Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][C:7]=1[C:15]([O:17][CH3:18])=[O:16].N1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:15]([C:7]1[O:8][C:9]([C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:10][C:6]=1[NH:5][C:1]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)=[O:2])([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1oc(C(C)(C)C)cc1N
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1oc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Phosgene (1.93M in toluene, 1.3 mL, 2.5 mmol, 10 equiv) was added rapidly to a solution of methyl 3-amino-5-tert-butylfuran-2-carboxylate (0.050 g, 0.25 mmol) and anh. pyridine (1.0 mL) in anh. toluene (5 mL) at room temp. After 30 min, the orange suspension was concentrated under reduced pressure, then successively charged with dry toluene (1 mL) and concentrated (2×). Finally, anh. toluene (3 mL) was added followed by p-toluidine (0.100 g, 0.93 mmol, 3.7 equiv). The orange mixture was stirred overnight, diluted with EtOAc, washed with a 1M HCl solution and a concentrated NaCl solution, then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography to give N-(2-carbomethoxy-5-tert-butyl-3-furyl)-N′-(4-methylphenyl)urea (0.080 g, 96%) as a pale yellow oil: 1H NMR (CDCl3) δ1.28 (s, 9H), 2.30 (s, 3H), 3.77 (s, 3H), 7.02 (s, 1H), 7.11 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 7.87 (br s, 1H), 8.68 (br s, 1H); 13C NMR (CDCl3) δ20.6, 28.3 (3C), 33.0, 51.0, 100.1, 121.4 (2C), 126.0, 129.5 (2C), 134.0, 134.8, 137.7, 152.5, 160.5, 168.2; FTIR (neat) 3400-3200 (br, m), 2966 (s), 1676 (s), 1622 (s), 1536 (s), 1306 (s), 1097 (m) cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][CH:9](C(OCC)=O)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:32].[Li+].O.C[CH:36]([OH:38])C>>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]([C:36]([OH:38])=[O:32])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: CCOC(=O)C(CCC(=O)OC(C)(C)C)COc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(C)O
Agent: [Li+]
Solvent: O
Product: CC(C)(C)OC(=O)CC(CCOc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
To a solution in 2-propanol (30 mL) of 4-carboethoxy-5-[4-(4-cyanophenyl)phenoxy]pentanoic acid tert-butyl ester (0.9 g), prepared in step 1, was added aqueous 1M lithium hydroxide (8.6 mmol) and water (5 mL) to form a clear solution, and the reaction mixture was stirred for 3 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted twice with ethyl ether and once with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (4% methanol-dichloromethane) provided 3-carboxy-5-[4-(4-cyanophenyl)phenoxy]pentanoic acid tert-butyl ester (0.62 g).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[S:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26](=[O:28])[N:27]=2)[N:17]=1)(=O)=O.[C:33](OCC)(=O)C>CN(C=O)C.O>[CH2:1]([S:8][CH2:33][C:16]1[N:17]=[C:18]([C:22]2[S:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26](=[O:28])[N:27]=2)[CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: SCc1ccccc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2cccc(CSCc3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
Benzyl mercaptan (0.41 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.18 g, 16%) as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Br:11])[CH2:4][CH:3]1[CH2:17][CH3:18].[Br:19]Br.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Br:11])[CH2:4][C:3]1([CH2:17][CH3:18])[Br:19]
Reactant: CCC1Cc2cc(OCC(=O)O)cc(Br)c2C1=O
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(Br)Cc2cc(OCC(=O)O)cc(Br)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of (1-oxo-2-ethyl-7-bromo-5-indanyloxy)acetic acid in acetic acid is treated over a 10-minute period with a solution of bromine in acetic acid. The reaction mixture is stirred at ambient temperature for 0.5 hour and poured into water containing sodium bisulfite (1 g.). The (1oxo-2-ethyl-2,7-dibromo-5-indanyloxy)-acetic acid is extracted from the reaction mixture with ether, and the ether solution washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent yields the products as an oil.
