Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[Na+].[I-].C(N(CC)CC)C.[CH3:33][Si:34](Cl)([CH3:36])[CH3:35]>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22]([O:23][Si:34]([CH3:36])([CH3:35])[CH3:33])=[CH:21][CH2:20][CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.8 %

Procedure:
To a solution of 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.17 g, 6.72 mmol), NaI (1.51 g, 10.07 mmol) and triethylamine (2.80 mL, 20.14 mmol) in CH3CN (30 mL), is added trimethylsilyl chloride (1.27 mL, 10.07 mmol) slowly via syringe. The reaction mixture is stirred at room temperature for 20 h. and then partitioned between 50 mL of ethyl acetate/hexanes (1:1 with a few drops of triethylamine) and 30 mL of sat. NaHCO3 solution. The layers are separated and the aqueous phase is extracted with ethyl acetate/hexanes (1:1) (3×20 mL). The combined organic layers are washed with brine, dried (Na2SO4) and evaporated to provide 4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.56 g, 100%) as viscous red oil. 1H NMR (400 MHz, CDCl3) δ 0.177 (9H, s), 1.308 (3H, t), 1.585 (9H, s), 1.906 (2H, m), 2.016 (2H, m), 2.974 (2H, t), 4.243 (2H, q), 5.353 (1H, t), 7.627 (1H, s). MS (ES+) 395 (M+1). Step 3:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[CH:8]=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:26])[CH3:27])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3)c2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
To a solution of potassium thiocyanate (8.09 g, 83.2 mmol) in acetic acid (150 ml) was added a solution of N-[3-(4-aminophenoxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide (7.34 g, 19.8 mmol) in acetic acid (150 ml), and the mixture was stirred at room temperature for 15 min. To the obtained solution was added dropwise a solution of bromine (4.0 g, 25.0 mmol) in acetic acid (100 mL) at room temperature over 30 min or longer and, after the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hr. The resulting yellow solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL) and ethyl acetate (200 mL), and basified with 2N aqueous sodium hydroxide solution. The aqueous layer was separated and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (7.4 g, 87%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH2:37]O)=[N:35][CH:36]=1.C([O-])([O-])=[O:40].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:33]3[C:34]([CH3:37])=[N:35][C:36]([OH:40])=[CH:31][CH:32]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:28])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: OCc1ccc(Br)cn1
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1nc(O)ccc1-c1ccc([C@H]2OC(C)(C)N(C(=O)C(F)F)[C@@H]2CF)cc1
Temperature: 90 °C
Yield: 35.1 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (2.0 g, 4.843 mmol) in toluene (40 mL), ethanol (10 mL), water (10 mL) and (5-Bromo-pyridin-2-yl)-methanol (0.91 g, 4.843 mmol) is added Na2CO3 (1.54 g, 14.528 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 30 minutes then Pd(PPh3)4 (0.559 g, 0.484 mmol) is added. The reaction mixture is heated to 90° C. for 6 hours. Solvent is evaporated in vacuo then diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 80% ethyl acetate in hexane as an eluent to afford the title compound (0.67 g): 1H-NMR (400 MHz, CDCl3) δ: 1.53 (s, 3H), 1.60 (S, 3H), 4.54-4.58 (m, 0.5H), 4.60 (d, J=5.84 Hz, 2H), 4.66-4.72 (m, 1H), 4.81-4.84 (m, 0.5H), 4.90-4.94 (m, 1H), 5.26 (d, J=3.72 Hz, 1H), 5.48 (t, J=5.8 Hz, 1H), 6.64 (t, J=52.4 Hz, 1H), 7.55-7.64 (m, 3H), 7.78 (d, J=8.2 Hz, 2H), 8.09-8.12 (dd, J=2.32 Hz, J=8.16 Hz, 1H), 8.81 (d, 2.04 Hz, 1H). LC-MS (m/z): [M+H]=395.0.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])=[CH:8][C:7]([Cl:21])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=1>CN(C=O)C>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:29][C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=3)[N:17]=[N:18][C:19]=2[C:11]=1[O:10][C:9]1[CH:8]=[C:7]([Cl:21])[CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[Cl:1]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1Cl
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4Cl)c(Cl)ccc32)c2cccnc21
Reaction time: 1 h

Procedure:
2,5-dichloro-3-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (1.00 g, 2.94 mmol) and cesium carbonate (1.15 g, 3.53 mmol) were suspended in dry DMF (10 mL) under N2 and tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.965 g, 3.09 mmol) was added as a solution in DMF (5 mL) at room temperature. After 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and diluted with water (50 mL). The mixture was then extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with water (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (120 g) eluting with 25-50% EtOAc/hexanes. LRMS (M+1)=569.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)[C@H:14]([C:31]([NH:33][C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[O:32])[CH2:13]1)(=[O:11])=[O:10].Cl.[F:40][C:41]1([F:45])[CH2:44][NH:43][CH2:42]1>C(#N)C>[C:37]([C:34]1([NH:33][C:31]([C@@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([N:43]4[CH2:44][C:41]([F:45])([F:40])[CH2:42]4)=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)=[O:32])[CH2:36][CH2:35]1)#[N:38]
Reactant: FC1(F)CNC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(CCc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(CCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-phenethyl-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 90° C. for 48 h to give the title compound as off-white foam. MS (ESI): m/z=629.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.Cl[CH2:16][C:17]1[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][CH:18]=1.O>CS(C)=O.O1CCCC1>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:16][C:17]2[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(CCl)n1
Reactant: Cc1ccc(CCCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(CCCCOCc2cccc(C=O)n2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
To a suspension of 1.1 g of 60% sodium hydride in 30 ml of dimethyl sulfoxide under stirring at 70° C. for 30 minutes was added 4.1 g of 4-(4-methylphenyl)butanol at room temperature and stirred for 30 minutes. To a mixture was added 40 ml of tetrahydrofuran and was cooled at 0° C. To the resulting mixture was added dropwise a solution of 3.9 g of 6-chloromethyl-2-formylpyridine in 40 ml of tetrahydrofuran. After completion of the addition, the mixture was stirred at the same temperature for 30 minutes and further was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give a residue as an oily substance. The residue was purified by column chromatography on silica gel by passing chloroform and methanol(100:1 ) to give 1.3 g of 6-[4-(4-methylphenyl) butoxy]methyl-2-formylpyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)=[C:4]([F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:18][C:4]1[CH:3]=[C:2]([C:21]2[C:20]([NH2:19])=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]1
Reactant: Fc1cc(Br)cc(F)c1-n1ccc(C(F)(F)F)n1
Reactant: Nc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1
Temperature: 85 °C

Procedure:
A mixture of 1-(4-bromo-2,6-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole (i.e. the product of Step C, 1.83 g, 5.6 mmol), B-(2-aminophenyl)-boronic acid (0.90 g, 6.58 mmol), sodium carbonate (2.07 g, 19.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.33 g, 0.76 mmol) in 1,2-dimethoxyethane (46 mL) and water (11 mL) was heated at 85° C. for 16 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to yield the title compound (1.02 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:17]=3)=[CH:10][N:11]=[C:5]2[N:4]=1.[Na].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>>[F:26][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:28]4[CH:32]=[CH:31][N:30]=[CH:29]4)=[N:4][C:5]3=[N:11][CH:10]=2)=[CH:17][C:16]=1[C:18]1[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(CBr)ccn23)ccc1F
Agent: [Na]
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(Cn4ccnc4)ccn23)ccc1F

Procedure:
5′-(7-Bromomethylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile was reacted with the sodium salt of imidazole as described in Example 34 to give 2′-fluoro-5′-[7-(imidazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile: δH (360 MHz, CDCl3) 5.33 (2H, s), 6.62 (1H, d, J 7), 7.05 (1H, s), 7.15 (1H, s), 7.38-7.43 (1H, m), 7.52-7.73 (6H, m), 7.83 (1H, d, J 7), 7.92 (1H, s), 8.80 (1H, s); m/z (ES+) 395 (M++H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][C@@H:24]([CH3:28])[NH:23]1.[C:29](=[O:32])([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:23]3[C@H:24]([CH3:28])[CH2:25][N:26]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:32][CH3:29])[CH:14]=5)[CH:4]=4)[CH2:27][C@@H:22]3[CH3:21])[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(CN3C[C@@H](C)N(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)[C@@H](C)C3)ccn2)cc(OC)c1OC
Product: Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (123 mg) and cis-2,6-dimethylpiperazine (23 mg) were dissolved in DMF (5 mL), and to the solution potassium carbonate (58 mg) was added. The mixture was stirred at 80° C. for 4 hours and concentrated under reduced pressure. Water was added to the residue to conduct extraction with chloroform. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1) to obtain a free base of the title compound. This compound was dissolved in ethyl acetate, and to the solution an ethyl acetate solution of 4 M hydrogen chloride was added to provide a hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:20])[F:19])[C:26](=[O:27])[C:25]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:23]([C:22]([F:21])([F:36])[F:37])[CH:24]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2-methoxy-[3,4]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow foam (21%). MS (ESI): m/z=524.100 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:47]1([C:50](O)=[O:51])[CH2:49][CH2:48]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:50]([CH:47]3[CH2:49][CH2:48]3)=[O:51])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NNc1cnc2ccc(Br)cc2n1)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the solution of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.83 mmol) in DMF (3 mL) was added HATU (380 mg, 1 mmol), DIPEA (0.205 mL, 1 mmol) and cyclopropanecarboxylic acid (71 mg, 0.83 mmol). After stirring at r.t. for 5 h, the mixture was diluted with EtOAc. The organic layer was washed with water for three times, then concentrated to afford N′-(7-bromoquinoxalin-2-yl)cyclopropane-carbohydrazide as yellow solid which was used directly in the next step. m/z 309 (M+H)+.
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3]CCCCCCC[CH2:11][CH3:12].[C:15]([O-:28])(=[O:27])CCCCCCCCCCC.C([Sn+2]CCCC)CCC.COC1C=CC(O)=CC=1.C(N=C=O)CCCCC[N:53]=C=O>>[C:1]([OH:14])(=[O:13])[CH:2]=[CH2:3].[NH2:53][C:15]([O:28][CH2:11][CH3:12])=[O:27]
Reactant: O=C=NCCCCCCN=C=O
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
Next, 0.1 g of urethanation catalyst dibutyl tin dilaurate and 0.1 g of polymerization inhibitor hydroquinone monomethyl ether were added to 200 g of the isocyanurate-modified hexamethylene diisocyanate, and 1.2 mols of the hydroxyalkyl acrylate as shown in Table 5 below was dropwise added thereto over a period of 30 minutes with the reaction liquid temperature being kept at 40° C. After addition, the reaction liquid temperature was elevated up to 60° C., and the reaction was continued until the isocyanate group in the reaction liquid disappeared to obtain urethane acrylate oligomer 6 through urethane acrylate oligomer 9 as shown in Table 5.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[I:15]N1C(=O)CCC1=O>B(F)(F)F.CCOCC.O>[I:15][C:10]1[C:6]2[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=2[S:8][C:9]=1[CH3:11]
Reactant: Cc1cc2c(=O)n(C)c(=O)n(C)c2s1
Reactant: O=C1CCC(=O)N1I
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: Cc1sc2c(c1I)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of Step 4 intermediate (12.5 g, 59.52 mmol) in boron trifluoride diethyl etherate (300 ml) was added N-iodosuccinimide (19.9 g, 89.28 mmol) and the mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (3×200 ml) and the combined organic layers were washed with water (2×150 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in chloroform to obtain 9.7 g of the product as a pale brown solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H), 3.21 (s, 3H), 3.42 (s, 3H); MS (m/z) 337.11 (M+H)+.
