Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16](=[C:20]([Cl:22])[Cl:21])[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:17]([C:16]([Cl:15])=[C:20]([Cl:22])[Cl:21])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N(NC(=O)C(Cl)=C(Cl)Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-t-butyl-1-benzoylhydrazine (1.5 g, 0.008M) in methylene chloride at 5° C. was added, simultaneously and separately, trichloroacryloylchloride (1.7 g, 0.009M) and triethylamine (0.9 g, 0.009M). After addition, the reaction was warmed to room temperature and stirred for 3 h. The flask's contents were diluted with 50 ml methylene chloride and washed with water (3×75 ml) and brine solution (1×75 ml). The organic layer was dried over magnesium sulfate and the solvent removed under vacuum to afford N'-t-butyl-N-(1,2,2-trichlorovinyl)carbonyl-N'-benzoylhydrazine as a white solid product.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:24])[N:17]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH2:27][CH2:26]3)[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:23]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(O)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of trans-3-[4-(benzyloxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.806 g, 1.62 mmol) in absolute ethanol (40 mL) was treated with palladium 10 wt. % on activated carbon (0.161 g, 0.324 mmol) and ammonium formate (0.511 g, 8.1 mmol). The reaction mixture was stirred at 80° C. for 3 h, very little product was seen by thin layer chromatography. Palladium 10 wt. % on activated carbon (0.161 g, 0.324 mmol) was added and stirred for an additional hour, still very little product detected. Ammonium formate (0.204 g, 3.24 mmol) was added and stirred over night. The reaction mixture was filtered through a pad of celite, which was washed with ethanol (500 mL). The organic layer was removed under reduced pressure. The resulting solid was triturated with ethyl acetate, and dried over night under high vacuum to give 0.491 g (75%) of trans-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol. 1H NMR (DMSO-d6, 400 MHz) δ 9.74 (s, 1H), 8.2 (s, 1H), 7.46-7.44 (d, 2H, J=8 Hz), 6.92-6.90 (d, 2H, J=8 Hz), 4.64-4.58 (m, 1H), 2.67-2.50 (m, 5H), 2.39-2.34 (m, 4H), 2.17 (s, 3H), 2.06-1.92 (m, 6H), 1.50-1.42 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 3.337 min (96%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C1COCC1.CCOCC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:16])([CH3:17])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(I)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To 2-bromo-5-iodo-pyridine (2.974 g, 10.2 mmol) in a mixture of THF (15 mL) and ether (20 mL) at −78° C. is added dropwise n-butyl lithium (2.5 M in hexane, 4 L, 10.2 mmol). The mixture is stirred at −78° C. for 30 min, then acetone (anhydrous, 0.749 uL, 10.2 mmol) is added drop wise. The mixture is slowly warmed up to −50° C. over 1.5 h and is quenched with saturated ammonium chloride, extracted with ethyl acetate. The organic phase is separated, dried and rotavaped. The residue is purified by silica gel chromatography (10-20% ethyl acetate in heptane) to give the title compound as white solid (1.40 g, 64%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].Cl[C:15]([O:17][C:18]([CH3:20])=[CH2:19])=[O:16]>CCOC(C)=O>[CH2:19]=[C:18]([O:17][C:15](=[O:16])[NH:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[CH3:20]
Reactant: NC1CCOCC1
Reactant: C=C(C)OC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)NC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A biphasic mixture of 4-aminotetrahydropyran hydrochloride (1.0 g, 7.27 mmol) in EtOAc (20 mL) and satd. NaHCO3 (20 mL) was treated with isopropenyl chloroformate (0.874 mL, 7.99 mmol), stirred at RT for 2 h and the layers separated. The aqueous layer was extracted with EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl(tetrahydro-2H-pyran-4-yl)carbamate (1.2 g, 89%). 1H NMR (400 MHz, DMSO-d6): δ 7.48 (d, J=7.7 Hz, 1 H), 4.57 (d, J=7.9 Hz, 2 H), 3.80-3.78 (m, 2 H), 3.51-3.40 (m, 1 H), 3.33-3.25 (m, 2H), 1.83 (s, 3 H), 1.69 (m, 2 H), 1.43-1.32 (m, 2H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[NH:14][N:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1)=O)(C)(C)C.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[NH2:8][CH2:9][C:10]1[NH:14][N:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]
Reactant: CCOC(=O)c1n[nH]c(CNC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1n[nH]c(CN)n1
Reaction time: 1 h

