Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][CH2:36][O:37][CH2:38][CH3:39]>Cl([O-])(=O)(=O)=O.[Ag+]>[CH2:36]([O:37][C@@H:38]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[C@H:35]([CH2:12][O:11][C:10](=[O:13])[CH3:9])[C@@H:15]([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:25][C@@H:39]1[O:25][C@@H:15]1[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:16]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:35]1[CH:31]=[CH:30][CH:29]=[CH:34][CH:33]=1
Reactant: CCOCC
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](COC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
Ethereal silver perchlorate (0.08 M, 9.58 mL, 7.67 mmol) is added with stirring at -30° C. to a solution of methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.592 g, 5.59 mmol), 2,3,6-tri-O-benzyl 1,4-dideoxy-4-acetyloxymethyl-D-glucopyranosyl chloride (3.661 g, 6.98 mmol) in ether (20 mL). The mixture is stirred 15 min at -30° C. and silver chloride precipitated. The mixture is filtered through a celite pad, the solids are washed with ether, the filtrate is concentrated under reduced pressure. The residue is dissolved in methylene chloride and the organic layer is washed successively with aqueous sodium thiosulfate and water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure so as to afford a foam. Flash chromatography on silica gel and elution with a graded mixture of hexane and ethyl acetate will afford methyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside as a foam.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([N:23]3[CH2:28]CNC[CH2:24]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([N:23]3[CH2:28][CH2:1][N:2]([CH2:4][C:5]4[C:13]5[C:8](=[N:9][CH:10]=[CH:11][CH:12]=5)[NH:7][CH:6]=4)[CH2:3][CH2:24]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: c1cc2cc(N3CCNCC3)ccc2[nH]1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: c1cnc2[nH]cc(CN3CCN(c4ccc5[nH]ccc5c4)CC3)c2c1
Yield: 31.8 %

Procedure:
A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.23 g, 1.33 mmol) and 1-(5-indolyl)piperazine (0.27 g, 1.34 mmol) in toluene (20 ml) was heated at reflux for 16 h under nitrogen. The mixture was allowed to cool and the solid present collected. Purification by flash chromatography, eluting with 90:8:1 dichloromethane/methanol/ammonia, twice gave the title compound (0.14 g, 32%) as a white solid. Recrystallisation from methanol afforded needles, m.p. 232.5°-233° C.; (Found: C, 72.14; H, 6.29; N, 21.07. C20H21N5.0.1H2O requires C, 72.09; H, 6.41; N, 21.02%); δH (DMSO-d6) 2.56 (4H, m, 2×piperazinyl CH2), 3.02 (4H, m, 2×piperazinyl CH2), 3.69 (1H, s, CH2N), 6.27 (1H, m, 3'-H), 6.83 (1H, dd, J 8.8, 2.1 Hz, 6'-H), 6.97 (1H, m, 2'-H), 7.05 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.22 (2H, m, 4'-H, 7'-H), 7.38 (1H, d, J 2.1 Hz, 2-H), 8.06 (1H, dd, J 7.8, 1.4 Hz, 4-H), 8.20 (1H, dd, J 4.6, 1.4 Hz, 6-H), 10.77 (1H, br s, NH), and 11.46 (1H, br s NH); m/z (CI+, NH3) 322 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4](/[CH:10]=[CH:11]/[CH2:12][CH:13]([OH:15])[CH3:14])[CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:15][CH:13]([CH2:12]/[CH:11]=[CH:10]/[C:4]2[CH2:3][N:2]([CH3:1])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=2)[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: COC1=CN(C)CC(/C=C/CC(C)O)=C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC1=CN(C)CC(/C=C/CC(C)OS(=O)(=O)c2ccc(C)cc2)=C1