Reaction SMILES: N([O:3][C:4](C)(C)C)=O.[Cu]C#N.[CH3:11][N:12]1[C:16](N)=[C:15]([CH3:18])[C:14]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[N:13]1.[OH-:26].[K+].Cl>C(#N)C.O>[CH3:11][N:12]1[C:16]([C:4]([OH:3])=[O:26])=[C:15]([CH3:18])[C:14]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[N:13]1
Reactant: Cc1c(C(F)(F)C(F)(F)F)nn(C)c1N
Reactant: CC(C)(C)ON=O
Reactant: [OH-]
Agent: N#C[Cu]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1c(C(F)(F)C(F)(F)F)nn(C)c1C(=O)O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
8.66 g (85.1 mmol) of tert-butyl nitrite and 6.0 g (67.4 mmol) of copper(I) cyanide are suspended in 360 ml of acetonitrile and heated to 65° C. A solution of 13.0 g (57.2 mmol) of 1,4-dimethyl-3-(pentafluoroethyl)-1H-pyrazole-5-amine in 20 ml of acetonitrile is then slowly added. The reaction mixture is further stirred for 24 hours at 65° C. The reaction mixture is then filtered over Celite. The filtrate is concentrated by evaporation under reduced pressure on a rotary evaporator. The residue is taken up in water and acidified with conc. hydrochloric acid. The aqueous phase is extracted several times with dichloromethane. The combined organic phases are concentrated by evaporation under reduced pressure on a rotary evaporator and the residue is purified by column chromatography on silica gel (hexane:ethyl acetate=5:1). The resulting product (2.3 g, 9.7 mmol) is heated under reflux with 3.44 g (63 mmol) of potassium hydroxide in 20 ml of water. After 3 h the reaction solution is cooled to 0° C. and adjusted to pH 6 with dilute hydrochloric acid. The resulting solid is filtered and dried. This gives 0.3 g of 1,4-dimethyl-3-(pentafluoroethyl)-1H-pyrazole-5-carboxylic acid (2%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2/[CH:21]=[CH:22]/[CH:23]([OH:32])[CH2:24][CH:25]([OH:31])[CH2:26][C:27]([O:29]C)=O)=[CH:4][C:3]=1[CH3:33].[OH-].[Na+].ClC(OCC)=O.CCN(CC)CC>CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2/[CH:21]=[CH:22]/[C@@H:23]2[O:32][C:27](=[O:29])[CH2:26][C@@H:25]([OH:31])[CH2:24]2)=[CH:4][C:3]=1[CH3:33]
Reactant: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)c(C)c2)CC(N2CCCC2)CC1(C)C
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O)CC(=O)O3)C(C)(C)CC(N3CCCC3)C2)ccc1F

Procedure:
In a manner similar to Scheme I, 34 (0.19 g) was treated with 2N NaOH in methanol at 0°-5° C. for 18 h, followed by ethyl chloroformate (0.254 mmol) and Et3N in CH2Cl2 at 0°-5° C. Workup and purification of the residue by SiO2 using 1% Et3N in EtOAc as eluent yielded the product. mp 120°-3° C. Anal. C26H34FNO3 ·0.5 H2O: Theory C: 71,53; H: 8.08; N: 3.21; Found C: 71.60; H: 8.17; N: 3.03.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.CS(C)=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH:10]=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H](CCO)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](CC=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine sulfur trioxide complex (37.7 g, 237 mmol) was added portionwise over 20 minutes to a stirred cold (0° C.) solution of N-[(1S)-1-(3-fluorophenyl)-3-hydroxypropyl]acetamide (25 g, 118 mmol), DMSO (16.5 ml, 233 mmol) and triethylamine (33 ml, 237 mmol) in dichloromethane (240 ml). After two hours stirring at room temperature, solvent was evaporated under reduced pressure and the residue applied directly to a silica gel column. Eluting with a gradient system starting with ethyl acetate:dichloromethane (50:50 by volume) then ethyl acetate:dichloromethane (80:20 by volume) and finally ethyl acetate gave the title compound as a colourless oil which solidified on standing (13.9 g).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.Cl>CO.C(Cl)(Cl)Cl>[CH2:22]([NH:29][CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: OC(CNCc1ccccc1)COc1ccc(-c2noc3cc(F)ccc23)cc1
