Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]1CCC[Br:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(C)[CH:28]=CC=C[CH:24]=1>C(Cl)(Cl)Cl>[Br-:22].[CH2:1]([N+:8]12[CH2:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:11][CH2:12][CH2:13]1)[CH2:28][CH2:23][CH2:24]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)C1CCCBr
Reactant: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C12CCC[N+](Cc3ccccc3)(CCC1)C2
Product: [Br-]
Temperature: 25 °C

Procedure:
A mixture of ethyl 1-benzyl-(3-bromopropyl)piperidine-3-carboxylate (1.08 g), toluene (10 mL), and CHCl3 (2 mL) was heated under reflux for 2 hours. It was cooled to room temperature and then concentrated under reduced pressure. To the residue was added EtOAc, and the solid was collected by filtration to obtain 1-benzyl-5-(ethoxycarbonyl)-1-azoniabicyclo[3.3.1]nonane bromide (942 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: Cc1ncc(C(CN)c2ccncc2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)c2ccncc2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+): m/z=371.1, tR (minutes, Method F)=1.73
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29]Cl)[C:24]=1[CH3:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO.C(OCC)(=O)C>[CH2:14]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:24]=1[CH3:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCOc1ccnc(CCl)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 32.2 %

Procedure:
To a liquid prepared by dissolving with stirring 6.7 g (0.045 mol, 0.95 eq.) of 2-mercaptobenzimidazole and 52.5 g (0.273 mol, 5.8 eq.) of a 28% sodium methoxide solution in 350 mL of methanol, a liquid prepared by dissolving the whole amount of 4-octyloxy-2-chloromethyl-3-methylpyridine in 180 mL of methanol was added at 27° C. Subsequently, the mixture was heated to reflux for one hour and cooled, and then methanol was solid dried under reduced pressure. A brown oily residue resulting therefrom was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 14.9 g of an orange-colored oily matter. The orange-colored oily matter was recrystallized from ethyl acetate (5 vol.), to obtain 5.8 g of colorless crystals (HPLC: 98.8 Area %, yield 32.2%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[NH:8]2)=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.Br[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:8]1[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Reactant: CCCCBr
Product: CCCCn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-(2-Chloro-6-morpholino-9H-purin-8-yl)propan-2-ol 100 mg was treated with bromobutane via General Procedure C to give crude intermediate 2-(9-butyl-2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol which was treated with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and was purified via reverse phase HPLC to give 55 mg of 103 as a white solid. MS (Q1) 413.3 (M)+.
Reaction SMILES: [CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].C[Si](Cl)(C)C.[C:23](Cl)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O.N>N1C=CC=CC=1.O>[CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH:15][C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:13][C:11]1=[O:12]
Reactant: C=C1[C@H](n2ccc(N)nc2=O)O[C@H](CO)[C@H]1O
Reactant: CCCCCCCCCC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: C=C1[C@H](n2ccc(NC(=O)CCCCCCCCC)nc2=O)O[C@H](CO)[C@H]1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
