Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CBr.[C:3]([O:6][CH:7]=[CH2:8])(=[O:5])[CH3:4]>C(O)(=O)C>[C:3]([O:6][CH:7]([O:6][C:3](=[O:5])[CH3:4])[CH3:8])(=[O:5])[CH3:4]
Reactant: C=COC(C)=O
Agent: CBr
Solvent: CC(=O)O
Product: CC(=O)OC(C)OC(C)=O
Reaction time: 6 h
Yield: 36567.6 %

Procedure:
The procedure of Example 9 was repeated except that 10 g of methyl bromide was used in place of methyl iodide and the reaction was effected for 6 hours. GC analysis showed that 0.212 g of vinyl acetate and 65.8 g of ethylidene diacetate were formed with considerable amount of acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[N:7]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[N:7]=1
Reactant: COC(=O)/C=C/c1cc(C)cc(NC(C)=O)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(C)cc(NC(C)=O)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.5 %

Procedure:
6.2 g (E)-3-(6-acetylamino-4-methyl-pyridin-2-yl)-acrylic acid methyl ester (compound D2) are dissolved in 250 ml of ethyl acetate. Subsequently, 1.86 g palladium on active carbon (10% Pd) are added. The suspension is vigorously stirred at r.t. for 14 h under a hydrogen atmosphere. Then the catalyst is removed by filtration over kieselguhr and rinsed with ethyl acetate. The filtrate is concentrated to dryness to afford 6.16 g of the title compound as a colourless solid. M.p. 82° C. ESI-MS: 237.1 (MH+). TLC: Rf=0.18 (cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:4]=1[CH:5]=O.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:4]=1[CH:5]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1cc2c(cc1C=O)OCO2
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Yield: 90.6 %

Procedure:
A solution of the 2-methoxy-4,5-methylenedioxy benzaldehyde (16.0 g, 0.089 mol), diethyl malonate (15.0 ml, 0.090 mol), piperidine (4.4 ml, 0.044 mol) and acetic acid (2.5 ml, 0.045 mol) in benzene (75 ml) was stirred at reflux, equipped with a Dean-Stark apparatus, for 24 h. Upon removal of the solvent the crude residue was extracted with ethyl acetate and washed with 10% sodium carbonate solution, water, dried (Na2SO4). After removing the solvent, flash chromatography of the residue (silica gel, 25% ethyl acetate/hexane) provided the title compound as a yellow solid (26.0 g, 91%).
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[CH3:12][C:13]1([CH2:16][NH:17][C:18](=[O:28])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:15][O:14]1.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:15][C:13]1([CH2:16][NH:17][C:18](=[O:28])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[O:14][C:4]2=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]2[CH2:12]1
Reactant: CC1(CNC(=O)OCc2ccc(Cl)cc2)CO1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(CNC(=O)OCc2ccc(Cl)cc2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 16.4 %

Procedure:
2,4-Dinitro-1H-imidazole (0.518 g, 3.28 mmol) and 4-chlorobenzyl (2-methyloxiran-2-ylmethyl)carbamate (2.097 g, 8.20 mmol) and sodium acetate (0.538 g, 6.56 mmol) in ethanol (6 ml) was stirred under reflux for 1 hour. To the solution, water was added and the precipitates were filtered off. The resulting solid was treated with diethyl ether to afford 4-chlorobenzyl (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate (0.197 g, yield 16%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[CH:16][CH:17]=3)[C:12]2=[O:22])=[CH:7][CH:6]=1)[CH3:4].I[CH3:24]>C(#N)C.O.C(OCC)(=O)C.[Ag]=O>[CH3:21][O:20][C:15]1[CH:14]=[C:13]2[C:18]([CH2:19][N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH:3]([CH3:4])[CH2:2][O:1][CH3:24])=[CH:10][CH:9]=3)[C:12]2=[O:22])=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1ccc(C(C)CO)cc1)C2
Reactant: CI
Agent: O=[Ag]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COCC(C)c1ccc(N2Cc3ccc(OC)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72 %

