Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[CH:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10][C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=2[N:7]=1.C(O)=O>ClCCl>[CH:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=3[CH2:10][CH2:11][C@@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]2=[N:5][CH:4]=1
Reactant: COC(CNC1=Nc2ccccc2CCC1NC(=O)OCc1ccccc1)OC
Solvent: O=CO
Solvent: ClCCl
Product: O=C(N[C@@H]1CCc2ccccc2-n2ccnc21)OCc1ccccc1
Reaction time: 0.01 h
Yield: 45 %

Procedure:
Heat a mixture of benzyl N-[2-(2,2-dimethoxyethylamino)-4,5-dihydro-3H-1-benzazepin-3-yl]carbamate (1.80 kg, 4.1 mol) and formic acid (6.4 L) at 95° C. for 80 minutes. Concentrate the mixture under reduced pressure to give a black oil and partition it between dichloromethane (7.0 L) and water (5 L). Add sodium carbonate until the pH of the aqueous layer is 7. Remove the organic layer and wash with water (3×). Extract the aqueous layers with dichloromethane. Combine the organic layers and concentrate under reduced pressure to give a black oil. Divide the 2.297 kg of the black oil into approximately 250 g sections and dissolve each section in dichloromethane (250 mL). Add to 3.5 kg Merck 9385, 60 A, 230-400 mesh silica. Elute target compound with 75:25 ethyl acetate/heptane beginning with six column volumes (faster eluting impurities elute first). Follow with 5:95 methanol/ethyl acetate to remove remaining product (1082 g recovered). Assay product mixture using chiral HPLC conditions as follows: 4.6×150 mm Chiralpak AD-H column, 15:85:0.2 acetonitrile/3A grade ethanol/dimethylethylamine mobile phase, 0.6 mL/min flow rate, 250 nm UV detection. Observe isomer ratio 3:2 desired/undesired under these conditions. Dissolve isomer mixture at 30 mg/mL 20:80 acetonitrile/3A ethanol. Purify isomers using prep chiral HPLC conditions as follows: 8×40.5 cm Chiralpak AD (20 micron) column, 20:80:0.2 acetonitrile/3A ethanol/N,N-dimethylethylamine (DMEA) mobile phase, 490 mL/min flow rate, 250 nm UV detection, 1.5 g (50 mL) injections, 4.6 minute cycle time/injection using Steady State Recycle (SSR) technology (J. H. Kennedy, M. D. Belvo, V. S. Sharp, J. D. Williams, Comparison of separation efficiency of early phase active pharmaceutical intermediates by steady state recycle and batch chromatographic techniques, Journal of Chromatography A, 1046 p 55-60 (2004)). The collection of isomer 1 is from 0.4-0.9 min and collection of isomer 2 is from 2.4-4.2 min. The desired isomer (Isomer 2; R isomer) is the second eluter: benzyl N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamate. Concentrate the product containing fractions under reduced pressure to give the title compound (615 g, 73%) as a white solid: MS (m/z): 334 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8](Cl)(=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1>>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:17]
Reactant: Nc1ccccn1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccccn2)c1
Yield: 21 %

Procedure:
Using 2-aminopyridine (670 mg, 7.12 mmol) and m-anisoyl chloride (1.2 ml, 8.55 mmol), the procedure of Reference Example 13 was repeated to obtain 341 mg (21.0%) of the title compound in the form of light yellow oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[C:18]([CH2:19][CH3:20])=[C:17]([CH2:21][N:22]3[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)[C:16]([CH2:36][CH3:37])=[N:15]2)=[C:9]([CH3:38])[CH:8]=1.CN(C)[CH:41]=[O:42]>O1CCCC1>[CH2:34]([O:33][CH2:32][C@H:31]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][N:22]1[CH2:21][C:17]1[C:16]([CH2:36][CH3:37])=[N:15][N:14]([C:10]2[C:11]([CH3:13])=[CH:12][C:7]([CH:41]=[O:42])=[CH:8][C:9]=2[CH3:38])[C:18]=1[CH2:19][CH3:20])[CH3:35]
Reactant: CN(C)C=O
Reactant: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(C=O)cc2C)c1CC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 155.4 %