2'-Deoxy-2'-methylidenecytidine, 239 mg, was dissolved in 5 ml of pyridine, and to the solution was added dropwise 0.63 ml of trimethylsilyl chloride under ice cooling. The mixture was stirred at room temperature for 5 minutes and then 0.83 ml of decanoyl chloride was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 2 hours. After the reaction, 2 ml of water was added to the reaction solution, stirring was conducted at room temperature for 5 minutes, and then 2 ml of concentrated ammonia water was added to the solution, followed by stirring for 15 minutes. After the reaction, the solution was partitioned with chloroform, and the chloroform layer was distilled off under reduced pressure. The residue was treated with a silica gel chromatography (elution solvent-chloroform: methanol=25:1) to give 179 mg of the objective compound as an oleaginous product. Yield: 45.6%
Reaction SMILES: C([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)(O)=O.C([N:29]([CH2:32]C)CC)C.C1([O:40]P(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[CH2:23]([C:11]1[C:10]([CH3:25])=[C:9]2[C:5]([C:6](=[O:26])[O:7][CH2:8]2)=[C:4]([N:29]=[C:32]=[O:40])[C:12]=1[CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH3:24]
Reactant: CCN(CC)CC
Reactant: CCc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(C)c2c(c(N=C=O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, 0° C. solution of 6.0 g of methyl (E)-6-(4-carboxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 150 ml of dimethylformamide is added 4.62 ml of triethylamine followed by dropwise addition of 4.5 ml of diphenylchlorophosphate. The mixture is allowed to stir at room temperature for 1 hour and then recooled to 0° C., and treated with 10.8 g of sodium azide. This mixture is stirred for 24 hours at 0° C. and then partitioned between aqueous sodium hydrogen sulfate and ethyl acetate. The organic phase is washed four times with water, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl (E)-6-(1,3-dihydro-6-ethyl-4-isocyanato-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: C([O:4][C@H:5]1[C:31](=O)[CH2:30][C@@:29]2([CH3:33])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@H:27]([O:34]C(=O)C)[CH2:26][C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=O)C.C[O-:40].[Na+]>CO.C1COCC1>[CH3:16][C@@H:15]1[C@:17]2([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]2)[O:18][C@H:13]2[CH2:12][C@@H:11]3[C@@:25]([CH3:38])([C@@H:14]12)[C:26](=[O:40])[C@@H:27]([OH:34])[C@H:28]1[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C@:29]1([CH3:33])[CH2:30][CH2:31][C@H:5]([OH:4])[CH2:6]2
Reactant: C[O-]
Reactant: CC(=O)O[C@@H]1C[C@@H]2CC[C@@H]3[C@H]([C@H](OC(C)=O)C[C@]4(C)[C@@H]5[C@H](C[C@@H]34)O[C@]3(CC[C@@H](C)CO3)[C@H]5C)[C@@]2(C)CC1=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@H](O)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,11α,25R)-3,11-di(acetoxy)spirostan-2-one was saponified with sodium methoxide in methanol and THF to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:3].[Br:16][CH2:17][CH2:18][Cl:19].CO>C(OC)(C)(C)C>[Br-:16].[Cl:19][CH2:18][CH2:17][N+:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: ClCCBr
Reactant: CCCCCCCCCCCCN(C)C
Solvent: COC(C)(C)C
Solvent: CO
Product: CCCCCCCCCCCC[N+](C)(C)CCCl
Product: [Br-]
Temperature: 65 °C