Procedure:
A mixture of 2-(4-(1-hydroxypropan-2-yl)phenyl)-6-methoxyisoindolin-1-one (0.042 g, 0.14 mmol), silver oxide (0.196 g, 0.42 mmol), iodomethane (0.070 mL) and 4 Å molecular sieves (0.050 g) in acetonitrile (2 mL) was stirred for 96 h at room temperature. After this time, the mixture was diluted with water (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an off-white solid Purification by flash chromatography (silica, 1:1 ethyl acetate/hexanes) afforded 6-methoxy-2-(4-(1-methoxypropan-2-yl)phenyl)isoindolin-1-one (0.031 g, 72%) as a white solid: mp 116-118° C.; 1H NMR (300 MHz, CDCl3) δ 7.78 (dd, J=8.7, 2.0 Hz, 2H), 7.40-7.38 (m, 2H), 7.29 (dd, J=8.6, 1.9 Hz, 2H), 7.15 (dd, J=8.3, 2.4 Hz, 1H), 4.78 (m, 2H), 3.89 (s, 3H), 3.55-3.41 (m, 2H), 3.34 (s, 3H), 3.04 (q, J=7.0 Hz, 1H), 1.29 (d, J=7.0 Hz, 3H); ESI MS m/z 312 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:38]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:38])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CO)cn4c3-c3ccccc3)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {1-[4-(6-hydroxymethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (67 mg) in DMF (0.6 mL) under argon at 0° C. was treated with sodium hydride (8.4 mg of a 60% dispersion in mineral oil) and stirred for 30 minutes. Methyl iodide (0.007 mL) was added dropwise, the mixture warmed to rt and stirred for 3 hours. The mixture was partitioned between ethyl acetate and water and the organic phase washed with brine, dried and concentrated in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:21](OC)=[O:22])=[N:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CO>[CH2:1]([O:8][C:9]1[C:10]([C:21]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[O:22])=[N:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)C(C)C2
Solvent: CO
Product: CC1Cn2nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2C(=O)N1C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-benzyloxy-5,6-dimethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (72 mg, 0.219 mmol) in MeOH was added 4-fluorobenzylamine (376 μL, 3.28 mmol). The mixture was heated to reflux overnight and then at 110° C. for 4 hours. The mixture was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA), and collection and concentration of the appropriate fractions afforded the amide as a yellow oil. ES MS (M+1)=423.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:9]=[N:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:27][CH2:26]1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CC1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 83 %

Procedure:
As described for example 67, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (78 mg, 0.24 mmol), was converted, using cyclopropylamine instead of isopropylamine, to the title compound (72 mg, 83%) which was obtained as a white foam. MS: m/e=368.2 [M+H]+.
Reaction SMILES: CN(OC)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl.CCCCCC>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:11])=[CH:5][N:6]=1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccc(C=O)cn1
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
6-Methylnicotinic acid N,O-dimethylhydroxylamide (737 mg, 4.09 mmol) was dissolved in dichloromethane. To this, diisobutylaluminum hydride (a 0.98 mol/L solution in hexane, 4.60 mL, 4.50 mmol) was added dropwise under a nitrogen atmosphere at −10° C. and the mixture was stirred at the same temperature for 10 minutes. To this, water (4.60 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give a 3:1 mixture (405 mg) of 2-methyl-5-formylpyridine and 6-methylnicotinic acid N,O-dimethylhydroxylamide. The mixture was dissolved in tetrahydrofuran (8.0 mL). To this, (trifluoromethyl)trimethylsilane (593 μL, 4.01 mmol) and tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 340 μL, 0.340 mmol) were added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a 1N aqueous hydrogen chloride solution (6.0 mL) was added and the mixture was further stirred for 10 minutes. Then, the reaction mixture was neutralized with a saturated sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 2-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CK) (387 mg, yield: 50%).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)=[O:6])([CH3:3])[CH3:2].[NH:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[N:20]=[N:19]1>>[NH:18]1[C:22]2[CH:23]=[CH:24][C:25](/[CH:27]=[C:11]3/[C:12](=[O:17])[NH:13][C:14]4[C:10]/3=[CH:9][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:16][CH:15]=4)=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: CC(C)NC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2[nH]nnc2c1
Product: CC(C)NC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3[nH]nnc3c1)C(=O)N2