Procedure:
To a solution of n-butyl lithium (2.5 M hexane solution; 0.043 ml, 0.11 mmol) chilled to -78° C., a solution of (R)-2-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-3-ethoxymethyl-1,2,3,4-tetrahydro-isoquinoline (50 mg, 0.098 mmol) in anhydrous tetrahydrofuran (0.2 ml) was added dropwise. After stirring at -78° C. for 10 minutes, anhydrous N,N-dimethylformamide (0.023 ml, 0.29 mmol) was added. The resulting mixture was warmed to ambient temperature and stirred for 1 hour. The reaction quenched by addition of aqueous ammonium chloride (1 ml) and then extracted with ethyl acetate/water (5 ml of each). The separated organic extract was washed with an equal volume solution of aqueous ammonium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow oil (70 mg). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl actate/hexane=1:4 in volume) afforded the title compound (14 mg) as a faint yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14](Cl)(=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].CO.C(Cl)(Cl)Cl>[OH-].[Na+].O1CCCC1>[CH3:1][N:2]([CH2:3][C@H:4]([OH:5])[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@H:10]([OH:11])[CH2:12][OH:13])[C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 1 h
Yield: 29.4 %

Procedure:
N-Methyl glucamine (1.95 g, 10.0 mmol) was dissolved in 10 mL of 1.00 N sodium hydroxide solution and 10 mL of tetrahydrofuran. Docosanoyl chloride (3.58 g, 10.0 mmol) was then added to the rapidly stirred solution followed by another 20 mL portion of tetrahydrofuran. After stirring for 60 min, the thick reaction mixture was placed on a rotary evaporator and tetrahydrofuran was removed under reduced pressure. The resulting thick slurry was filtered, washed with water and dried with suction to give a waxy white solid. Chromatography (SiO2, 15%-30% MeOH/CHCl3) yielded 1.52 g of the following compound as a waxy solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=2)=[N:3]1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[C:13]([O:14][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=2)=[N:3]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(-c2cc(C)n(C)n2)n1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cc(C)n(C)n3)c2cc1OC
Temperature: 160 °C
Reaction time: 48 h
Yield: 4.2 %

Procedure:
2-(1,5-Dimethyl-1H-pyrazol-3-yl)-6-methyl-pyridin-3-ol (111 mg), 4-chloro-6,7-dimethoxyquinoline (218 mg), and 4-dimethylaminopyridine (130 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 2 days. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (9 mg, yield 4%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:5]([O:6][C:7]2[C:12]([O:13]C)=[C:11]([C:15](=[O:21])[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]([CH3:22])[N:8]=2)=[C:4]([CH3:26])[CH:3]=1.B(Br)(Br)Br.B(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:5]([O:6][C:7]2[C:12]([OH:13])=[C:11]([C:15](=[O:21])[CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[CH:10]=[C:9]([CH3:22])[N:8]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: CCC(CC)C(=O)c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1OC
Agent: BrB(Br)Br
Agent: ClB(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(CC)C(=O)c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1O

Procedure:
The title compound was prepared by reacting 1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one with BBr3 or BCl3 in THF or methylene chloride.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C1(=O)O[CH2:23][CH2:22][O:21]1.[OH-].[Na+].CN(C)C=O>C(OCC)(=O)C>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[O:19][CH2:23][CH2:22][OH:21])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Oc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Reactant: O=C1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCOc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Temperature: 100 °C