Reaction SMILES: C([N+:8]12[CH2:14][C:11]([C:15]([O-:17])=[O:16])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)C1C=CC=CC=1.[CH3:18]O>[Pd].[C]>[N:8]12[CH2:14][C:11]([C:15]([O:17][CH3:18])=[O:16])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2
Reactant: CO
Reactant: O=C([O-])C12CC[N+](Cc3ccccc3)(CC1)C2
Agent: [Pd]
Product: COC(=O)C12CCN(CC1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-benzyl-1-azoniabicyclo[2.2.1]heptane-4-carboxylate (3.25 g) in MeOH was added 10% Pd carbon with a 50% hydration (650 mg), followed by stirring at room temperature for 5 hours under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was dissolved in MeOH and added with sulfuric acid (3 mL), followed by heating under reflux for 1 hour. The reaction mixture was neutralized with an aqueous K2CO3 solution and extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3: MeOH: 28% aqueous ammonia) to obtain methyl 1-azabicyclo[2.2.1]heptane-4-carboxylate (890 mg) as a colorless oily substance.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH:7]=[CH:6][C:5]=12.C(O)(C(F)(F)F)=O>ClCCl>[NH:13]1[CH2:12][CH2:11][CH:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([CH:3]=[N:2][N:1]=3)[CH:9]=2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nncn3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2nncn2cc1C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 749.1 %

Procedure:
To a solution of tert-Butyl 4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)piperidine-1-carboxylate (compound 36.1, 0.05 g, 0.165 mmol) in dichloromethane (2 mL) was added TFA (0.2 mL). The mixture was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure. The residue was purified by prep-TLC (10% MeOH in dichloromethane+˜0.5% NH4OH) to give 0.25 g (76%) of the title compound as a light brown oil. m/z (ES+) 203 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1.C(#N)C.P([O-])([O-])([O-])=[O:16].S([O-])(O[O-])(=O)=O.[K+].[K+]>O.CC(C)=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][N+:2]([O-:16])=[O:1])=[CH:5][N:6]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: COc1ccc(C=NO)cn1
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C[N+](=O)[O-])cn1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a mixture of 2 g of N-hydroxy-1-(6-methoxypyridin-3-yl)methanimine, 50 ml of acetonitrile, and 50 ml of an aqueous phosphate buffer solution (pH 6.9) was added a mixed liquid of 20 g of potassium peroxymonosulfate (Oxone: 2KHSO5.KHSO4.K2SO4) in 50 ml water and 50 ml of acetone at room temperature, followed by stirring at 45° C. for 4 hours. The insoluble materials were separated by filtration and washed with diethyl ether. The organic layer was washed with a saturated aqueous sodium sulfite solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 251 mg of 2-methoxy-5-(nitromethyl)pyridine.
Reaction SMILES: [OH:1][CH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl.CO>[OH:1][CH:2]1[C:6]2=[N+:7]([O-:30])[CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2cccnc2C(O)N1c1cnn(CC(F)(F)F)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc[n+]([O-])c2C(O)N1c1cnn(CC(F)(F)F)c1
Reaction time: 24 h
Yield: 54.3 %

Procedure:
As shown in step 18-i of Scheme 18, to 7-hydroxy-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 2055, 4.35 g, 14.6 mmol) in CHCl3 (80 mL) and MeOH (40 mL) was added mCPBA (5.39 g, 21.9 mmol). After stirring for 24 hours, additional mCPBA (1.26 g, 7.30 mmol) was added. After stirring an additional 16 hours, the resulting precipitate was collected by filtration and washed with DCM (10 mL) and Et2O (20 mL) to give 7-hydroxy-5-oxo-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine 1-oxide (Compound 2059, 2.49 g) as a white solid: ESMS (M+H) 315.25; 1H NMR (DMSO-d6, 300 MHz) δ 8.44 (d, J=6 Hz, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.65 (m, 2H), 7.43 (d, J=9 Hz, 1H), 6.41 (d, J=9 Hz, 1H), 5.20 (q, J=9 Hz, 2H).