cl)cc(NC(=O)OC(C)C)cc1COC
Temperature: 0 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
3-Chloro-4-methylcarbamoyloxy-5-methoxymethylaniline (1.0 g) and N,N-diethylaniline (0.90 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.75 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3-chloro- 4-methylcarbamoyloxy-5-methoxymethylphenyl)carbamate (1.22 g) in a yield of 90.5%. M.P., 113°-114° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:15]([OH:18])[CH2:16]O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)(C)C([O-])([O-])[O-].Cl[Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>ClCCl.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:15]2[CH2:16][O:18]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H](O)c1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)C([O-])([O-])[O-]
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: c1ccc(COc2cccc([C@H]3CO3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 2 (16.22 g, 66 mmol) in dichloromethane (150 mL), trimethylorthoacetate (10.0 mL, 79 mmol) and chlorotrimethylsilane (10.0 mL, 79 mmol) were added. The reaction was stirred at room temperature under argon for 2 hours, then the solvent removed in vacuo. Potassium carbonate (11.59 g, 84 mmol) and methanol (260 mL) were added, and the reaction was stirred at room temperature under argon for 2 hours then poured into saturated ammonium chloride solution (550 mL) and extracted with dichloromethane (1650 mL). The organics were dried (MgSO4) and the solvent removed in vacuo. Column chromatography (heptane:ethyl acetate 4:1) gave the product as a yellow oil, 56 mmol, 85%.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].CO.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(OCC)(=O)C>[C@@H:1]1([N:10]2[C:19]3[C:13](=[C:14]([N+:16]([O-:27])=[CH:17][N:18]=3)[NH2:15])[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Temperature: 25 °C

Procedure:
In a 1-L round-bottomed flask protected with a calcium sulfate drying tube was placed a 5.0 g (18.7 mmol) of adenosine and 500 mL of methanol. The mixture was stirred at room temperature and 4.85 g (22.5 mmol) of m-chloroperoxybenzoic acid (MCPBA) was added in 7-10 portions over 2 hours. If thin-layer chromatography after 15-20 hours of stirring indicates the presence of starting material an additional 0.5 g (2.9 mmol) of MCPBA should be added and the reaction stirred an additional 4 hours. If the TLC continues to show starting material another portion of MCPBA must be added and the stirring continued overnight. After the TLC showed little or no starting material left the reaction mixture was poured slowly in 2 L of ethyl acetate with good stirring. After having been stirred 2 hours, the product was collected, washed with ethyl acetate, and dried in vacuo over phosphorus pentoxide: yield 4.6 g. Melting point and elemental analysis data are set forth in Table I.
Reaction SMILES: C(NC(C1SC(N2CCN(CC3C=C(C=CC=3)C(OCC)=O)C2=O)=NC=1C)=O)C1C=CC=CC=1.[F:35][C:36]1[CH:62]=[CH:61][C:39]([CH2:40][N:41]2[CH2:45][CH2:44][N:43]([C:46]3[S:47][C:48]([C:55]([O:57]CC)=[O:56])=[C:49]([C:51]([F:54])([F:53])[F:52])[N:50]=3)[C:42]2=[O:60])=[CH:38][CH:37]=1>>[F:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:40][N:41]2[CH2:45][CH2:44][N:43]([C:46]3[S:47][C:48]([C:55]([OH:57])=[O:56])=[C:49]([C:51]([F:54])([F:52])[F:53])[N:50]=3)[C:42]2=[O:60])=[CH:61][CH:62]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Agent: CCOC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Product: O=C(O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Yield: 69 %

Procedure:
Following the procedure as described in Example 25, making variations as required to replace ethyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate with ethyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 69% yield: 1H NMR (300 MHz, DMSO-d6) δ 13.74 (br s, 1H), 7.36-7.30 (m, 2H), 7.19-7.13 (m, 2H), 4.41 (s, 2H), 4.02-3.97 (m, 2H), 3.47-3.41 (m, 2H); MS (ES+) m/z 390.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:23])[C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1.CCN(CC)CC>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:23][CH2:12][C:13]2[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: COc1ccc(CN)cc1OC
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3[nH]cnc23)cc1OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
