Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].Br[CH2:28][CH2:29][C:30]#[N:31]>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:28][CH2:29][C:30]#[N:31])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: N#CCCBr
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCC#N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 and 3-bromopropionitrile using an analogous procedure to that outlined in the preparation of Compound 205.11-1 NMR (400 MHz, MeOD) δ ppm 1.28 (d, J=14.65 Hz, 2H) 1.28 (s, 2H) 2.30 (s, 3H) 3.10 (t, J=6.69 Hz, 2H) 5.12 (t, J=6.82 Hz, 2H) 7.00-7.05 (m, 2H) 7.53 (dd, J=2.02, 0.76 Hz, 1H) 7.81 (t, J=7.45 Hz, 1H) 7.92 (ddd, J=7.89, 1.45, 1.26 Hz, 1H) 8.02 (dt, J=7.83, 1.52 Hz, 1H) 8.10 (t, J=1.89 Hz, 1H) 8.26 (d, J=2.02 Hz, 1H) [M+H] calc'd for C23H21N3O3S, 421; found, 421.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:9]#[CH:10])=[CH:4][CH:3]=1.[CH2:18]([SnH:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:27]([Sn:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:23][CH2:24][CH2:25][CH3:26])/[CH:10]=[CH:9]/[CH:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(COc1ccc(F)cc1)O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/C(COc1ccc(F)cc1)O[Si](C)(C)C)(CCCC)CCCC
Temperature: 140 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 2.52 g (10 mmoles) of 3-trimethylsilyloxy-4-p-fluorophenoxy-1-butyne (Example 158), 2.91 g (10 mmoles) of tri-n-butyl-tin hydride, and 10 mg of azobisiso-butyronitrile is heated, under an argon atmosphere, with stirring, for 2 hours at 140° C. After cooling to room temperature, the crude reaction mixture is fractionally distilled at 180°-185° C. (0.05 mm), to give 4.6 g (85%) of the subject product as a colorless liquid.
Reaction SMILES: Cl[CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:12]([NH:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11]1=[O:46])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:47]1([P:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.N1C=CC=CC=1>C1COCC1.O1CCOCC1>[C:6]([O:5][C:3]([C:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:12]([NH:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:11]1=[O:46])=[P:53]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:4])([CH3:9])([CH3:7])[CH3:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 53.9 %

Procedure:
1-(1-chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio) azetidin-2-one (650mg) was dissolved in 1:1 THF/dioxan (12ml) under nitrogen. Triphenylphosphine (525mg) and pyridine (158mg) were added and the mixture heated at 55° for 15.5 hours. The reaction mixture was filtered and the filtrate evaporated. Dry toluene was added to the residue and the solution decanted from any solid and evaporated. Chromatography on silica afforded 1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4(4-tetrahydropyranyloxybut-2-ynylthio)azetidin-2-one as an amorphous solid (470mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)OC(C)C
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCN(C(=O)OC(C)C)c1ccc(Br)cc1C(=O)OC
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Heat a suspension of methyl 5-bromo-2-isopropoxycarbonylaminobenzoate (10.0 g, 31.6 mmol), methyl 4-bromobutyrate (22.9 g, 126 mmol) and cesium carbonate (41.6 g, 126 mmol) in N,N-dimethylformamide (150 mL) under nitrogen at 80° C. for 24 h. Cool the mixture to room temperature and pour into water (200 mL). Extract with ethyl acetate (3×100 mL) and wash the organic extracts with water (3×100 mL) and brine (100 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a colorless oil (11.8 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 1.05-1.07 (m, 4H), 1.30-1.32 (m, 2H), 1.89-1.94 (m, 2H), 2.38-2.44 (m, 2H), 3.46-3.60 (m, 1H), 3.65 (s, 3H), 3.68-3.79 (m, 1H), 3.86 (s, 3H), 4.85-5.01 (m, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.62 (dd, J=1.7, 8.4 Hz, 1H), 8.07 (brs, 1H); ESI MS m/z 416 [C17H22BrNO6+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([OH:44])[C@@H:12]1[O:16][C@@H:15]([C@@H:17]2[O:21][C@@H:20]([C@H:22]([OH:43])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C@@H:33](O)[CH2:34][C:35]3[C:39](=[O:40])[O:38][C@@H:37]([CH3:41])[CH:36]=3)[CH2:19][CH2:18]2)[CH2:14][CH2:13]1>CO>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([OH:44])[C@@H:12]1[O:16][C@@H:15]([C@@H:17]2[O:21][C@@H:20]([C@H:22]([OH:43])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]3[C:39](=[O:40])[O:38][C@@H:37]([CH3:41])[CH:36]=3)[CH2:19][CH2:18]2)[CH2:14][CH2:13]1.[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:44])[CH:12]1[O:16][CH:15]([CH:17]2[O:21][CH:20]([CH:22]([OH:43])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]3[C:39](=[O:40])[O:38][CH:37]([CH3:41])[CH:36]=3)[CH2:19][CH2:18]2)[CH2:14][CH2:13]1