Procedure:
In another embodiment, a compound such as (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-amine can be synthesized by coupling a halo-substituted pyridine, 5-bromo-3-methoxypyridine with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions; and the resulting pyridinyl alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine. Typically, the types of procedures set forth in W. C. Frank et al., J. Org. Chem. 43: 2947 (1978) and N. J. Malek et al., J. Org. Chem. 47: 5395 (1982) involving a palladium-catalyzed coupling of an olefin and an aromatic halide are used. The halo-substituted pyridine, 5-bromo-3-methoxypyridine is synthesized using methodology similar to that described by H. J. den Hertog et al., Rec. Trav. Chim. Pays-Bas 67:377 (1948), namely by heating 3,5-dibromopyridine with 2.5 molar equivalents of sodium methoxide in dry methanol in the presence of copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glass tube at 150° C. for 14 hours to produce 5-bromo-3-methoxypyridine. The resulting 5-bromo-3-methoxypyridine, previously described by D. L. Comins, et al., J. Org. Chem. 55: 69 (1990), can be coupled with 4-penten-2-ol in acetonitrile-triethylamine (1:1:1, v/v) using a catalyst consisting of 1 mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. The reaction is carried out by heating the components in a sealed glass tube at 140° C. for 14 hours to yield (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-ol. The resulting alcohol is treated with 2 molar equivalents of p-toluenesulfonyl chloride in dry pyridine at 0° C. to produce (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-ol p-toluensulfonate. The tosylate intermediate is treated with 120-molar equivalents of methylamine as a 40% aqueous solution, containing a small amount of ethanol as a co-solvent to produce (4E)-N-methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-amine. When 3,5-dibromopyridine is submitted to Heck coupling with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, under conditions described above, N-methyl-N-(tert-butoxycarbonyl)-5-(5-bromo-3-pyridinyl)-4-penten-2-amine is produced. This can be coupled in a subsequent Heck reaction with styrene and deprotected (removal of the tert-butoxycarbonyl group), as described previously, to give (4E)-N-methyl-5-[3-(5-trans-beta-styrylpyridin)yl]-4-penten-2-amine. Similar second coupling with ethynylbenzene, and subsequent deprotection, will give (4E)-N-methyl-5-[3-(5-phenylethynylpyridin)yl]-4-penten-2-amine.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[C:3](=[N:9][O:10][CH2:11][CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][CH2:14][C:2](=[O:1])[C:3](=[N:9][O:10][CH2:11][CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCCON=C(C(=O)CCl)C(=O)OCC
Temperature: 0 °C
Yield: 85.4 %

Procedure:
Ethyl 3-oxo-2-n-propoxyiminobutyrate (syn isomer) (15.4 g.) and sulfuryl chloride (10.6 g.) were dissolved in acetic acid (15.4 ml.), warmed at 35° to 40° C. for 10 minutes with stirring and then stirred at ambient temperature for additional 6 hours. The reaction mixture was poured into ice-water (200 ml.) and the resultant mixture was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, twice a saturated aqueous solution of sodium bicarbonate and once with water in turn, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 4-chloro-3-oxo-2-n-propoxyiminobutyrate (syn isomer) (15.4 g.), oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=O)[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[S:19]([NH2:22])(=[O:21])=[O:20]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[N:22][S:19]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])[CH:11]=1
Reactant: O=C1C=C(Cl)C(=O)c2ccccc21
Reactant: NS(=O)(=O)c1cccs1
Solvent: CCOC(C)=O
Product: O=C1C(Cl)=CC(=NS(=O)(=O)c2cccs2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
385.2 mg 2-chloro-1,4-naphthoquinone (11) was mixed with 326.4 mg thiophene-2-sulfonamide in 15 ml dichloromethylene, to which at 0° C. was added 2 ml TiCl4 dichloromethylene solution followed by 613.3 μl. The mixture was heated at 60° C. with M.W. for 15 min and the black mixture was poured into 100 ml ethyl acetate. The insoluble was removed by filtrate through a pad of celite. The filtrate was concentrated and the residue was suspended in dichloromethylene. The brown insoluble stuff was removed by filtration and the filtrate was again concentrated to dryness. The residue was suspended in ethyl acteate/hexane (1:1) and the yellow solid was filtered. The solid was washed with ethyl acteate/hexane (1:1) and dried over vacuum affording title compound 377.7 mg (55.9%) as a yellow solid. When TiCl4.2THF and THF were used instead, the reaction afforded the title compound 522 mg (77.3%) as a yellow solid, m.p.: 167-169° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:41])[CH2:3][CH2:4][CH:5]1OCC[O:37][CH:6]1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[C:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13]=1[C:14]([OH:16])=[O:15].O1CCCC1.Cl(O)(=O)(=O)=O>O>[OH:1][C@H:2]([CH3:41])[CH2:3][CH2:4][CH2:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[C:17]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: C[C@@H](O)CCC1OCCOC1CCC/C=C/c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)CCCC(=O)CCC/C=C/c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 20 g. of 2-(10(R)-hydroxy-6-ethylenedioxy-trans-undecenyl)-4,6-dibenzyloxybenzoic acid in 150 ml. of tetrahydrofuran is added, while cooling, 100 ml. of an aqueous solution containing 220 g. perchloric acid per liter. The mixture is stirred for 6 hours at room temperature, then poured into water and extracted with chloroform. The extract is washed with water and an aqueous solution saturated with sodium chloride and is dried over sodium sulfate. Upon removal of the solvents, 17.8 g. of oil containing 2-(10(R)-hydroxy-6-oxo-trans-undecenyl)-4,6-dibenzyloxybenzoic acid are obtained.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:32]=[CH:31][C:16]([CH2:17][CH2:18][N:19](C)[C:20](=O)OCC4C=CC=CC=4)=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[CH3:20][NH:19][CH2:18][CH2:17][C:16]1[CH:31]=[CH:32][C:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)=[CH:14][CH:15]=1
Reactant: CN(CCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNCCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1
Yield: 26 %