Procedure:
A mixture of 3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol (0.29 g), ethylene carbonate (0.11 g), a trace of solid sodium hydroxide (spatula tip of 20-40 mesh beads) and dry dimethylformamide (3 ml) was stirred under nitrogen and heated at 100° C. for 45 minutes. The external temperature was raised to 140° C. and the mixture heated at this temperature for 3.5 hours. The reaction mixture was cooled and diluted with ethyl acetate and the mixture washed with dilute aqueous sodium hydroxide solution and then with water. The organic phase was dried, filtered and evaporated to give a residue which was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid with was triturated with diethyl ether and filtered to give 2-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]ethanol, m.p. 203-205° C.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([S:23][C:24]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[NH:46][N:45]=[N:44][N:43]=3)=[CH:32][CH:31]=2)[C:27]2=[C:47]([C:51]([OH:53])=[O:52])[S:48][C:49]([CH3:50])=[C:26]2[N:25]=1)[CH3:22].C(N(CC)CC)C>ClCCl>[CH2:21]([S:23][C:24]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:43]([C:1]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:44]=[N:45][N:46]=3)=[CH:32][CH:31]=2)[C:27]2=[C:47]([C:51]([OH:53])=[O:52])[S:48][C:49]([CH3:50])=[C:26]2[N:25]=1)[CH3:22]
Reactant: CCSc1nc2c(C)sc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCSc1nc2c(C)sc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trityl chloride (0.6 g) was added to a solution of 2-ethylthio-4-methyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl ]methyl]thieno[3,4-d]imidazole-6-carboxylic acid (0.92 g) and triethylamine (0.3 ml) in dichloromethane (20 ml). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was washed with water, dried, and then the solvent was evaporated ...in vacuo. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate - hexane afforded colorless needles (1.36 g, 98%), m.p. 138°-140° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][OH:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>CN(C)C=O>[S:21]([O:19][CH2:18][C@@H:9]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:23])(=[O:22])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
The product from (A) (3.8 mmol) was dissolved in dimethylformamide (DMF) (20 mL) and the solution was cooled to 0° C. Methanesulfonyl chloride (14.4 mmol) and triethylamine At3N) (14.4 mmol) were added. The reaction was stirred at 0° C. for 2 hr, quenched with H2O (2×25 mL), saturated NaHCO3 (1×25 mL) and brine (1×25 mL). The organic layer was dried over Na2SO4, filtered and dried to give the title compound (1.2g, 92%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.60 (9H, s), 1.91-2.05 (2H, m), 2.77-2.90 (2H, m), 3.68-3.82, 3.12 (3H, s), 3.9-4.05 (1H, m), 4.27-4.4 (2H, m), 4.72-4.82 (1H, m), 7.25-7.48 (5H, m).
Reaction SMILES: [S:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:3]=[CH:2]1.Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1.C(O[Na])(C)(C)C.C(P)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C(C)=CC=CC=1>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([N:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]3[S:1][CH:2]=[CH:3][C:4]2=3)=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: c1ccc2c(c1)[nH]c1ccsc12
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P
Solvent: Cc1ccccc1C
Product: CCCCCCCCOc1ccc(-n2c3ccccc3c3sccc32)cc1
Yield: 81.9 %

Procedure:
3.0 g (17.3 mmol) of 4H-thieno[3,2-b]indole (C′), 4.93 g (17.3 mmol) of 1-bromo-4-octyloxybenzene, and 0.0025 g (1.114×10−2 mmol) of tris(dibenzylideneacetone)dipalladium(0) were dissolved in 1.9 g (19.8 mmol) of t-BuONa, 0.003 g (1.5×102 mmol) of t-butylphosphine, and 50 ml of xylene and the solution was refluxed at 120° C. for 24 hours. Then, the solvent was removed and the resulting product was isolated and purified by column chromatography using toluene/hexane (⅓ by volume) as an eluent, thereby obtaining 5.35 g (yield: 82%) of 4-(4′-octyloxy-phenyl)-4H-thieno[3,2-b]indole (D′).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:15]C([O-])=O)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O.CN(C1C=CC=CN=1)C.[CH2:28]([CH:31]1[CH2:35][NH:34][C:33](=[O:36])[CH2:32]1)[CH2:29][CH3:30]>C(Cl)Cl>[O:36]=[C:33]1[CH2:32][CH:31]([CH2:28][CH2:29][CH3:30])[CH2:35][N:34]1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCCC1CNC(=O)C1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.9 %