Procedure:
Into a 1000 mL, round-bottomed flask equipped with air condensers and a magnetic stirring plate was charged N,N-dimethyldodecylamine (186.46 grams, 0.875 moles), 1-bromo-2-chloroethane (125.60 grams, 0.875 moles) and methanol (150 mL). The reaction was maintained at 65° C. for 48 hours. Solvent was removed by rotary evaporation under reduced pressure to yield brown oil. The oil was placed in a beaker and stirred with t-butylmethylether (2 L) causing a brownish white precipitate to form. The solids were collected by vacuum filtration. Solids were dried in a vacuum oven at 30° C. overnight Yield 197.0 grams (0.55 moles, 63%).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:12][N:13]([C:15]1[CH:31]=[CH:30][C:18]([CH:19](O)[C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)[CH3:14].COC.O1CCCC1>CS(O)(=O)=O.CN(C)C(=N)N(C)C.CCCCCC>[CH3:28][N:26]([CH3:27])[C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:18]2[CH:30]=[CH:31][C:15]([N:13]([CH3:14])[CH3:12])=[CH:16][CH:17]=2)[O:1][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Reactant: O=C(CO)Nc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: COC
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(OCC(=O)Nc2ccccc2)c2ccc(N(C)C)cc2)cc1

Procedure:
A solution of alpha-hydroxyacetanilide (3.62 g, 0.024 mole), 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether (6.81 g, 0.024 mole) 50 ml of tetrahydrofuran, 153 ml of n-hexane, and one drop of methanesulfonic acid was refluxed for 11 hours, during which time an additional 300 ml of solvent was added. The blue-green solution was decolorized with 4 drops of tetramethylguanidine and the reaction mixture was filtered hot and the filtrate chilled. Yellow-green crystals formed, which were recrystallized from 30 ml petroleum ether/15 ml acetone to give a white solid, mp 118°-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:14][CH2:13]2.[Li+].[OH-]>CCO.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([OH:22])=[O:21])[CH2:14][CH2:13]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4ccsc4)cc3OC)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(-c2ccsc2)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 50 °C
Yield: 76 %

Procedure:
The ester prepared in Example 98 (83 mg 0.18 mmol) was dissolved in a mixture of EtOH (3 mL), THF (3 mL), and water (1 mL), LiOH (42.6 mg, 1.78 mmol) was added and the reaction mixture was heated at 50° C. for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by preparative HPLC (CH3CN, 0.01% TFA/Water, 0.01% TFA (v/v)=2:3 to 100% CH3CN, 0.01% TFA) to give 60 mg (73%) of the title compound as a white solid. 1H NMR (400 MHz, acetone-d6): δ 7.62-7.61 (m, 1H), 7.52-7.47 (m, 2H), 7.29 (d, 1H), 7.23-7.20 (m, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 6.33-6.32 (m, 1H), 6.77-6.74 (m, 1H), 4.23-4.18 (m, 4H), 3.89 (s, 3H), 3.48-3.45 (m, 1H), 3.22-2.71 (b, 1H), 2.93-2.71 (m, 3H), 2.42-2.32 (m, 2H), 2.28-2.22 (q, 2H), 1.76-1.70 (m, 1H). LC-MS: RT=5.28 min, (M−H) 437.3.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[C:25]1([S:31]([O-:34])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+].C(OCC)(=O)C>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:25]1([S:31]([O:34][C@@H:6]2[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S([O-])(=S)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OS(=O)(=S)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 70 °C
Yield: 89.2 %

Procedure:
2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl bromide (207 mg, 0.5 mmol) was dissolved in anhydrous acetonitrile (5 mL). To this sodium phenylthiosulfonate (201 mg, 1 mmol) and tetrabutylammonium bromide (16 mg, 0.05 mmol) were added. The resulting mixture was stirred under argon at 70° C. After a 4.5 h period, thin layer chromatography (t.l.c.) (petrol:ethyl acetate, 1:1) indicated the formation of a product (Rf 0.5) with complete consumption of the starting material (Rf 0.3). The solution was concentrated in vacuo. The crude solid was partitioned between dichloromethane (DCM, 20 mL) and water (20 mL), and the aqueous layer re-extracted with DCM (2×20 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petrol:ethyl acetate, 1:1) to afford the title product (225 mg, 88%) as a white crystalline solid; mp 129-130° C.; [α]D25+51.2 (c, 1.0 in CHCl3); νmax (KBr) 1754 (s, C═O), 1376 (s, C═C) cm−1; δH; (400 MHz, C6D6) 1.68, 1.72, 1.73, 1.75 (4×3H, 4×s, 4×OAc), 3.09 (1H, ddd, J4,5 10.2 Hz, J5,6 2.4 Hz, J5,6′ 4.2 Hz, H-5), 3.83 (1H, dd, J5,6 2.4 Hz, J6,6′ 12.7 Hz, H-6),4.08 (1H, dd, J5,6′ 4.2 Hz, J6,6′ 12.6 Hz, H-6′), 5.17-5.23 (2H, m, H-2, H -4), 5.40 (1H, d, J1,2 10.2 Hz, H-1), 5.44 (1H, at, J9.4 Hz, H-3), 6.98-7.03 (3H, m, Ar—H), 7.90-7.92 (2H, m, Ar—H). The structure of the product was further confirmed by single crystal X-ray diffraction.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:8]=1)(=[O:24])=[O:23]
Reactant: Nc1nc(-c2sccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1ccc(Cl)c(Cl)c1Cl