Reactant: CCCCCCCCCC[C@H](O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC3=C[C@H](C)OC3=O)O2)O1
Solvent: CO
Product: CCCCCCCCCCC(O)C1CCC(C2CCC(C(O)CCCCCCCCCCCCC3=CC(C)OC3=O)O2)O1
Product: CCCCCCCCCC[C@H](O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H](O)CCCCCCCCCCCCC3=C[C@H](C)OC3=O)O2)O1
Reaction time: 2 h

Procedure:
Insect antifeedant bioassay of squamocin-G and isosquamocin were found to be toxic to the first and third instar larvae of origental armyworm (Mythimna separata WLK) at a concentration of 10.05% (MeOH) at 27° causing 70% mortality compared to 7% mortality of untreated control. The sample solutions (10 μl of a 0.05% solution) were applied evenly to the lower surface of leaf discs (5 cm2) cut from sorghum hybrid variety CSH5 and the discs were allowed to dry on filter papers. After drying the leaf, discs were offered to 10 first instar M. separata larvae in plastic cups or to one third instar larva in 9-cm (diameter) plastic petric dishes. All larvae were starved for 2 h before the test and the leaf and the leaf discs were kept on moisture filter papers to keep them turgid. The larvae were confined to leaf discs for 24 h and during the period the larvae scratched or consumed >80% of the leaf disc area in the untreated controls. The leaf discs were rated visually for the extent of feeding on a scale upto 1 to 9 (1=<10%, 2=11 to 20%, 3=21 to 30%, 4=31 to 40%, 5=41 to 7=61 to 70%, 8=71 to 80%, 9=>80% leaf area scratched consumed). The larvae were then stirred for 12 h and weighed. Isosquamocin was evaluated by this procedure and the results have shown that it drastically. The feeding of the leaves of sorghum hybrid variety CSH 5 at a concentration of 0.05% in methanol) in comparison with control (methanol) against the first instar and third instar larvae of oriental armyworm (Mythimna separata WLK). It is very toxic to first instar larvae causing high larval mortality and the results are presented below:
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:4]([CH:21]([CH3:23])[CH3:22])[C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Br-:1].[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:20])[N:4]([CH:21]([CH3:23])[CH3:22])[C:3]=2[CH2:2][P+:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:14][CH:15]=1
Reactant: CC(C)n1c(CBr)c(-c2ccc(F)cc2)c2ccccc2c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)n1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(-c2ccc(F)cc2)c2ccccc2c1=O
Product: [Br-]

Procedure:
A solution of 3-bromomethyl-4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinoline (5.8 g) in toluene (120 ml) was treated with triphenylphosphine (4.1 g), and the resulting mixture was stirred and heated at reflux for 1 hour, during which time a white crystalline solid precipitated from the solution. The solid was filtered off, and washed with petroleum ether (b.p. 60°-80° C.), to give [4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]methyltriphenylphosphonium bromide, in the form of a white crystalline solid (9.64 g), m.p. 274° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCBr)C=CC=CC=1.[Mg].Cl[Si:22]([CH2:25][Cl:26])([CH3:24])[CH3:23].Cl>O1CCCC1.O>[Cl:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: Br[Mg]CCc1ccccc1
Agent: BrCCc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(CCl)CCc1ccccc1
Yield: 48.5 %

Procedure:
To a solution of 2-phenylethylmagnesium bromide, prepared from 2-phenylethyl bromide (9.25 g, 50 mmol) and magnesium (1.34 g, 55 mmol) in tetrahydrofuran (50 ml), is added chlorochlormethyldimethylsilane (6.43 g, 45 mmol) in tetrahydrofuran (25 ml). The mixture is refluxed for 18 hours, cooled to 0° C. and hydrolyzed with 3N HCl (50 ml). The mixture is then poured in water (50 ml) and diethyl ether (50 ml), the organic layer is washed with water, brine, dried over MgSO4 and the solvents removed in vacuo. Fractional distillation affords the title compound (5.15 g, 48.5% yield).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][NH:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]([NH:28][C:29]4[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=4[F:36])=[O:27])[CH:23]=[CH:22][C:21]=3[F:37])[CH:16]=[CH:15][N:14]=2)[NH:10][CH:9]=1)=[O:7].C1COCC1.CO.[OH-].[Na+].Cl>O>[F:37][C:21]1[CH:22]=[CH:23][C:24]([C:26]([NH:28][C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=2[F:36])=[O:27])=[CH:25][C:20]=1[O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:11]2[NH:10][CH:9]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:38])=[O:2])=[O:7])[CH:12]=2)[CH:18]=1
Reactant: COC(=O)CNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCC(=O)O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetate (110 mg, 0.21 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 1 hour, and poured into 100 ml of water. 2M HCl was added until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetic acid as white solid. Yield: 100 mg, 93%.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([CH3:27])[O:16][C@@H:11]([O:12]CC=C)[C@@H:10]1[O:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II>C1COCC1.C1COCC1.O>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([CH3:27])[O:16][C@@H:11]([OH:12])[C@@H:10]1[O:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OC(=O)CCC(C)=O
Agent: II
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CCC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](C)O[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
1,5-Cyclooctadiene-bis(methyldiphenylphosphine)iridium hexafluorophosphate (25 mg, 20 μmol) was dissolved THF and the resulting red solution was degassed in an argon stream. Hydrogen was then bubbled through the solution, causing the colour to change to yellow. The solution was then degassed again in an argon stream. A solution of 210(1.4 g, 3.12 mmol) in THF was degassed and added. The mixture was stirred at rt overnight, then concentrated to dryness. The residue was dissolved in a solution of I2 (1.37 g, 5.4 mmol) in 30 mL of THF/H2O (15:4). The mixture was stirred at rt for 1 h, and THF was evaporated. The resulting suspension was taken up in DCM, washed twice with water, satd aq NaHSO3, water, satd aq NaHCO3, water and said aq NaCl, successively. The organic layer was dried and concentrated. The residue was eluted from a column of silica gel with 7:3 to 6:4 Cyclohexane-EtOAc to give the corresponding hemiacetal 211 (1.3 g, 93%). 1H NMR: δ 7.40-7.30 (m, 10H, Ph), 5.40 (dq, 1H, J1,2=1.8, J2,3=3.4 Hz, H-2), 4.93 (d, 1H, J=10.8 Hz, CH2Ph), 4.78 (d, 1H, J1,2=16 Hz, H-1), 4.78 (d, 1H, J=11.2 Hz, CH2Ph), 4.63 (d, 1H, CH2Ph), 4.51 (d, 1H, CH2Ph), 3.99 (m, 1H, J3,4=9.5 Hz, H-3), 3.78 (dq, 1H, J4,5=9.5, J5,6=6.2 Hz, H-5), 3.43 (pt, 1H, H-4), 2.80 (m, 4H, Lev), 2.19 (s, 3H, Ac), 1.37 (d, 3H, H-6). Anal. Calcd for C28H34O7: C, 67.86; H, 6.83. Found: C. 67.94; H, 6.87.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].C([Li])(C)(C)C.ClC[C@@H](O)[CH2:33][N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CO>[CH2:42]([N:34]([CH2:33][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: -30 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (0.33 g, 1 mmol) was added to 8 mL of methanol. The solution was cooled to −30° C. under the protection of nitrogen flow and then the methanol solution containing 1 mmol of tert-butyl lithium was added. The mixture was stirred at −78° C.˜−20° C. for 2 hours. (S)-1-chloro-3-(dibenzylamino)propan-2-ol (0.29 g, 1 mmol) was added and then the mixture was heated slowly to 100° C. and stirred for 2 hours. After the solution was cooled down, saturated ammonium chloride solution and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to provide 0.31 g of white solid in 65% yield. HPLC: 99.2%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[CH3:12][S:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1)[OH:19]
Reactant: Cn1ccnc1
