Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>ClCCl>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1[Br:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]ncc2c1cc(Br)n2COCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncc2c(cc(Br)n2COCc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To 300 ml of dichloromethane solution containing 33.4 g (0.100 mol) of 1-benzyloxymethyl-2-bromo-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 17-(d) was added 25.8 g (0.200 mol) of N,N-diisopropylethylamine, and 25.0 g (0.15 mol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture under ice-cooling. After completion of the dropwise addition, the mixture was stirred at 40° C. for 3 hours. After completion of the reaction, the reaction mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the obtained concentrate was added 300 ml of cyclohexane, and precipitated solid was collected by filtration. The obtained solid was washed with cyclohexane, and dried under reduced pressure to obtain 33.1 g of the title compound as a beige solid. (Yield: 71%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][S:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])[C:5](Cl)=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>COCCOC>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:5]2[C:4]([C:9]3[N:10]=[CH:11][S:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[Cl:21])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:26][CH:25]=1
Reactant: Clc1cccc(-c2scnc2-c2cc(Br)cnc2Cl)c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: COCCOC
Product: COc1ccc(CNc2ncc(Br)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Yield: 85 %

Procedure:
A solution of 5-bromo-2-chloro-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridine (520 mg, 1.24 mmol) and p-methoxybenzyl amine (373 mg, 2.72 mmol) in DME (12 mL) was stirred at 80° C. for 48 hours. The reaction mixture was concentrated and the residue purified by silica gel chromatography (0-25% EtOAc/hexanes) to give N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine as a pale yellow solid [631 mg, 85% yield; LC-MS, M+H=519.9; 1H-NMR (300 MHz, CDCl3) 8.85 (1 H, s), 8.00 (1 H, d, J=2.3 Hz), 7.45 (1H, dd, J=1.9, 7.6 Hz), 7.10-7.17 (4 H, m), 7.01 (1 H, d, J=2.4 Hz), 6.77 (1 H, t, J=6.7 Hz)].
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][C@@H:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]4[F:30])[C:12]4[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:11]=4[C:10]=3[C:9](=[O:36])[NH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1.CC(O)C>[CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][C@@H:17]4[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]4[F:30])[C:12]4[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:11]=4[C:10]=3[C:9](=[O:36])[NH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2nc3c(C#CC4CC4)c[nH]c(=O)c3c3cc(F)ccc23)[C@H](F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=c1[nH]cc(C#CC2CC2)c2nc(N[C@@H]3CCNC[C@H]3F)c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl trans-4-{[4-(cyclopropylethynyl)-9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-6-yl]amino}-3-fluoropiperidine-1-carboxylate (160 mg, 0.324 mmol) in THF (5 mL) under a nitrogen atmosphere was added HCl (4.0 M in 1,4-dioxane) (2 mL, 8.0 mmol), and the reaction was left stirring for two days at room temperature. The reaction mixture was then added to a separatory funnel containing 3:1 CHCl3:2-propanol and saturated aqueous NaHCO3. The phases were separated, and the organic layer was washed with water, then brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product mixture was purified by silica gel chromatography (0-10% CH3OH in CH2Cl2), followed by trituration with methanol afforded the title compound 4-(cyclopropylethynyl)-9-fluoro-6-[(trans-3-fluoropiperidin-4-yl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. LRMS (APCI) calc'd (C22H20F2N4O3) [M+H]+, 395.2; found 395.1. 1H NMR (500 MHz, DMSO-d6) δ 11.51 (d, 1H), 9.57 (dd, 1H), 8.51 (dd, 1H), 8.19 (d, 1H), 7.57 (d, 1H), 7.53 (dt, 1H), 4.80-4.64 (m, 2H), 3.35 (m [under H2O], 1H), 2.97 (d, 1H), 2.55 (t, 2H), 2.12 (m, 1H), 1.56 (m, 1H), 1.50 (m, 1H), 1.15 (m, 1H), 0.89 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:21])([CH:19]=[CH2:20])[CH3:18])[CH3:13])[CH3:8])[CH3:3].