Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]12[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11]C(=O)O[C:7]2=[O:8]>O1CCCC1>[NH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[C:7]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: C1CCNC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
Pyrrolidine (2.46 g, 34.6 mmol) was added dropwise to isatoic anhydride (3.76 g, 23.05 mmol) in tetrahydrofuran (25 mL) at room temperature. The solution was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. The volatiles were removed by evaporation under reduced pressure. The residue was slurried in toluene (50 mL) and the volatiles were removed by evaporation under reduced pressure (2×). The residue was dissolved in hot toluene, then allowed to cool to room temperature. The solution was placed in a freezer for 16 hours to produce a precipitate. The precipitate was filtered and dried to give 3.05 g of crude 1-(2-aminobenzoyl)-pyrrolidine. The crude material (2.65 g) was purified by column chromatography over silica gel using 5-20% ethyl acetate in hexanes. The best fractions were combined and the volatiles were removed by evaporation under reduced pressure. The residue was taken up in dichloromethane (50 mL) and washed with 0.5N sodium hydroxide solution (2×25 mL), washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to yield 1.35 g of 1-(2-aminobenzoyl)pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][C:35](Cl)=[N:34][CH:33]=1.C1N2CCN(CC2)C1>>[CH3:29][O:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:34][CH:33]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, Step 4) was reacted with methyl-4,6-dichloronicotinate and DABCO (5 h, r.t.) to give the title compound as a white solid. MS (m/e)=585.1 [M+H+]
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:35]2([CH3:36])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH3:22])[CH2:12][C@@H:11]([O:38][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:35]2([CH3:36])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([N:28]([CH3:29])[CH3:30])=[O:27])[CH3:22])[CH2:12][C@@H:11]([OH:38])[CH2:10]1
Reactant: C[C@H](OCCC(=O)N(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](OCCC(=O)N(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(N,N-dimethylaminocarbonylethoxy)pregna-5,7,16-triene (100 mg, 0.15 mmol) in tetrahydrofuran (6.0 ml), a 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride (1.5 ml) was added and stirred at 50° C. for 1 hour under a nitrogen stream. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed sequentially with 0.5N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by preparative thin layer chromatography (1.0 mm×2 plates, chloroform:methanol=10:1) to give the titled compound (45 mg, 70.3%) as a colorless foam.
Reaction SMILES: [OH:1][CH:2]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=N)[CH2:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:26]>>[OH:26][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:6][CH:7]=2)[O:12][C:11](=[O:15])[CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: N=C1CC(=O)Oc2cc(OCC(O)COc3ccccc3)ccc21
Product: O=c1cc(O)c2ccc(OCC(O)COc3ccccc3)cc2o1
Reaction time: 4.5 h
Yield: 34 %

Procedure:
A solution of 3,4-dihydro-7-(2-hydroxy-3-phenoxypropoxy)-4-iminocoumarin (6.5g; 0.02 mole) in 50% w/v sulphuric acid (80g) was stirred at 100° for 3-6 hours. The initial pale red solution precipitated a yellow solid which after cooling and dilution with water was separated by decantation. After several decantations with water the oily solid was taken up in hot ethanol, charcoaled, filtered and the filtrate gradually diluted with water. The precipitated oily solid crystallised overnight to give 2.934 of buff solid of m.p. 145°-175°. Recrystallisation from aqueous methanol gave 2.275g (34%) of material of m.p. 181°-183°, νmax (mull) 3250, 3060, 1705, 1610 cm-1 ; τ(DMSO); 5.85 (5H, m); 4.75 (1H broad exchangeable); 4.50 (1H, sharp exchangeable singlet); 3.19-2.50 (7H, complex m); 2.22 (1H, d, J 9.0Hz); 1 low field exchangeable singlet. (Found; C, 65.48; H, 5.19; C18H16O6 requires; C, 65.85; H, 4.91%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1)#[N:2].[CH3:12][C:13](O)([CH:15]([CH3:17])[CH3:16])[CH3:14].S(=O)(=O)(O)[OH:20].Cl>O.C(O)(=O)C>[CH3:12][C:13]([NH:2][C:1](=[O:20])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1)([CH3:14])[CH:15]([CH3:17])[CH3:16]