Reactant: CSc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2nccn2C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-methylimidazole (10.0 g, 122 mmol) in 500 mL THF at −78° C. was added n-butyllithium (2.5 M in hexanes, 48.7 mL, 118 mmol) dropwise and the resulting solution was stirred at −78° C. for 30 min. 4-(Methylthio)benzaldehyde (14.73 mL, 110 mmol) was then added at −78° C. and the mixture was stirred until completion by TLC, and quenched with NH4Cl (sat). The mixture was then diluted with EtOAc, extracted and washed (NaHCO3 (sat.), brine). The organic phase was dried over MgSO4, filtered and concentrated. Crystallization (EtOAc/Hexanes) yielded (1-Methyl-1H-imidazol-2-yl)[4-(methylthio)phenyl]methanol.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](/[CH:25]=[CH:26]/[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)#[N:24].N12CCCN=C1CCCCC2.C(#N)C>>[C:23]([CH2:25][CH:26]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C#N)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Temperature: 55 °C
Yield: 88.6 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 0.0317 mol), tert-butyl 4-[(E)-2-cyanovinyl]piperidine-1-carboxylate (10.7 g, 0.0430 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (470 uL, 0.0032 mol) in acetonitrile (100 mL, 2 mol) was heated at 55° C. overnight. The solvent was removed by rotary evaporation to give an orange foam. The resultant material was chromatographed with 0-100 ethyl acetate/hexane to give 15.5 g white solid/foam (100% yield). 1H NMR (400 MHz, CDCl3): δ 8.93 (1H, s); 8.41 (1H, s); 8.38 (1H, s); 7.45 (1H, d); 6.85 (1H, d); 5.75 (2H, s); 4.32 (2H, m); 4.15 (1H, br); 3.6 (2H, t); 3.22-3.05 (2H, m); 2.95-2.6 (2H, m); 2.15 (1H, m); 1.95 (1H, m); 1.45 (9H, s); 1.35 (3H, m); 0.97 (3H, t); 0 (9H, s). LCMS (M+1): 552.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2.N1CCCC1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1(C)C=CC=CC=1.O>[CH2:19]([CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COc1ccc2c(c1)CCC(=O)C2Cc1ccccc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of 51 g (0.289 mol) of 6-methoxy-2-tetralone of formula A-1 wherein D is C, R10 is methoxy; R14, R15 and R16 are each H, and 24.2 mL (0.289 mol) of pyrrolidine in 1.5 L of toluene was heated to reflux, over a Dean-Stark trap, overnight. After removal of the azeotroped water, the reaction mixture was cooled to RT, concentrated to an oil, and dissolved in 725 mL of dioxane. To this solution was added 52 mL (0.434 mol) of benzyl bromide and the resulting solution was heated to reflux overnight. Water (100 mL) was added to the solution the resultant mixture was heated to reflux for an additional 2 h. The mixture was cooled to room temperature and poured into a solution of 1 N HCl and extracted 3 times with EtOAc. The organic layers were washed with H2O and saturated NaHCO3, then dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by flash chromatography over SiO2 using 10% EtOAc to 15% EtOAc in hexanes as the gradient eluant to give 65.2 g of the title product of this preparation as a yellow oil (85%). IR (neat) 2937, 1712, 1500 cm−1; 1H NMR (400 MHz, CDCl3) δ2.41-2.59 (m, 3H), 2.76 (dt, 1H, J=5.4, 15.5), 3.15-3.70 (m, 2H), 3.67 (t, 1H, J=6.3), 3.77 (s, 3H), 6.67-6.70 (m, 2H), 6.81 (d, 1H, J=8.1), 6.87-6.89 (m, 2H), 7.13-7.17 (m, 3H); 13C NMR (100 MHz, CDCl3) δ27.44, 38.19, 39.19, 54.13, 55.14, 112.11, 112.96, 126.30, 128.07, 128.26, 129.35, 129.53, 138.05, 138.20, 158.30, 212.41; MS m/z 267 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([C:53]1[S:54][C:55]2[CH2:56][NH:57][CH2:58][CH2:59][C:60]=2[N:61]=1)=[O:52]>CN(C=O)C>[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([C:53]1[S:54][C:55]2[CH2:56][N:57]([C:12](=[O:14])[CH:11]=[CH:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:58][CH2:59][C:60]=2[N:61]=1)=[O:52]
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)C=Cc1ccc3c(c1)OCO3)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of 3-Benzo[1,3]dioxol-5-yl-acrylic acid (1.0 mmol) in dry 10 mL DMF, were added 1-hydroxybenzotriazole (1.2 mmol), 1 ethyl 3(3′ dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C. N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained from step VIII of example I was then added and mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to get the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]([F:18])([F:31])[F:30])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccccc3OC(F)(F)F)cc21

Procedure:
Compound 9A was prepared from Compound 1A using the procedure described in Example 1B, except using 2-trifluoromethoxy benzene boronic acid as the starting material. MS (electrospray): mass calculated for C21H22F3NO2, 377.16; m/z found m/z found, 378.2 [M+H]+.