2,6-Dichloro-9H-purine (1.7 g, 9 mmol), veratrylamine (1.5 g, 9 mmol) and Et3N (2.51 mL, 18 mmol) were dissolved in BunOH (10 ML). The solution was stirred for 2 h at 90° C. After cooling, PriOH (90 mL) was added slowly with stirring. After 1 h the precipitate was filtered, washed successively with small quantities of PriOH and Pri2O, and dried in vacuo to afford the title compound as a white powder (2.69 g, 93.4%). TLC (9:1 CH2Cl3/MeOH/AcOH): RF=0.33.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].N1([C:34]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[C:50]4[C:45](=[N:46][CH:47]=[CH:48][CH:49]=4)[NH:44][C:43]3=[O:51])[CH2:38][CH2:37]2)=[O:35])C=CN=C1.[Na+].[I-]>CN(C)C=O>[O:51]=[C:43]1[NH:44][C:45]2=[N:46][CH:47]=[CH:48][CH:49]=[C:50]2[N:42]1[CH:39]1[CH2:38][CH2:37][N:36]([C:34]([O:20][C@H:17]2[C:12]3[C:11](=[N:16][CH:15]=[CH:14][N:13]=3)[C@@H:10]([NH:21][C:22]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:28])[C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:19][CH2:18]2)=[O:35])[CH2:41][CH2:40]1
Reactant: O=C(N1CCC(n2c(=O)[nH]c3ncccc32)CC1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
In a 100 mL round-bottomed flask was dissolved tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-5-ylcarbamate (40 mg, 0.102 mmol) (azeotroped with dry benzene) and 1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (41.5 mg, 0.133 mmol) in dimethylformamide (1 mL) to give a colorless suspension under nitrogen. After cooling to −15° C. (ice/methanol bath), NaI-RN/IDS (0.378 mL, 0.378 mmol) was added dropwise. The cooling bath was removed and the resulting tan solution was stirred under nitrogen at rt for 2 h. LCMS showed complete conversion. The reaction was quenched with sodium bicarbonate solution, and diluted with ethyl acetate. The layers were separated. The organic layer was washed with brine, dried with sodium sulfate, and concentrated to give a slightly tan oil. Purification by flash column chromatography up to 10% methanol (with 2M ammonia)/methylene chloride afforded the desired product (39.5 mg, 61%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 11.17 (s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.12 (d, J=5.0 Hz, 1H), 7.43 (d, J=6.0 Hz, 1H), 7.33-7.26 (m, 1H), 7.05 (dt, J=7.8, 5.9 Hz, 3H), 6.34 (d, J=8.8 Hz, 1H), 6.15 (d, J=11.0 Hz, 1H), 5.36-5.25 (m, 1H), 4.63 (t, J=12.4 Hz, 2H), 4.46 (s, 1H), 3.07 (t, J=9.7 Hz, 3H), 2.62 (dd, J=23.9, 11.8 Hz, 1H), 2.49-2.26 (m, 3H), 2.21 (d, J=12.0 Hz, 1H), 2.03-1.78 (m, 3H), 1.23 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[CH3:12][O:13][C:14](=[O:35])[CH2:15][O:16][CH:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:18][C:19]1[C:20]([C:25](OC)=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C1(C)C(C)=CC=CC=1>[OH:26][C:25]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][CH:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:16][C:15]=1[C:14]([O:13][CH3:12])=[O:35]
Reactant: COC(=O)COC(Cc1cccnc1C(=O)OC)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)c2ncccc2CC(c2ccccc2)O1
Temperature: 82 °C

Procedure:
A solution of potassium tert-butoxide in THF (1M, 10 mL, 10 mmol), was added dropwise to a solution of methyl 3-(2-(2-methoxy-2-oxoethoxy)-2-phenylethyl)picolinate (3.0 g, 9.1 mmol) in xylene (20 mL) at 28° C. The resulting mixture was heated at 82° C. for 2 h, then cooled and concentrated. The residue was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in petroleum ether to give the title compound. MS: m/z=298.2 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[S:12][C:13]([C:16]2[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=2)=[CH:14][CH:15]=1)=[O:10].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[S:12][C:13]([C:16]2[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=2)=[CH:14][CH:15]=1)=[O:10]
Reactant: COc1ccccc1C(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(-c2ccc(C(=O)c3ccccc3O)s2)noc1C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