Procedure:
Ethyl 5-((tert-butoxycarbonylamino)methyl)-1H-1,2,4-triazole-3-carboxylate (100 mg, 0.37 mmol) [Borg, S. et al., J. Org. Chem., 60:3112-3120 (1995)] was dissolved in CH2Cl2 (2 mL) and TFA (1 mL). After 1 h, this was concentrated to give ethyl 5-(aminomethyl)-1H-1,2,4-triazole-3-carboxylate, TFA (Int-XIV, 95 mg, 0.33 mmol, 90%); LCMS=171.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 4.45 (2 H, q, J=7.12 Hz), 4.35 (2 H, s), 1.40 (3 H, t, J=7.15 Hz).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl.[H][H].CCOCC>C(O)C.CO.[Pd]>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[CH:30][CH:31]=1
Reactant: c1ccc(COc2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: Oc1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 1-[2-(4-benzyloxyphenoxy)ethyl]-4-benzylpiperidine hydrochloride (401 mg, 1.0 mmol) in 25 mL of ethanol was added 1.0 mL of 1 M HCl in methanol and 100 mg of 10% Pd/C. The resulting mixture was hydrogenated at 30 psi of hydrogen for 2 h. The catalyst was removed through a short column of celite (5 g) and washed with methanol (3×15 mL). The combined flitrate was evaporated in vacuo to give an oil and then ether (30 mL) was added to the residue. The resulting mixture was allowed to stir at rt overnight. The white solid was collected by filtration and dried in vacuo, giving 330 mg (100%) of the title product. mp 212-215° C. 1H NMR (CDCl3 +DMSO-d3) 1.656 (m, 3 H), 1.829 (m, 2 H), 2.425 (s, 2 H), 2.626 (m, 2 H), 3.187 (m, 2 H), 3.4 (brs, 1 H), 4.253 (s, 2 H), 6.549 (m, 4 H), 6.942-7.092 (m, 5 H), 12.0 (brs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([C:19](=O)[CH3:20])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([CH:19]([NH2:28])[CH3:20])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-1-(3-fluorophenyl)-2-naphthyl]ethanone (58 mg, 0.19 mmol) and ammonium acetate (150 mg, 1.94 mmol) in methanol (1.1 mL) and acetonitrile (1.1 mL) was heated at 65° C., in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (24.4 mg, 0.388 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was used directly in the next step (58 mg, 100%). LCMS calculated for C18H13ClF (M−NH2)+: m/z=283.1; Found: 283.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:19]([O:21][P:22]([O-:26])[O:23][CH2:24][CH3:25])[CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9]([CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:22](=[O:26])([O:23][CH2:24][CH3:25])[O:21][CH2:19][CH3:20])=[CH:3][CH:4]=1)=[O:10]
Reactant: CCOP([O-])OCC
Reactant: COC(=O)C(c1ccccc1)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)OC)c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of compound Methyl 2-(4-bromophenyl)-2-phenylacetate, 14-d, (1.52 g, 5.0 mmol), diethylphosphite (2.42 g, 17.5 mmol) and triethylamine (3.13 g, 31 mmol) in toluene (20 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dicholoropalladium (100 mg). The mixture was allowed to stir overnight at 110° C. and filtrated. The solution was concentrated to afford the crude product which was purified by column chromatography to give compound 14-e as colorless oil (1.7 g, 94%). 1H NMR (300 MHz, CDCl3) δ1.29-1.35 (m, 6H), 3.73 (s, 3H), 4.10-4.13 (m, 4H), 5.03 (s, 1H), 7.23-7.40 (m, 7H), 7.69-7.77 (m, 2H). LC-MS: (M+H)+ 363.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:16].C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[NH:16][C:15]1[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:22])=[O:21]
Reactant: Cc1ccc2ccccc2c1Br
Reactant: Nc1ccccc1C(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc2ccccc2c1Nc1ccccc1C(=O)O

Procedure:
As pointed above, in Monatsh, 71, pages 122-127 (1937), W. Knap reports that when 1-bromo-2-methylnaphthalene and anthranilic acid were heated in the presence of copper powder and potassium carbonate in nitrobenzene (boiling at 210° C.) to the boiling point of nitrobenzene, N-(2-methyl-1-naphthyl)-anthranilic acid was obtained in the form of a grayish yellow crystal having a melting point of 215°-216° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1>O1CCCC1>[N:9]1([C:4]2[N:5]=[C:6]([N:9]3[CH:13]=[CH:12][CH:11]=[N:10]3)[CH:7]=[CH:2][N:3]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1cn[nH]c1
Solvent: C1CCOC1
Product: c1cnn(-c2ccnc(-n3cccn3)n2)c1
Yield: 84.4 %