Yield: 33.9 %

Procedure:
Combine (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole (29) (500 mg, 1.75 mmol), benzylamine (755 mg, 7.05 mmol), ethanol (5.0 ml) and heat (˜80° C.) for 18.5 hours. At room temperature the reaction solidified. Dissolve reaction mixture with chloroform and concentrate (in vacuo). Purify the compound by column chromatography (silica) eluting with 10% ethanol in chloroform to obtain a white solid. Dissolve the free base in hot methanol and add ethereal HCl to a pH ˜2-3. Concentrate the reaction mixture (in vacuo) and recrystallize (methanol) the salt and dry (60° C., 1.0 mm Hg) to give the title compound as white solid (233 mg, 46% Yield). mp=251-253° C. Microanalysis (C, H, N) is consistent with the final, desired compound. [α]22D=+9.17, c (MeOH)=0.60.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].CO[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=1>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCCc1ccccc1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCc2ccccc2)=N1
Reaction time: 24 h

Procedure:
8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride. A solution of 8-phenylocatanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil. To 8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-triimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmol) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmol). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][CH2:17][C@@:16]2([CH2:21][OH:22])[C:3]=1[CH2:4][C@@H:5]([CH3:24])[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:23].[CH3:25][C@@H:26]1[CH2:43][C:42]2[C@:37]([CH2:45][OH:46])([CH2:38][CH2:39][C@H:40]([OH:44])[CH:41]=2)[C@@H:36]2[C@@H:27]1[C@H:28]1[C@@:32]([CH2:34][CH2:35]2)([CH3:33])[C@@H:31]([OH:47])[CH2:30][CH2:29]1>>[OH:23][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH2:21][OH:22])[C:3](=[C:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)[CH2:4][C@H:5]3[CH3:24].[OH:47][C@@:31]1([C:1]#[C:2][CH3:3])[CH2:30][CH2:29][C@H:28]2[C@H:27]3[C@H:36]([CH2:35][CH2:34][C@:32]12[CH3:33])[C@:37]1([CH2:45][OH:46])[C:42](=[CH:41][C:40](=[O:44])[CH2:39][CH2:38]1)[CH2:43][C@H:26]3[CH3:25]
Reactant: C[C@@H]1CC2=C[C@@H](O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: CC1=C2C[C@@H](C)[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CC[C@@H]1O
Product: CC#C[C@]1(O)CC[C@H]2[C@@H]3[C@H](C)CC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@@]21C
Product: CC1=C2C[C@@H](C)[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CCC1=O

Procedure:
Substituting 4,7α-dimethyl-4-androstene-3β,17β,19-triol, 7α,17α-dimethyl-4-androstene-3β,17β,19-triol and 7α-methyl-17α-propinyl-4-androstene-3β,17β,19-triol for the 7α-methyl-4-androstene-3β,17β,19-triol above results in the formation of 17β,19-dihydroxy-4,7α-dimethyl-4-androsten-3-one, 17β,19-dihydroxy-7α,17α-dimethyl-4-androsten-3-one and 17β,19-dihydroxy-7α-methyl-17α-propinyl-4-androsten-3-one, respectively.
Reaction SMILES: Br[CH:2]([CH:11]([OH:18])[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[H-].[Na+]>C1COCC1.C(OCC)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:11]2[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[O:18]2)[CH:13]=1
Reactant: COC(=O)CCCCC(Br)C(O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC1OC1c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.3 g of methyl 6-bromo-7-hydroxy-7-(3-pyridyl)-heptanoate is dissolved in 200 mL of THF and 4.5 g of 50% sodium hydride added in portions. After stirring at room temperature for 3 hours, the reaction is diluted with ethyl acetate, filtered and concentrated to give crude product which is further purified by column chromatography on silica gel using ethyl acetate as eluent to yield 2-(3-pyridyl)-3-(4-methoxycarbonylbutyl)-oxirane.