A solution of (2-methoxyphenyl){5-[4-methyl-5-(trifluoromethyl)isoxazol-3-yl]thien-2-yl}methanone (Example 95, 37 mg, 0.1 mmol) in dichloromethane (2 mL) at −78° C. was treated with boron tribromide (100 μL of a 1 M dichloromethane solution, 0.1 mol) and allowed to warm to 0° C. and stir at that temperature for 16 h. After that time the reaction was quenched with water (3 mL) and partitioned between water (10 mL) and EtOAc (10 mL). The organic extract was washed with a brine solution (10 mL) then dried over Na2SO4, filtered, and concentrated in vacuo to afford crude product. The crude product was chromatographed on silica gel with EtOAc/hexanes (20%) as eluant to afford product as a yellow colored solid (29 mg, 82%). 1H NMR (CDCl3) 2.92 (d, J=1.8, 3 H), 7.46-7.76 (m, 2 H), 8.03-8.08 (m, 1 H), 8.12 (d, J=4.0, 1 H), 8.28 (d, J=4.0, 1 H), 8.46 (dd, J=8.4, 1.8, 1 H), 11.50 (s, 1 H). 19F NMR −63.1.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C(C1C=C2C(=CC=1)NC=C2)#CCCCCCC>>[F:25][C:2]([F:1])([F:24])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCCC#Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: CCCCCCC#Cc1ccc2[nH]ccc2c1
Product: CCCCCCCCc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2

Procedure:
When the product of Step C was substituted for 5-(oct-1-ynyl)-1H-indole in Example 3, Step B, the similar process afforded the title compound in 90%, as pale oil. 1H-NMR (CDCl3) 0.87 (tr, 3H, J=6.96 Hz), 1.25-1.28 (m, 10H); 1.4-1.46 (m, 2H); 2.50-2.56 (m, 2H); 2.90-2.95 (m, 4H); 3.64-3.66 (m, 2H); 3.73-3.75 (m, 2H); 6.81-7.07 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:21])[CH:3]=1.[CH2:22]([O:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][N:9]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:8]3=[O:18])=[C:4]([Cl:21])[CH:3]=2)=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:41])[CH3:23]
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCCCC1
Product: CCOC(=O)c1ccccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Yield: 48.3 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (500 mg, 1.35 mmol) and ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (560 mg, 2.0 mmol) affords 287 mg (48%) of the title compound: Mass spectrum (apci) m/z=440.2 (M+H).
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:31])[CH:5]=[C:6]3[C@:28]([CH3:29])([C@@H:2]12)[C@@H:27]1[C@H:9]([C@H:10]2[C@:24]([CH3:30])([CH2:25][CH2:26]1)[C@@H:13]([C@H:14]([CH3:23])[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.[Li].N.[Cl-].[NH4+]>CCOCC>[OH:1][C@@H:2]1[C@@:28]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:23])[CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:5][C@@H:4]([OH:31])[CH2:3]1
Reactant: C[C@H](COC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Product: C[C@H](COC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
A solution of 22.4 g (52 mmol, 1 equivalent) of (20S)-1α,2α-epoxy-20-methyl-21-tetrahydropyranyloxy-pregna-4,6-dien-3-one in 1.25 liters of absolute ether is added dropwise within 45 minutes while stirring in an argon atmoshere at -33° C. to a solution of 1.453 g (0.21 g-atom), 4 equivalents) of lithium in 2.1 liters of liquid ammonia. In so doing, when the resulting mixture is only just light blue in colour, the dropwise addition is interrupted briefly and 0.363 g (52.3 mg-atom), 1 equivalent) of lithium is added. After completion of the dropwise addition, the mixture is stirred for 15 minutes and the blue colour is removed from the mixture by the addition of 2 ml of isoprene. With stirring there are added in portions 13.98 g (0.26 mol, 5 equivalents) of ammonium chloride. The mixture is treated in portions under argon at -33° C. with 16.048 g (0.30 mol, 5.7 equivalents) of ammonium chloride, and then with 2.082 g (0.3 g-atom, 5.7 equivalents) of lithium and, as soon as these additions have reacted, the same procedure, i.e. the addition of 16.048 g of ammonium chloride followed by 2.082 g of lithium is repeated a further four times. The mixture is treated with 75 g of ammonium chloride and ammonia is evaporated until the temperature of the mixture has reached 0° C. The residue is treated with 0.2 liter of saturated sodium chloride solution and 1 liter of water, extracted with 3 liters of ether and twice with 2.5 liters of ethyl acetate. The extracts are washed twice with 0.5 liter of saturated sodium chloride solution, combined, dried over sodium sulphate and concentrated at 40° C./11 Torr. The residue is dissolved in 75 ml of benzene and added to a column of 340 g of silica gel prepared in hexane/ether (9:1). Elution (a) with 3 liters of hexane/ether (4:1) and 14 liters of hexane/ether (1:1) yield 2.39 g of apolar fractions and (b) with 19 liters of ether yields 19.7 g (86.78%) of crude (20S)-1α,3β-dihydroxy-20-methyl-21-tetrahydropyranyloxy-pregn-5-ene. Recrystallisation from methanol gives white crystals of melting point 138°-141° C.; [α]D25 =-48.8° (c=0.5 in chloroform).