[CH3:22][C:23]1[C:24]([OH:32])=[C:25]([CH3:31])[C:26]([CH3:30])=[C:27]([CH:29]=1)O.FC(F)(F)C(O)=O.O>CCCCCC>[CH3:31][C:25]1[C:24]([OH:32])=[C:23]([CH3:22])[C:29]2[CH2:20][CH2:19][C@:17]([CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])([CH3:18])[O:21][C:27]=2[C:26]=1[CH3:30]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Solvent: CCCCCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Isophytol (98%, 25.5 g.) was added, dropwise, over three hours to a mixture of trimethylhydroquinone (14.5 g.), trifluoroacetic acid (65 ml.) and water (10 ml.). The product was diluted with hexane (200 ml.), washed with methanol-water (1:1, v:v)(3×100 ml.) and saturated aqueous sodium bicarbonate solution (100 ml.). A 1% by weight solution of potassium hydroxide in methanol (100 ml.) was added and the mixture was stirred at room temperature for 30 minutes. Then 2N aqueous hydrochloric acid (100 ml.) was added, the organic phase was separated, washed with saturated aqueous sodium bicarbonate solution (100 ml.) and methanol-water (1:1, v:v) (100 ml.). The hexane was removed by concentrating on a rotary evaporator and the resulting oil was flashdistilled to give α-tocopherol (29.6 g.; bp 220° C./0.1 mm.). Purity by area % glc was 100%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>O1CCCC1.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:6][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
Under argon condition, 4-bromobenzoic acid methyl ester (500 mg, 2.33 mmol), bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2; 86.1 mg, 0.116 mmol), triphenylphosphine (PPh3; 18.3 mg, 0.0698 mmol), trimethylsilyl acetylene (TMS acetylene; 493 μL, 3.49 mmol), and triethylamine (Et3N; 486 μL, 3.49 mmol) were dissolved in 10 mL of well-dried tetrahydrofuran (dry THF) and stirred for 20 minutes at room temperature. To this was added again cuprous iodide (CuI; 8.86 mg, 0.0465 mmol) and the reaction mixture was stirred for 15 hours at room temperature. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure, and 20 mL of n-pentane was added to the residue. The mixture was filtered through celite pad to remove the precipitate. The resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 503 mg (2.16 mmol, 93%) of the desired compound.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C(O[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH3:23])C.[C:24]([O-:27])([O-])=O.[K+].[K+].F[C:31](F)(F)[C:32](O)=O>>[CH2:31]([C:18]1[CH:19]=[C:14]([CH:24]=[O:27])[C:15]([O:22][CH3:23])=[CH:16][C:17]=1[O:20][CH3:21])[CH3:32]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1ccc(OC)cc1OC
Reactant: O=C([O-])[O-]
Agent: C1N2CN3CN1CN(C2)C3
Agent: [K+]
Product: CCc1cc(C=O)c(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.7 %

Procedure:
To a solution of hexamethylenetetramine (HMTA)(6.75 g, 48.1 mmol) in trifluoroacetic acid (TFA)(40 ml) heated at reflux was added a solution of 4-ethoxy-1,3-dimethoxybenzene, (4.0 g, 24.1 mmol) in TFA (40 ml) dropwise over 90 min. The reaction mixture was heated at reflux for 2 h. The dark solution was concentrated in vacuo with mild heating leaving a dark red syrup. Ice water was added to the syrup until it became cloudy, then stirred at room temperature for 20 min. The mixture was basified with solid K2CO3, then stirred at room temperature for 20 min, and extracted with CH2Cl2 (200 ml×4). The combined CH2Cl2 solution was washed with water and brine, dried over MgSO4, and concentrated in vacuo to give a crude title compound (4.46 g) as a orange solid. The crude product was recrystallized from hexane-ethyl acetate to give title compound (2.51 g, 53.7%) as a pale yellow solid. 1H-NMR δ: 10.30 (s, 1H), 7.63 (s, 1H), 6.40 (s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 2.56 (q, J=7.3 Hz, 2H), 1.16 (t, J=7.3 Hz, 3H) IR(KBr, cm-1): 1662, 1610, 1578, 1505, 1488, 1477, 1457, 1437, 1408, 1354, 1320, 1279, 1261, 1216, 1189, 1111, 1025, 908, 825, 697.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2([CH2:13][CH2:14][O:15][CH3:16])[CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH2:13][CH2:14][O:15][CH3:16])[CH3:12]
Reactant: COCCC1(C)C(=O)Nc2ccc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCCC1(C)CNc2ccc(F)cc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 0.12 g (0.54 mmol) 5-fluoro-3-(2-methoxy-ethyl)-3-methyl-1,3-dihydro-indol-2-one were placed in 20 mL THF. 0.56 mL (0.56 mmol) of a 1M lithium aluminium hydride solution in 10 mL THF were added dropwise. The reaction mixture was stirred for 1 h at 70° C., then mixed with water and dried, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:30]=[CH:29][C:21]([C:22](OC(C)(C)C)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>FC(F)(F)C(O)=O.ClCCl>[CH3:5][CH:4]([NH:3][C:22](=[O:23])[C:21]1[CH:29]=[CH:30][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([N:3]3[C:4]4[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=4[CH2:6][O:7][C:2]3=[O:1])[CH2:17][CH2:16]2)=[CH:19][CH:20]=1)[CH3:11]
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from step (i) (0.29 g) in a mixture of trifluoroacetic acid (10 ml) and dichloromethane (10 ml) was stirred at room temperature for 1 h. The solution was evaporated under reduced pressure, the residue dissolved in N,N-dimethylformamide then bromo-tris-pyyrolidino-phosphonium hexafluorophosphate (0.16 g), isopropylamine (0.06 ml) and N,N-diisopropylethylamine (0.06 ml) added. The solution was stirred at room temperature for 16 h then evaporated under reduced pressure. Purification was by chromatography eluting with (1:5) ethyl acetate/dichloromethane. Yield 0.01 g as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[Cl:1][C:2]1[C:3]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Cl)c(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 6 h