Procedure:
In anhydrous tetrahydrofuran, 149 mg of 4,6-dichloropyrimidine was substituted with 136 mg of pyrazole. The reaction mixture was treated according to the procedure of Example 1 to yield 179 mg of 2,4-bis(1-pyrazolyl)pyrimidine, recrystallized from n-hexane, the compound had a melting point of 152°-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([O:13][C:14](=[O:35])[N:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][N:23]2[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)=[CH:19][CH:18]=1)[CH3:16])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)C>[C:9]([O:13][C:14](=[O:35])[N:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])=[CH:22][N:23]2[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)=[CH:19][CH:18]=1)[CH3:16])([CH3:12])([CH3:10])[CH3:11]
Reactant: Sc1ccccc1Br
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2ccn(Cc3cc(F)cc(F)c3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ccc2c(Sc3ccccc3Br)cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
—Sulfuryl chloride (1.08 ml, 13.4 mmol) was added to a solution of 2-bromobenzenethiol (1.27 g, 6.69 mmol) in dichloromethane (45 ml). The reaction mixture was stirred at room temperature for 15 min. and concentrated under reduced pressure. The resulting material was dissolved in diethyl ether and added dropwise to a solution of [1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (Example 6, method 1, step i; 2.50 g, 6.71 mmol) in diethyl ether (45 ml). The reaction mixture was stirred for 3.5 h and then poured into a saturated aqueous solution of sodium hydrogencarbonate. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 9:1→8:2) afforded [3-(2-bromo-phenylsulfanyl)-1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (3.02 g).
Reaction SMILES: C(O[C:6]([N:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][C:19]2[C:23]3[CH:24]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=[CH:27][C:22]=3[O:21][C:20]=2[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)=[O:33])=[O:17])[CH2:12][CH2:11]1)C)=O)(C)(C)C.Cl>O1CCOCC1.C(OCC)C>[ClH:41].[CH3:31][O:30][C:28]([C:25]1[CH:26]=[CH:27][C:22]2[O:21][C:20]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=3)=[O:33])=[C:19]([NH:18][C:16]([C@H:13]3[CH2:12][CH2:11][C@H:10]([NH:8][CH3:6])[CH2:15][CH2:14]3)=[O:17])[C:23]=2[CH:24]=1)=[O:29]
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)OC)cc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trans-3-[4-(N-t-butoxycarbonyl-N-methylamino)cyclohexylcarbonylamino]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (4.60 g) obtained in Example 202 is dissolved in dioxane (20 ml), and thereto is added 4N hydrogen chloride in dioxane (10 ml), and the mixture is stirred at room temperature for 48 hours. The reaction solution is diluted with diethyl ether, and the precipitates are collected by filtration, washed several times with diethyl ether and dried to give the title compound (4.02 g).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:29][C:30]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[F:29][C:30]1([F:35])[CH2:34][CH2:33][N:32]([C:2]2[C:21]([C:22]3[CH:27]=[N:26][CH:25]=[N:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:17])([F:19])[F:18])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:31]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(F)(F)C2)c(-c2cncnc2)c1
Temperature: 140 °C
Reaction time: 23 h

Procedure:
6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 100 mg, 0.253 mmol) was suspended in iPrOH (0.5 mL). 3,3-Difluoropyrrolidine hydrochloride (72.7 mg, 0.507 mmol) and DIPEA (0.177 mL, 1.013 mmol) were added at RT. The light brown solution was stirred at 140° C. for 23 h. The RM was diluted with EtOAc (50 mL) and washed with a 2 N citric acid solution (20 mL) and water (3×20 mL). The combined aq. phases were extracted with EtOAc and the combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure to give the crude material that was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/EtOAc 7:3). The resulting product was dissolved in MeOH (2 mL). The resulting white suspension was stirred at RT for 15 min then filtered. The solid was washed with MeOH (5 mL) and dried to afford the title product as a white solid. HPLC (Condition 10) tR=7.017 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=466.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.39 (spt, J=7.04 Hz, 2H) 3.37 (t, J=7.23 Hz, 2H) 3.62 (t, J=13.10 Hz, 2H) 7.37 (d, J=8.99 Hz, 2H) 7.82-7.89 (m, 2H) 8.15-8.19 (m, 1H) 8.82-8.85 (m, 1H) 8.94 (d, J=0.78 Hz, 2H) 9.23 (s, 1H) 10.27 (s, 1H).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.S([O-])([O-])(=O)=O.[OH:17][NH3+:18].O[NH3+]>O>[OH:17][N:18]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: [NH3+]O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1O
Temperature: 130 °C