Reactant: COc1cc(C#N)ccc1O
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C)(C)O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)NC(C)(C)C(C)C)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.0 g of 4-cyano-2-methoxyphenol, 0.6 g of 2,3-dimethyl-2-butanol and 9 ml of acetic acid was slowly added dropwise to 3 ml of concentrated sulfuric acid. The mixture obtained was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was separated with aqueous sodium hydroxide solution and the aqueous layer obtained was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue obtained was subjected to silica gel column chromatography to obtain 0.6 g of N-(1,1,2-trimethylpropyl)-4-hydroxy-3-methoxybenzamide. N-(1,1,2-trimethylpropyl)-4-hydroxy-3-methoxybenzamide:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.O1CCCC1>[C:19]([NH:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture containing 8.21 g of L-Phenylalanine, 5.565 g of Na2CO3 in 40 ml of water and 20 ml of tetrahydrofuran (THF) was stirred at room temperature. Benzoyl chloride, 7.73 g, dissolved in 20 ml of anhydrous THF, was added gradually over a period of 45 minutes with continued stirring at room temperature. Stirring was allowed to continue for an additional hour, at which time the reaction mixture was transferred to a rotary evaporator at 30° C. to remove the THF. An excess of water was then added and the reaction mixture extracted four times with ethyl acetate. The aqueous phase was then titrated to pH 2 with 3N HCl. A white crystalline precipitate formed which was recovered by filtration, washed three times with cold dilute HCl and three times with cold water, and dried in a vacuum oven over P2O5 at about 50° C. The product was recrystallized from aqueous 30 ethanol, yielding 8.37 g, m.p. 183° C.- 184° C., which migrated as a single compound on thin layer chromatography in five separate solvent systems.
Reaction SMILES: [NH2:1][CH:2]=[CH:3]C=O.[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=O)[CH3:7].[C:13]([O-])(=O)C.[NH4+]>C(OC(C)C)(C)C>[C:10]([C:9]1[C:2]([CH3:3])=[N:1][CH:13]=[CH:7][CH:6]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)[O-]
Reactant: NC=CC=O
Reactant: CC(=O)CC(C)=O
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Product: CC(=O)c1cccnc1C
Temperature: 110 °C

Procedure:
To a mixture of 3-amino acrolein (4.52 g) and acetylacetone (7.64 g) was added catalytic amount of ammonium acetate. The mixture was heated for 19 hours at ca. 110° C., After cooling to room temperature, the mixture was poured into 100 ml of isopropyl ether and dried over magnesium sulfate. The resultant mixture was filtered off by suction in vacuo to remove an insoluble material and the filtrate was concentrated in vacuo. The crude compound was purified by column chromatography on silica gel with chloroform to give 3-acetyl-2-methylpyridine (3.58 g) as a yellow oil.
Reaction SMILES: C(O[C@@H:6]1[O:20][C@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@H:7]1[O:8][C:9](=[O:12])[CH2:10][CH3:11])(=O)CC.[NH:33]1[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]1=[O:35].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CC#N>[C:9]([O:8][C@@H:7]1[C@@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[O:20][C@H:6]1[N:33]1[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]1=[O:35])(=[O:12])[CH2:10][CH3:11]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](OC(=O)CC)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Temperature: 60 °C
Yield: 98 %

Procedure:
To a suspension of 1,2,3,5,6-penta-O-propanoyl-β-D-glucofuranose (2.0 g, 4.3 mmol) and uracil (730 mg, 6.5 mmol) in CH3CN (30 mL) was added N,O-bis(trimethylsilyl)acetamide (6.4 mL, 26.1 mmol) dropwise. The mixture was heated at 60° C. for 1 h by which time the suspension had dissolved. The mixture was cooled to 0° C. and trimethylsilyl trifluoromethanesulfonate (1.6 mL, 8.7 mmol) was added dropwise. After 5 h reflux, the solution was concentrated in vacuo to half the volume and cooled in an ice-bath. Saturated aqueous NaHCO3 (60 mL) was added and the mixture extracted with CH2Cl2 (60, 2×30 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Flash silica chromatography of the residue, eluting with 1% CH3OH in CHCl3, gave 1-(2,3,5,6-tetra-O-propanoyl-β-D-glucofuranosyl)uracil as a colourless syrup (2.1 g, 96%), [α]D22=+14.6 (c 1.0 in CHCl3), (Found: C. 52.7; H, 6.1; N, 5.7. C22H30N2O11 requires C, 53.0; H, 6.1; N 5.6%); δH (CDCl3) 9.34 (1H, s, NH), 7.47 (1H, d, J 8.2, 6-H), 6.06 (1H, d, J 2.0, 1′-H), 5.82 (1H, d, J 8.2, 5-H), 5.45 l1H, d, J 3.3, 3′-H), 5.36 (1H, ddd, J 9.6, 5.4 and 2.4, 5′-H), 5.07 (1H, d, J 2.0, 2′-H), 4.61 (1H, dd, J 12.3 and 2.4, 6′a-H), 4.38 (1H, dd, J 9.6 and 3.3, 4′-H), 4.11 (1H, dd, J 12.3 and 5.4, 6′b-H), 2.45 (2H, qd, J 7.5 and 1.5, CH2), 2.36 (2H, q, J 7.5, CH2), 2.35 (2H, q, J 7.5, CH2), 2.29 (2H, q, J 7.5, CH2), 1.18 (3H, t, J 7.5, CH3), 1.15 (3H, t, J 7.5, CH3), 1.12 (3H, t, J 7.5, CH3), 1.10 (3H, t, J 7.5, CH3); δC (CDCl3) 174.3, 173.4, 172.8, 172.3 (4×C═O), 163.2 (3-C), 150.4 (2-C), 139.4 (6-C), 103.5 (5-C), 89.7 (1′-C), 80.6 (2′-C), 79.3 (4′-C), 73.5 (3′-C), 67.1 (5′-C), 63.2 (6′-C), 27.7, 27.6, 27.6, 27.5 (4×CH2), 9.4, 9.1, 9.1, 9.0 (4×CH3); m/z (FAB) 499.191398 (MH+, C22H31N2O11 requires 499.192785).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23]C)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC2CCCCC=2C=1C(OC)=O.[Cl:39]C1C=C(S(Cl)(=O)=O)C=CC=1>>[Cl:39][C:3]1[CH:2]=[C:1]([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: COC(=O)c1c(N)sc2c1CCCC2
Product: COC(=O)c1c(NS(=O)(=O)c2cccc(Cl)c2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from methyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and 3-chlorobenzene-sulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[C:4](/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[CH:5]/[CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH:4]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)/C(=C/C1CCCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
A solution of nickel(II) chloride hexahydrate (7.8 mg, 0.033 mmol) and (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (111 mg, 0.33 mmol) in methanol (3 mL) was cooled to 0° C. and then treated with sodium borohydride (25 mg, 0.66 mmol) in two portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The black solid was filtered using filter paper and washed with methanol. The combined solvents were concentrated in vacuo, and the residue was diluted with water (25 mL) and ethyl acetate (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (101 mg, 91%) as a colorless oil: EI-HRMS m/e calcd for C18H26O4S (M+) 338.1552, found 338.1555.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:17]([O:16][C@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1csc(N2CC[C@H](O)C2)n1
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CC[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of (3S)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (4.1 g, 16.9 mmol) (obtained as described in Reference Example 20(3)) in dimethylformamide (120 ml) were added t-butyldiphenylsilyl chloride (8.8 ml, 33.8 mmol) and imidazole (2.3 g, 33.8 mmol) in an ice bath, and then the reaction mixture was brought to room temperature in 10 minutes, and stirred for overnight. After checking the completion of the reaction, ethanol (1.18 ml) was added thereto in an ice bath, and then the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→1:1) as the eluant to afford (3S)-3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (7.60 g, yield 94%) as a pale brown solid.