Procedure:
Triethylamine (81.4 ml, 10 mmol), tert-butyl dicarbonate (4.2 g, 19.2 mmol) and dimethylaminopyridine (1.18 g, 9.58 mmol) were added to a solution of 4-propyl-2-pyrrolidinone (1.22 g, 9.59 mmol) in methylene chloride (20 ml) and the mixture was stirred at room temperature for 12 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.35 g) as a colorless oil. 1H-NMR (CDCl3) δ(ppm) 0.93 (3H, t, J=7.2 Hz), 1.28-1.50 (4H, m), 1.52 (9H, s), 2.14-2.32 (2H, m), 2.61 (1H, dd, J=15.0 Hz, 7.0 Hz), 3.30 (1H, dd, J=10.8 Hz, 7.2 Hz), 3.87 (1H, dd, J=10.8 Hz, 8.0 Hz)
Reaction SMILES: [CH3:1][C:2]1[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3)[N:9]=[C:4]2[C:3]=1[C:31]([OH:33])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:67]([NH2:71])([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C>[C:67]([NH:71][C:31]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3)[N:9]=2)[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:2]=1[CH3:1])=[O:33])([CH3:70])([CH3:69])[CH3:68]
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)O)c(C)n3COCC[Si](C)(C)C)cc(OC)c1OC
Reactant: CC(C)(C)N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)c(C)n3COCC[Si](C)(C)C)cc(OC)c1OC
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (95 mg) in 1.5 mL of DMF was added PyBOP (128 mg) followed by tert-Butyl amine (70 mg). After stirring for 2 h, the mixture was partitioned between water and diethylether. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (4:1 Hexanes:ethylacetate) afforded 70 mg of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)[CH2:8][CH2:7]1.[ClH:22].[CH2:23]([OH:25])[CH3:24]>N1C=CC=CC=1>[ClH:22].[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]4[C:23](=[O:25])[C@H:24]5[C@H:16]([CH2:12][CH2:9][CH2:8][CH2:7]5)[C:15]4=[O:14])[CH2:7][CH2:8]3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(4aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 16.1 mmol) and cis-1,2-cyclohexanedicarboxy]ic anhydride (3.23 g, 21 mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the end of the reaction, pyridine was removed to dryness. The crude product was purified on a silica gel column. The material thus obtained weighed 3.18 g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), then was treated with HCl in ethanol (45 ml). Crystallization took place upon cooling. The crystals were collected, 3.2 g, m.p.=229°-231 ° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([C:17]3[CH2:21][C:20]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)([C:22]([F:25])([F:24])[F:23])[O:19][N:18]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:17]3[CH2:21][C:20]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)([C:22]([F:25])([F:23])[F:24])[O:19][N:18]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)nn1-c1ncccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.9 g of methyl 1-(3-chloropyridin-2-yl)-3-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-1H-pyrazole-5-carboxylate were dissolved in a mixture of 10 ml of water and 20 ml of ethanol, 0.2 g of sodium hydroxide were added and the mixture was stirred at RT for 3 h. The reaction was acidified with 2N hydrochloric acid, extracted three times with methyl tert-butyl ether and dried over magnesium sulphate. The product was obtained after distillative removal of the solvent.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:16]=[C:17]([C:23](=[O:25])[CH3:24])[CH:18]=[N:19][C:20]=1[O:21][CH3:22].[CH2:26]([NH:29][C:30](=[O:33])[O:31][CH3:32])[C:27]#[CH:28]>CCCCCC.C(NC(C)C)(C)C.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:23]([C:17]1[CH:16]=[C:15]([C:28]#[C:27][CH2:26][NH:29][C:30](=[O:33])[O:31][CH3:32])[C:20]([O:21][CH3:22])=[N:19][CH:18]=1)(=[O:25])[CH3:24]
Reactant: C#CCNC(=O)OC
Reactant: COc1ncc(C(C)=O)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COC(=O)NCC#Cc1cc(C(C)=O)cnc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.7 %

Procedure:
Bis(benzonitrile)dichloropalladium (II) (12 mg) and copper (I) iodide (3.8 mg) were added to 1,4-dioxane (1 mL) under argon, and then thereto were added a solution of 10% tri-t-butylphosphine in hexane (179 μL), diisopropylamine (168 μL), 1-(5-bromo-6-methoxypyridin-3-yl)ethanone (230 mg) and a solution of methyl prop-2-yn-1-ylcarbamate (149 mg) in 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1→1/3) to give methyl [3-(5-acetyl-2-methoxypyridin-3-yl)prop-2-yn-1-yl]carbamate [Ex(296-2)] (188 mg) as a pale yellow powder.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:35])[CH:21]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:53])[C@@H:15]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si](C(C)(C)C)(C)C)[CH2:39]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:35])[CH:21]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:53])[C@@H:15]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([OH:45])[CH2:39]2)=[CH:10]1
Reactant: CCC(Oc1cccc2ccccc12)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1cccc2ccccc12)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 54 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 719 mg of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(1-naphthyloxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 46, above] and 18.8 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 272 mg of the title compound as white crystals, melting at between 138° and 140° C.
Reaction SMILES: [Li]CCCC.I[C:7]1[C:8]([CH3:13])=[N:9][O:10][C:11]=1[CH3:12].[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1>[CH3:13][C:8]1[C:7]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:11]([CH3:12])[O:10][N:9]=1
Reactant: Cc1noc(C)c1I
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)noc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.2 %

Procedure:
n-BuLi (1.6 M solution in hexanes, 6 mL, 9.6 mmol) was added to a cooled (−78° C.) solution of 4-iodo-3,5-dimethylisoxazole (1.47 g, 6.60 mmol) in THF (24 mL) under nitrogen. After 15 min, tributyltin chloride (26 mL, 9.60 mmol) was added and the reaction was stirred over night while warming to room temperature. The reaction was quenched by 1 M HCl, CH2Cl2 was added, the phases separated and the solvent were evaporated. The residue was purified by flash chromatography with heptane: CH2Cl2 (75:25-0:100) to give 3,5-dimethyl-4-(tributylstannyl)isoxazole (1.00 g, 39%).