Procedure:
A mixture of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)phenethyl(methyl)carbamate (110 mg, 0.26 mmol), 10% Pd/C (20 mg) in methanol (20 ml) was stirred at room temperature over 1 atm hydrogen for 3 h. Then the mixture solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by prep-HPLC to give 2-(4-(2-(methylamino)ethyl)phenyl)benzo[d]oxazole-7-carboxamide (20 mg, yield 26%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.45 (s, 3H), 2.91-2.94 (m, 4H), 7.47-7.52 (m, 3 H), 7.88-7.92 (t, J=7.2 Hz, 2H), 8.26-8.28 (d, J=8.4 Hz, 2H). LC-MS (ESI) m/z: 296 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1C(=O)Cl

Procedure:
To a mixture of 2,6-dimethylbenzoic acid (3 g; 0.02 mol) in toluene (50 ml) was added thionyl chloride (3.6 ml; 0.05 mol). The mixture thus obtained was refluxed for 2 hours. The solvent and the excess thionyl chloride were then evaporated off under reduced pressure. The residue thus obtained was taken up in toluene (50 ml) three times and evaporated under reduced pressure. The product thus obtained (3.6 g) was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)([C:11]#[N:12])[CH3:10])[CH:7]=1.[C:30]([O-:33])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[C:26]([C:4]1[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])=[CH:17][CH:18]=2)([C:11]#[N:12])[CH3:10])[CH:7]=[C:2]([C:6]2[C:30](=[O:33])[NH:12][CH:11]=[CH:9][CH:8]=2)[CH:3]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: COc1c(CC(C)(C#N)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1c(CC(C)(C#N)c2ccc(NS(C)(=O)=O)cc2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Yield: 49 %

Procedure:
step 5—A sealed tube containing 288 (69 mg, 0.144 mmol), 112 (30 mg, 0.216 mmol), Pd(PPh3)4 (16 mg, 0.014 mmol), Na2CO3 (41 mg, 0.387 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was irradiated in a microwave reactor at 115° C. for 30 minutes. The reaction mixture was concentrated, diluted with EtOAc, washed with brine, and dried na2so4, filtered and concentrated. The crude product was purified on a SiO2 preparative TLC plate developed with 20% EtOAc/hexane to afford 33 mg (49%) of I-196 a white solid (49% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]([CH3:35])[CH2:32][CH2:33][NH2:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:34][CH2:33][CH2:32][N:31]([CH3:35])[C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: COc1ccc(N(C)CCN)cc1OC
Product: COc1ccc(N(C)CCNCCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 2-[N-(3,4-dimethoxyphenyl)-methylamino]-ethylamine analogously to Example 6.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:11]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16].O>ClC(Cl)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:9][C:10]1[C:11]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(CBr)c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A mixture of N-bromosuccinimide (464 mg, 2.61 mmol), 2,2′-azobis(2-methylpropionitrile) (16 mg, 0.10 mmol) and methyl 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinate (500 mg, 2.01 mmol, Step-1) in dichloroethane (10 mL) is stirred at 85° C. for 4 hours. After cooling to room temperature, the reaction mixture is poured into water extracted with dichloroethane and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-Hexane/ethyl acetate (10:1) to give 658 mg (>99% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:6]([CH3:30])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:6]([CH3:30])=[N:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][S:19]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=3)=[O:40])=[CH:16][CH:17]=2)[C:9]=1[CH3:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(CSc3ccc(C(F)(F)F)cc3)cc2)c1C
Solvent: ClCCl
Product: COC(=O)Cc1c(C)nn(Cc2ccc(CS(=O)c3ccc(C(F)(F)F)cc3)cc2)c1C
Reaction time: 1 h