Reaction SMILES: CO[CH2:3][N:4]([CH2:13][Si](C)(C)C)[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[C:18]([O:22][CH3:23])(=[O:21])[C:19]#[CH:20]>ClCCl.FC(F)(F)C(O)=O>[C:7]1([C@H:5]([N:4]2[CH2:3][CH:20]=[C:19]([C:18]([O:22][CH3:23])=[O:21])[CH2:13]2)[CH3:6])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C#CC(=O)OC
Reactant: COCN(C[Si](C)(C)C)[C@H](C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=CCN([C@H](C)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
To a stirred solution of (1R)-N-(methoxymethyl)-1-phenyl-N-[(trimethylsilyl)-methyl]ethanamine (55.83 mL, 205.62 mmol) and methyl prop-2-ynoate (22.5 mL, 252.9 mmol) in dichloromethane (500 mL) at 0° C. under nitrogen was added trifluoroacetic acid (800 μL, 10.45 mmol). The reaction mixture was allowed to stir at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was purified by FCC, eluting with 0-70% EtOAc in heptane, to afford the title compound (26.5 g, 56%) as a yellow oil. δH (500 MHz, CDCl3) 7.41-7.29 (m, 4H), 7.28-7.21 (m, 1H), 6.77-6.70 (m, 1H), 3.72 (s, 3H), 3.71-3.65 (m, 1H), 3.65-3.42 (m, 4H), 1.40 (d, J 6.6 Hz, 3H). Method F HPLC-MS: MH+ m/z 232, RT 1.62 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23](Cl)(=[O:25])[CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:25])[CH3:24])=[CH:21][C:14]=3[O:13]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)cc(OC)c1
Temperature: 25 °C

Procedure:
After 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.2 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the ethyl acetate phase was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 249.1 mg.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][N:28]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:27]([Cl:26])=[N:28]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Clc1n[nH]c2ccccc12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(Cl)c4ccccc43)nc12
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (136 mg, 318 μmol), 3-chloro-1H-indazole (48.6 mg, 318 mmol) in dioxane (3.5 mL) was added sodium tert-butoxide (67.3 mg, 700 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.3 mg, 31.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(3-chloro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) δ: 9.12 (s, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.36 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.58 (ddd, J=8.5, 7.2, 1.1 Hz, 1H), 7.42 (ddd, J=8.1, 7.1, 0.9 Hz, 1H), 5.72 (s, 2H), 3.55-3.62 (m, 2H), 1.61 (s, 9H), 0.95 (d, J=16.6 Hz, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][OH:16].[Li]CCCC.[CH3:22][S:23]SC.Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([S:23][CH3:22])[C:4]=1[CH2:15][OH:16]
Reactant: CSSC
Reactant: COc1cc(CO)c(OC)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(CO)c(SC)c(OC)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
Following the procedure of Flader et al.,22 alcohol 26 (0.521 g, 2.39 mmol) was dissolved in THF (9.0 ml) in a flame-dried 25 mL round bottom flask under Argon, and then cooled to 0° C. At 0° C. nBuLi (2.5 M in hexanes, 2.4 ml, 6.0 mmol) was added slowly, then the ice bath was removed and the reaction was stirred at room temperature for 1 hour. Dimethyldisulfide (0.50 mL, 5.6 mmol) was added slowly at room temperature and the reaction was stirred for another 30 minutes at room temperature before being poured into water, acidified with 2 M HCl, and extracted with ethyl acetate. The organic fractions were combined and washed with brine, dried over MgSO4, and filtered. The resulting solid was purified via flash column chromatography (1:4 EtOAc:hexanes) to afford 56 (0.446 g, 1.69 mmol, 71%) as a green solid.
Reaction SMILES: N[C@@H:2]1[C@@H:7]([OH:8])[C@@H:6]([N:9]=[N+:10]=[N-:11])[C@@H:5]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[O:4][CH2:3]1.C1(=O)[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[CH3:34]O>>[N:9]([C@H:6]1[C@@H:5]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[O:4][CH2:3][C@H:2]([CH2:34][C:30]2[CH:31]=[CH:32][CH:24]=[C:25]([C:26]([OH:28])=[O:27])[CH:29]=2)[C@H:7]1[OH:8])=[N+:10]=[N-:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc(COC[C@H]2OC[C@H](N)[C@@H](O)[C@H]2N=[N+]=[N-])cc1
Reactant: CO
Product: COc1ccc(COC[C@H]2OC[C@H](Cc3cccc(C(=O)O)c3)[C@@H](O)[C@H]2N=[N+]=[N-])cc1
Reaction time: 2 h

Procedure:
To a solution of the amine 57 (16.2 mmol) in methanol (55 ml), was added phthalic anhydride (216.2 mmol), and the whole stirred for 2 h. The mixture was then evaporated to dryness under reduced pressure and the residue azeotroped with toluene to leave a cream solid 58.