Yield: 63.3 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (50 g, 289.74 mmol) in AcOH (200 ml) was added NIS (63 g, 280.02 mmol) with stirring overnight at room temperature. Then the solids were collected by filtration and washed with water (50 ml). The solid was dried in an oven under reduced pressure to afford 5-chloro-4-iodo-2-nitroaniline as a yellow solid (70 g, 81%). Next, to a solution of 5-chloro-4-iodo-2-nitroaniline (15 g, 50.26 mmol) in dioxane (200 ml) and water (20 ml) was added (4-chlorophenyl)boronic acid (15.7 g, 100.40 mmol), K3PO4 (21.2 g, 99.87 mmol) and Pd(PPh3)4 (3 g, 2.60 mmol) with stirring for 6 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to afford 5-chloro-4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (9 g, 63%). To a solution of 5-chloro-4-(4-chlorophenyl)-2-nitroaniline (12 g, 42.39 mmol) in ethanol (150 ml) was added hydrogen chloride (conc, 10 ml) to this was followed by the addition of Zn powder (16.6 g, 253.34 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. Then the resulting mixture was concentrated under vacuum, dissolved in water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (8.7 g, 81%). Finally, a solution of 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine (7 g, 27.65 mmol) in heptafluorobutanoic acid (70 ml) was stirred for 1.5 h at 120° C. Then the mixture was poured into water (200 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford 5-chloro-6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as an off-white solid (7.3977 g, 62%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[N:11]=1>O>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Solvent: O
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc([N+](=O)[O-])cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
740 mg of trans-1,4-diaminocyclohexane is taken to approximately 150° C. then 466 mg of the product obtained in Stage 1 above is added, the reaction medium is maintained under agitation at 140° C. for 6 hours then left to return to ambient temperature. Then 15 ml of water is added, followed by extracting with dichloromethane, drying and evaporating the solvent. The residue is chromatographed on silica (eluent: MeOH/NH4OH 98/2), 270 mg of the product obtained is removed and taken up in 10 ml of ethanol, 6 ml of an ethanolic solution of hydrochloric acid is added, followed by separating, washing with ether, drying under reduced pressure at 60° C. and 79 mg of expected product is recovered.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:19]=[C:20]([Si:24]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Br:43])[CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:43][C:39]1[CH:38]=[C:37]([Si:24]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:36]=2)([C:20]2[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture solution of dibenzo[b,d]thiophen-4-boronic acid (1.84 g, 8.04 mmol), bis(3-bromophenyl)diphenylsilane (9.97 g, 20.17 mmol), Pd(PPh3)4 (0.19 g, 0.16 mmol) and potassium carbonate (6.69 g, 48.4 mmol,) in toluene (60 mL) and water (20 mL) was heated at 100° C. under nitrogen overnight. After cooling to room temperature, the reaction mixture was quenched with water, extracted with DCM, washed with brine and water, and dried over Na2SO4. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM (9.5:0.5 to 9:1, v/v) as eluent. The crude product was dissolved in DCM, precipitated with methanol, and filtered to yield (3-bromophenyl)(3-(dibenzo[b,d]thiophen-4-yl)phenyl)diphenylsilane (3.0 g, 62%) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)=O)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20].Cl.Cl.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][NH2:34])[CH:29]=[N:30][CH:31]=1.CCN(C(C)C)C(C)C>CS(C)=O>[OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:34][CH2:33][CH2:32][C:28]3[CH:29]=[N:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=3)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20]
Reactant: CS(=O)c1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Reactant: COc1cncc(CCN)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cncc(CCNc2ncc(C#N)c(N[C@@H]3CC[C@H](O)C(C)(C)C3)n2)c1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
A 1 dram vial equipped with a septum cap was charged with 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile (55.0 mg, 0.178 mmol), 2-(5-methoxypyridin-3-yl)ethan-1-amine dihydrochloride (56.3 mg, 0.214 mmol) and DMSO (1.4 mL). The resulting solution was treated with DIEA (0.125 mL, 0.715 mmol), and the vial was sealed and shaken (250 rpm) at 60° C. for 14 h. The mixture was cooled to room temperature, diluted with DMSO (1.5 mL), and filtered. The solution was purified by standard methods to provide the title compound. MS (ESI) m/z 379.2 [M+1]1.