Procedure:
0.15 g (1.0 mmol) of phthalic anhydride was mixed with 0.2 to 1 equivalent of hydroxylammonium sulfate (see Table 1) and, optionally after the addition of water (see Table 1), heated to 130° C. in a sealed ampoule. The reaction times were varied for the individual mixtures in accordance with Table 1. The cooled reaction mixture was dissolved in d6-DMSO and analyzed using 1H-NMR spectroscopy. The yields are given in each case in Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1.[H-].[Na+].[CH3:22]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1
Reactant: Cn1cc(C(=O)Cc2ccc(Br)cc2Cl)ccc1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of the 5-[2-(4-bromo-2-chloro-phenyl)-acetyl]-1-methyl-1H-pyridin-2-one obtained in step 1 (583 mg) in tetrahydrofuran (12 ml) was added sodium hydride (60% dispersion in mineral oil, 72 mg). The mixture was stirred at room temperature for 2 h and at 40° C. for 30 min. The mixture was cooled in an ice bath. Methyl iodide (267 mg) was added dropwise. After 10 min the ice bath was removed and the mixture was stirred at room temperature for 4 h. Sodium hydride (60% dispersion in mineral oil, 35 mg) and methyl iodide (121 mg) were added and the mixture was stirred overnight at room temperature. The reaction was quenched with ice water and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 7:3=>0:1) to give the title compound (353 mg) as a colorless foam. MS (m/e, ISP neg. ion)=352.0 [M−H+].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25]CCO)=[CH:21][CH:20]=1.C(O)C>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:25][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCCCc1ccncc1
Reactant: CCOC(=O)CC(=O)COCCN1CCCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccncc1
Reaction time: 18 h
Yield: 165.4 %

Procedure:
A solution of ethyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (6.46 g, 25.20 mmol) and 3-(4-pyridyl)propanol (1.9 ml, 14.49 mmol) was heated in toluene (500 ml), with azeotropic removal of ethanol, for 4 h. The solution was allowed to cool with stirring for 18 h and was then concentrated to give the title compound (8.35 g). Electrospray MS m/z 349 [M+H]+.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1)(=[O:21])[CH3:20]
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Reactant: CC(=O)O
Product: CC(=O)OCC(O)COc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 100 °C

Procedure:
A suspension of 6-(2,3-epoxypropoxy)benzothiazole-2-sulfonamide (1.57 gm, 5.5 mmol) in acetic acid (25 mL) was heated at 100° C. for 3-4 hours. The solvent was evaporated. Traces of solvent were removed by chasing with toluene. The residue was dissolved in acetonitrile and diluted with chloroform. Upon standing, product crystallized (0.77 gm), m.p. 173°-175° C.
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].I[C:7]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([CH3:28])[N:8]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:13][C:12]1[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH2:1][OH:4])=[CH:20][CH:19]=2)=[N:8][C:9]([CH3:28])=[CH:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(CO)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and (4-hydroxymethyl)phenylboronic acid (90 mg) under an argon atmosphere, and the mixture was stirred at 80° C. for 5 hr. The reaction solution was cooled to room temperature, an aqueous sodium hydroxide solution was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (11 mg, yield 24%).
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20](=O)[CH2:21][Br:22])=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)(=[O:10])[CH3:9]>FC(F)(F)C(O)=O>[Br:22][CH2:21][CH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:8](=[O:10])[CH3:9])[CH2:12][CH2:13]2
Reactant: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2cc(CCBr)ccc21
Temperature: 55 °C

Procedure:
Triethylsilane (8.8 mL, 54.9 mmol) was added to a solution of 1-(1-acetylindolin-5-yl)-2-bromo-ethanone (1.9 g, 6.73 mmol) in trifluoroacetic acid (70 mL) at rt. The mixture was heated at 55° C. for 18 h, then cooled and concentrated under reduced pressure. The product was purified by flash chromatography (SiO2; hexane/EtOAc; 75/25). Yield: 1.2 g (67%).