Procedure:
{3,5-Dimethyl-1-[4-(4-trifluoromethyl-phenylsulfanylmethyl)-benzyl]-1H-pyrazol-4-yl}-acetic acid methyl ester (intermediate 16.1.3, 170 mg, 0.38 mmol) was dissolved in 3 ml dichloromethane and 3-chloroperbenzoic acid (79 mg, 0.45 mmol) was added at 5° C. After 1 h at that temperature, the mixture was diluted with dichloromethane and washed with aqueous NaHCO3 solution. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:9]=1)=[O:7])[CH3:4].[OH-].[K+].[CH2:38]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[CH3:38][O:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:9]=1)=[O:7])[CH3:4]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide (44 mg, 0.085 mmol) was dissolved in THF (0.85 ml) to give a colorless solution. The reaction was cooled in an ice bath. Crushed KOH (64 mg, 1.14 mmol), catalytic 18-crown-6, and iodomethane (9 μl, 0.147 mmol) were added successively to the cooled solution. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-100% EtOAc) to afford 22 mg (49%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a white solid. MS: [M+Na]+=551.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C=O>>[C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:17])[CH:13]([CH2:24][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:14]([CH3:15])[CH3:16])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: CC(C)CC(=O)c1cc(-c2ccccc2)no1
Agent: C=O
Agent: Cl
Product: CC(C)C(CN1CCCC1)C(=O)c1cc(-c2ccccc2)no1

Procedure:
From 1.5 g (6.6 mmol) of 3-phenyl-5-(3-methylbutyryl)isoxazole prepared above in the procedure (2), 0.84 g (7.9 mmol) of piperidine hydrochloride, and 0.26 g (8.7 mmol) of paraformaldehyde, the free base of 3-phenyl-5-{2-(1-pyrrolidinylmethyl)-3-methylbutyryl}isoxazole was obtained as crystals in a manner similar to Example 28.
Reaction SMILES: [CH3:1][C:2](=[N:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:3].[H][H]>[Pd].C(O)(=O)C.CO>[CH:2]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])([CH3:3])[CH3:1]
Reactant: CC(C)=NNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NNC(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2-isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:47]4[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][OH:41])[CH2:45][CH2:46]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CN4CCN(CCO)CC4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 36.4 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), N-(2-hydroxyethyl)piperazine (0.035 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 14 h. Additional portions of N-(2-hydroxyethyl)piperazine (0.010 g, 0.077 mmol) and sodium triacetoxyborohydride (0.020 g, 0.094 mmol) were added and the reaction mixture was shaken for 16 h. 1N NaOH (1.5 mL) was added and the precipitate was collected by filtration and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 10-60% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 21.9-22.9 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[4-(2-hydroxyethyl)piperazino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.034 g, 0.051 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.35-8.37 (2H, m), 8.15 (2H, d, J=8.8 Hz), 8.00 (1H, t, J=8.0 Hz), 7.90 (1H, d, J=10.4 Hz), 7.75 (1H, d, J=8.0 Hz), 7.49 (1H, s), 7.46 (2H, d, J=7.2 Hz), 7.40 (1H, d, J=8.4 Hz), 3.96 (3H, s), 3.51 (2H, s), 3.46-3.49 (4H, m), and 2.35-2.44 (8H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.92 min. MS: MH+ 664.7.