Reaction SMILES: [F:1][C:2]([F:21])(SC)[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.OO.[S:24]([O-:28])([O-])(=[O:26])=S.[Na+].[Na+].[CH3:31]O>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:21][C:2]([F:1])([S:24]([CH3:31])(=[O:28])=[O:26])[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: CO
Reactant: O=S([O-])([O-])=S
Reactant: CSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CS(=O)(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
To a 10 ml solution of 0.50 g (1.6 mol) of 3,3-difluoro-2-(2',4'-difluorophenyl)-3-methylthio-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol [Compound (1a-1)] in methanol, 0.01 g (0.03 mmol) of sodium tungstate dehydrate was added, followed by the dropwise addition of 0.53 g (4.7 mmol) of a 30% aqueous solution of hydrogen peroxide at room temperature under stirring. The resulting mixture was stirred at room temperature for 16 hours. To the reaction mixture, a 10% aqueous solution of sodium thiosulfate was added to decompose an excess oxidizing agent. Methanol was then distilled off under reduced pressure. To the residue, chloroform was added, followed by washing successively with water and saturated saline and drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The crystals so precipitated were recrystallized from chloroform, whereby 8.0 g of the title Compound (1c-1) were obtained in the form of colorless crystals (yield: 74%).
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[O:18][CH3:19])[C:6](=O)[CH3:7])C.Cl.[CH3:22][C:23]1[CH:24]=[C:25]([NH:30][NH2:31])[CH:26]=[CH:27][C:28]=1[CH3:29].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=3[O:18][CH3:19])[C:6]([CH3:7])=[N:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(NN)cc1C
Reactant: CCOC(=O)C(=NNc1cccc(Br)c1OC)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(Br)cccc1NN=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C

Procedure:
A solution of ethyl-2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate (5 g) prepared as in Example 1, and 3,4-dimethylphenylhydrazine hydrochloride (2.48 g) and sodium acetate (1.4 g) in glacial acetic acid (100 mL) was stirred and heated to reflux for about 3 hours. The mixture was cooled to about room temperature and stirred for about 1 hour. It was filtered, washed with water (25 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours to obtain an orange solid product. Yield: 4.15 g; Melting point: 197.4-198.2° C.; Purity (HPLC): 99.33%
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[C:22](OCC)(=[O:25])[CH:23]=[CH2:24]>CCO.C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:24][CH2:23][C:22](=[O:25])[NH:17]2)=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: C=CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCN(c2ccc(OCc3ccccc3)cc2)N1
Temperature: 85 °C

Procedure:
To a mixture of 2.5 g of 4-benzyloxyphenylhydrazine HCl and sodium ethoxide (1.6 g) in 10 ml of EtOH and 10 ml of toluene are added 1.08 of ethyl acrylate at room temperature. The reaction mixture is then heated at 85° C. overnight. The reaction mixture is evaporated to dryness under vacuum and water added to the residue and the pH adjusted to pH 6 by 1N-HCl solution. Extraction with ethyl acetate and drying the organic solution and evaporating to dryness yields 2.8 g of crude product. Purification by dry column chromatography gives 0.3 g of product; mp. 130°-134° C.