Procedure:
According to the method of Example A20, except substituting 1-isopropyl-3-(2-oxoindolin-5-yl)urea (23 mg, 0.099 mmol) and 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (15 mg, 0.11 mmol), the title compound was obtained as an orange solid (6 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.01 (s 1H), 7.75 (s, 1H), 7.57-7.59 (m, 2H), 7.31 (d, J=7.6 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.76 (d, J=7.6 Hz, 1H), 3.75-3.70 (m, 1H), 1.03-1.00 (d, 6H); MS ESI 363.1 [M+H]+, calcd for [C20H19N5O2+H]+ 363.2.
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.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[C:28]([N:15]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][C:17]([F:18])([F:20])[F:19])=[O:29])(=[O:24])=[O:23]
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine (example 135, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 85:15), followed by preparative HPLC using a gradient of methanol:water (10:50 to 95:5). Light yellow foam (28%). MS (ESI): m/z=534.090 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH2:32][CH2:31][CH2:30][CH2:29][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:33])([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(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>[C:1]([N:5]1[CH2:32][CH2:31][CH2:30][CH2:29][C:8]2[C:9]([C:37]3[CH2:38][CH2:39][O:34][CH2:35][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1-c1cccnc1)-c1c(C3=CCOCC3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 125 °C

Procedure:
A mixture of 75 mg of 25b, 37 mg of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane, 41 mg of K2CO3 and 17 mg of tetrakis(triphenylphosphine)palladium(0) in 3 ml of degassed DMF was heated under N2 atmosphere at 125° C. for 2 hr. The reaction was cooled and diluted with 15 ml of water. The product was extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated. The remainder was chromatographed over silcagel (using a gradient of heptane/acetone as eluent). The product isolated was triturated with diethyl ether, providing 57 mg of white crystalline 25c; Mp 208-210° C. LC-MS-ESI: [M+1] 512.13. NMR (CDCl3) δ 8.70, 8.58, 7.88, and 7.37 (4×m, 4, pyridine-H), 7.68 and 6.87 (2×s, 2, Ar—H), 1.60 (s, 9, tertC4H9), 3.87 (s, 3, OCH3), 5.75 (m, 1, CH), 4.30 (m, 2, CH2O), 4.70 (bm, 1, CH2), 3.55 (bm, 1, CH), 3.85 (bm, 4, 2×CH2) 3.00 and 3.20 (2×bm, 2, CH2), 2.63 (bm, 2, CH2), 2.35 (m, 2, CH2), 1.70-2.05 (bm, 4, 2×CH2).
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>C(#N)C>[CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH:22]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(C(OCCc2ccncc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: C1=C(CCOC(c2ccccc2)c2ccccc2)CCN(Cc2ccccc2)C1
Reaction time: 4 h
Yield: 94.3 %

Procedure:
With reference to FIG. 7, 4-(2-(benzhydryloxy)ethyl)pyridine 3 (4.0 g, 13.82 mmol) and benzyl bromide (2.86 g, 16.73 mmol) were dissolved in 20 ml of dry acetonitrile and refluxed for 6 hrs. The solvent was removed in vacuo. After drying the residue for 2 hrs under high vacuum, it was dissolved in 30 ml of dry methanol and cooled in an ice-bath. Sodium borohydride (0.76 g, 20.05 mmol) was then added very slowly portionwise over a period of 1.5 hrs, and the solution was gradually brought to room temperature. The reaction was quenched with water after stirring for 4 h, and methanol was removed in vacuo. The residual product was dissolved in ethyl acetate, washed with water, dried (Na2SO4), and concentrated. The crude product was purified by column chromatography over silica gel (hexane:ethyl acetate 5:1) to produce 4 (5.0 g, 94%) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): 2.086 (brs, 2H, H-3), 2.32-2.35 (t, 2H, J=6.8 Hz, OCH2CH2), 2.52-2.54 (t, 2H, J=5.6 Hz, H-2), 2.94-2.94 (brm, 2H, H-6) 3.52-3.55 (m, 4H, NCH2Ph, OCH2CH2), 5.34 (s, 1H, PhCH(O)Ph), 5.41-5.42 (brs, 1H, CH═C), 7.12-7.37 (m, 15H, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12]2)=[O:5]>O1CCOCC1.[Pt](=O)=O>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12]2)=[O:5]
Reactant: CCOC(=O)/C=C/c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: O=[Pt]=O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-3-((E)-2-ethoxycarbonylvinyl)quinoline (40 mg) and platinum (IV) oxide (5 mg) in dioxane (1 ml) was stirred for 3 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate-n-hexane) to give 8-(2,6-dichlorobenzoylamino)-3-(2-ethoxycarbonylethyl)quinoline (16 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:34]([O:41][C:42]1[S:46][C:45]([CH2:47][NH2:48])=[CH:44][CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CS(C)=O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:48][CH2:47][C:45]1[S:46][C:42]([O:41][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:43][CH:44]=1)=[O:6]
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: NCc1ccc(OCc2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(C(=O)NCc2ccc(OCc3ccccc3)s2)c(N)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 62 %