Reaction SMILES: [CH3:1][S:2][C:3](=[CH:8]OS(C1C=CC(C)=CC=1)(=O)=O)[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.C(Cl)(Cl)Cl.[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COC(C)(C)C>[CH3:1][S:2][C:3](=[CH:8][S:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Sc1ccccc1
Reactant: COC(=O)C(=COS(=O)(=O)c1ccc(C)cc1)SC
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)C(=CSc1ccccc1)SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a mixture of methyl 2-methylthio-3-(p-toluenesulfonyloxy)acrylate (3.05 g), triethylamine (2 mL) and chloroform (20 mL) was added slowly thiophenol (1.28 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added tert-butyl methyl ether, and then a 1N aqueous sodium hydroxide solution, thereby layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain methyl 2-methylthio-3-(phenylthio)acrylate (1.64 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:50]=[CH:51][CH:52]=2)[CH2:44][O:45]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:53][N:54]1[CH2:59][C@@H:58]2[CH2:60][C@H:55]1[CH2:56][NH:57]2.C1C[O:64]CC1>>[CH:44]([OH:45])=[O:64].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:52]=[CH:51][CH:50]=[C:43]([CH2:44][N:57]3[CH2:56][C@@H:55]4[CH2:60][C@H:58]3[CH2:59][N:54]4[CH3:53])[CH:42]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Reactant: CN1C[C@@H]2C[C@H]1CN2
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CN5C[C@@H]6C[C@H]5CN6C)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 9 %

Procedure:
To a solution of Intermediate 167b (0.15 mmol) in THF (20 mL) was added (1S,4S)-2-methyl-2,5-diaza-bicyclo[2.2.1]heptane (366 mg, 3.3 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, then further purified by HPLC (C18 X-select column, 10-75% MeCN in H2O, 0.1% formic acid) to give the title compound (11 mg, 9%). LCMS (Method 5): Rt 3.45 min, m/z 743 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.86 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.42-1.50 (2H, m), 1.54-1.66 (4H, m), 1.72-1.84 (3H, m), 1.84-1.92 (1H, m), 1.95-2.15 (2H, m), 2.22 (3H, s), 2.46-2.48 (1H, m), 2.52 (1H, dd, J=9.6, 2.4 Hz), 2.59 (1H, d, J=9.7 Hz), 2.71 (1H, d, J=9.6 Hz), 2.86 (1H, ddd, J=12.7, 9.0, 3.9 Hz), 3.09-3.13 (2H, m), 3.22 (1H, s), 3.28-3.32 (1H, m), 3.63 (1H, d, J=13.9 Hz), 3.70 (1H, d, J=13.9 Hz), 4.77 (1H, td, J=8.4, 5.7 Hz), 5.47 (1H, t, J=4.2 Hz), 6.28 (1H, s), 7.04 (1H, d, J=8.6 Hz), 7.14 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.25 (2H, m), 7.26-7.36 (4H, m), 7.36-7.41 (2H, m), 7.59 (1H, d, J=10.0 Hz), 7.64 (1H, d, J=1.8 Hz), 8.11 (1H, s), 8.25 (0.7H, s).
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:17])([CH3:16])[O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:18]([O:20][C:21]([C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](Cl)=[O:29])=[O:22])[CH3:19]>C1COCC1.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([S:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:17])[CH3:16])[CH:10]=1)=[O:29])=[O:22])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCCN1C(=O)Sc1cccc(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of sodium hydride (0.25 g, 6.3 mmol) in anhydrous THF (20 mL) is added 3-(t-butyl-dimethyl-silanyloxy)-benzenethiol (1.3 g, 5.22 mmol) at RT. After 10 min, the title A compound, (R)-1-chlorocarbonyl-pyrrolidine-2-carboxylic acid ethyl ester (1.1 g, 5.22 mmol) is added and the reaction is stirred for 24 h. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 25% ethyl acetate in hexane to yield (R)-1-[3-(t-butyl-dimethyl-silanyloxy)-phenyl-sulfanylcarbonyl]-pyrrolidine-2-carboxylic acid ethyl ester as a clear oil.
Reaction SMILES: Br[C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:13]1([C:3]2[C:2]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:9]=[C:8]3[C:4]=2[CH2:5][C:6](=[O:12])[N:7]3[CH3:11])[CH2:15][CH2:14]1
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)Cc2c1ccc(Br)c2C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2C1CC1
Temperature: 130 °C

Procedure:
To 5-bromo-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one, prepared as described in Example 40c, (320 mg, 1.202 mmol), was added 3-pyridine boronic acid (CAS#1692=25-7, 177 mg, 1.443 mmol), 1,2-dimethoxyethane (7.5 mL), and 2 M aqueous sodium carbonate (1.503 ml, 3.01 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3—Pd(0) (Biotage), 0.11 mmol/g loading, (328 mg, 0.036 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 130° C. for 4 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 10 to 100%) to furnish 4-cyclopropyl-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one, HRMS: (ESI) m/z 265.1342 (M+H)+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.12-0.24 (m, 2H), 0.68-0.78 (m, 2H), 1.86-2.00 (m, 1H), 3.19 (s, 3H), 3.59 (s, 2H), 6.80 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.34 (dd, J=7.7, 4.9 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 8.53 (d, J=4.6 Hz, 1H), 8.63 (s, 1H).