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (5.0 mg) with purity >90%: MS (pos) m/z 459.2, 461.2, 463.2.
Reaction SMILES: [F:1][C:2]1([F:29])[C@@H:19]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:18][CH2:17][C@@:16]2([CH3:27])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:28].[CH2:30](OC=C)[CH3:31]>>[F:29][C:2]1([F:1])[C@@H:19]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:18][CH2:17][C@@:16]2([CH3:27])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:28][CH:30]=[CH2:31]
Reactant: C=COCC
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](OC5CCCCO5)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Product: C=CO[C@H]1CC[C@H]2[C@@H]3CC=C4C(F)(F)[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4 g of 4,4-difluoro-3β-(2-tetrahydropyranyloxy)androst-5-en-17β-ol in 50 ml of vinyl ethyl ether, there is added 0.25 g of mercuric acetate. The mixture is stirred at room temperature for 24 hours, quenched with triethylamine, and then poured into dilute aqueous potassium carbonate solution. The aqueous mixture is extracted three times with 100-ml portions of diethyl ether and the combined organic extracts are washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent is then removed under reduced pressure and the residue is purified by flash chromatography to give 4,4-difluoro-3β-(2-tetrahydropyranyloxy)-17β-ethenyloxyandrost-5-ene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][N:14]([C@@H:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH3:17])[C:13](=[O:26])[CH2:12]2)[CH3:10])[C:5]2[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:28]([CH3:30])=[N:29][C:4]=2[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[O:47][CH3:48].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOC1>O>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([C:2]2[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][N:14]([C@@H:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[CH3:17])[C:13](=[O:26])[CH2:12]3)[CH3:10])[C:5]3[N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:28]([CH3:30])=[N:29][C:4]=3[CH:3]=2)[CH:44]=[CH:45][C:46]=1[O:47][CH3:48]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4nc(C)n(COCC[Si](C)(C)C)c34)CC2=O)cc1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4nc(C)n(COCC[Si](C)(C)C)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
To a (R)-4-((R)-1-(6-chloro-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.65B (1 eq), 3,4-dimethoxy phenyl boronic acid (1.3 eq), Cs2CO3 (3.0 eq) and PEPPSI″-IPr catalyst (0.1 eq) was added 1-4 Dioxane and water (2:1) and the reaction was heated to 100° C. for 1 hr. The reaction mixture was concentrated and purified by normal phase chromatography (Hexanes:Acetone 1:1) to afford (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one.[M+H]+ calcd C36H48N4O6Si: 661.33; found 661.3
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:40][C:39]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:10][C:36](=[O:37])[C:35]=1[S:34][CH2:33][CH2:32][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(O)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-hydroxyacetophenone (0.688 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (1.84 g, 11.1 mmol), chlorotrimethylsilane (1.41 mL, 11.1 mmol), THF (111 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). 1H NMR (400 MHz, DMSO-d6) δ 2.78 (t, 2 H), 2.95 (t, 2 H), 6.62 (s, 1 H), 6.89 (dd, 2 H), 7.21 (m, 5 H), 7.65 (d, 2 H), 10.22 (s, 1 H), 11.05 (bs, 1 H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:54])/[C:16](/[N:20]2[CH:23]([S:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:22]([NH:35][C:36](=[O:52])[CH:37]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:21]2=[O:53])=[C:17](\[OH:19])/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:57])=[N-]>C(Cl)Cl.CO.CCOCC>[C:1]1([CH:7]([O:14][C:15](=[O:54])/[C:16](/[N:20]2[CH:23]([S:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[CH:22]([NH:35][C:36](=[O:52])[CH:37]([NH:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:21]2=[O:53])=[C:17](\[O:19][CH3:57])/[CH3:18])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CO/C(C)=C(\C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 0.54 g (0.7 mmol) of 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester in 20 ml of methylene chloride/methanol, 1:1, is stirred for 15 minutes with an excess of a solution of diazomethane in ether at 0° C. and is then concentrated by evaporation in vacuo. Preparative layer chromatography of the residue on silica gel, using toluene/ethyl acetate, 1:1, as the running agent, and elution of the zone which is visible in UV light gives 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenylmethyl ester, which is recrystallised from methylene chloride/diethyl ether/hexane.