Procedure:
To a solution of 2,6-diaminonicotinic acid described in Preparation Example A-15 (109 mg, 0.71 mmol) in dimethylsulfoxide (10 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (272 mg, 1.42 mmol), 1-hydroxybenzotriazole (217 mg, 1.42 mmol) and C-(5-benzyloxy-thiophen-2-yl)methylamine described in Example E-76 (156 mg, 0.71 mmol), and the solution was stirred at room temperature for 14 hours. The reaction solution was poured into brine, extracted with ethyl acetate, the fractionated organic layer was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was subjected to NH silica gel column chromatography, eluted with solvent (ethyl acetate) and the title compound (157 mg, 0.44 mmol, 62%) was obtained.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:9][C:10](=[O:43])[NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][C:20](=O)[NH:21][NH:22][C:23]2[N:24]=[C:25]3[CH:31]=[CH:30][N:29](S(C4C=CC(C)=CC=4)(=O)=O)[C:26]3=[N:27][CH:28]=2)[CH2:15][CH2:14]1)([CH3:8])([CH3:7])[CH3:6].C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.O1CCOCC1>[C:5]([O:9][C:10](=[O:43])[NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][C:20]2[N:24]3[C:25]4[CH:31]=[CH:30][NH:29][C:26]=4[N:27]=[CH:28][C:23]3=[N:22][N:21]=2)[CH2:15][CH2:14]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C[C@H]4CC[C@H](CNC(=O)OC(C)(C)C)CC4)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Cc2nnc3cnc4[nH]ccc4n23)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.030 mL, 0.41 mmol) was added dropwise to a solution of tert-butyl(trans-4-(2-oxo-2-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinyl)ethyl)cyclohexyl)methyl-carbamate (0.127 g, 0.228 mmol, prepared using M from trans-(4-aminomethylcyclohexyl)acetic acid hydrochloride [AstaTech], H from Example #1, Step D, HATU, TEA), TEA (0.160 mL, 1.15 mmol), and 1,4-dioxane (2.3 mL) under nitrogen. A reflux condenser was attached and the reaction mixture was warmed to about 80° C. After about 2 h, the solution was cooled to ambient temperature and aqueous Na2CO3 (2 M, 3.4 mL, 6.8 mmol) was added and the biphasic mixture was warmed to about 80° C. After about 2 h, aqueous NaOH (2 M, 0.570 mL, 1.14 mmol) was added due to slow rate of deprotection. After about 17 h, the mixture was allowed to cool to ambient temperature. The reaction solution was diluted with water (5 mL) and then extracted with EtOAc (2×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 2-8% MeOH in DCM to give tert-butyl(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)cyclohexyl)methylcarbamate (0.0565 g, 63%): LC/MS (Table 1, Method a) Rt=1.85 min; MS m/z: 385 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:33].[NH4+]>C(Cl)Cl.C(O)C>[ClH:27].[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)(=[NH:33])[NH2:2]
Reactant: N#Cc1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: N=C(N)c1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 150 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl)methoxy]phenyl ester (280 mg, 0.7 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (15 mL) at 0° C. The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue was co-evaporated with methylene chloride several times. The residue was then dissolved in ethanol (10 mL) and ammonium carbonate (300 mg, 3.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride (150 mL), washed with 10% K2CO3 (2×50 mL), and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) was added, and then concentrated in vacuo. The residue was purified by flash chromatography (10% methanol in methylene chloride) to give the title compound as a white foam (238 mg, 75%). 1H-NMR (300 MHz, DMSO-d6) δ 5.15 (s, 2 H), 6.67 (d, 1 H, J=4.0 Hz), 6.81 (s, 1H), 7.03 (d, 1 H, J=4.0 Hz), 7.32 (t, 1 H, J=8.3 Hz), 7.58 (t, 1 H, J=7.5 Hz), 7.65 (t, 1 H, J=7.7 Hz), 7.75-7.94 (m, 6 H), 9.27 (br s, 2 H), and 9.45 (br s, 2 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C20H17N2ClO4S: 417.1 (M+H), 439.0 (M+Na). Found: 417.4, 439.1.