Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:11]=1[CH3:27]>C1COCC1>[CH3:16][C:14]1[N:13]=[C:12]([NH:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])[C:11]([CH3:27])=[C:10]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[N:15]=1
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2C)c(C)c1
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Nc2nc(C)nc(OC3CCOC3)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-hydroxy-tetrahydrofuran (0.5 ml) and sodium hydride (60% in oil, 53 mg, 1.33 mmol) in dry THF was stirred at room temperature for 5 minutes, (6-chloro-2,5-dimethyl-pyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine (107 mg, 0.388 mmol) was added. The mixture was heated at reflux for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a yellow oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give 48 mg of the title compound as off-white crystals, mp 126-128° C. 1H NMR (CDCl3) δ 6.89 (s, 2H), 5.50 (brs, 2H), 3.8-4.0 (m, 4H), 2.27 (s, 6H), 2.13 (s, 6H), 2.1-2.25 (m, 2H), 1.93 (s, 3H) ppm.
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:40]1[CH2:44][C@@H:43]([O:45][CH2:46][CH2:47][CH3:48])[CH2:42][N:41]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:39])[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([C:29]([N:31]2[CH2:35]C[CH2:33][C@@H:32]2COC)=[O:30])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.[C:56](NC1C=C(C=C(C)C=1)C(N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O)(=O)[C:57]1C=CC=CC=1.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=C(C)C=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCCC>ClCCl>[CH2:32]([N:31]([CH3:35])[C:29](=[O:30])[C:24]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([C:21]([NH:20][C@@H:10]([CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)[C@H:9]([OH:8])[C@H:40]2[CH2:44][C@@H:43]([O:45][CH2:46][CH2:47][CH3:48])[CH2:42][NH:41]2)=[O:39])[CH:23]=1)[CH2:33][CH2:56][CH3:57]
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)N3CCC[C@@H]3COC)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(NC(=O)c3ccccc3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCCNC
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](OCCC)CN2)c1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Step 9 (A): (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid (Preparation G, 26 mg, 0.037 mmol) in dichloromethane (1 mL) was added Hunig's base (15 mg, 0.114 mmol) to make a clear solution and HATU (19 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added methylbutylamine (5 mg, 0.057 mmol) and the reaction mixture was stirred at rt for 6 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient) to give 24 mg of the title compound (85% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.06 (3H, s), 0.72-0.97 (15H, m), 1.12 (1H, m), 1.36-1.53 (11H, m), 1.61 (1H, m), 1.78 (2H, s), 2.05 (1H, m), 2.19 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.91-2.95 (3H, m), 3.04 (1H, s), 3.21 (1H, m), 3.27-3.36 (3H, m), 3.50 (1H, m), 3.76 (1H, m), 3.98 (1H, m), 4.03-4.06 (1H, m), 4.10-4.12 (1H, m), 4.56 (1H, m), 6.59 (1H, m), 6.76 (2H, d, J=5 Hz), 7.29 (1H, d, J=10 Hz), 7.64 (1H, s), 7.71 (1H, s), 8.03 (1H, brd s). MS (ESI) (M+H)+ 760.61.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C(OCC)(=O)C.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>[S:9]1[CH:13]=[CH:12][C:11]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:10]1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: Nc1cnc(-c2ccsc2)cn1
Yield: 69 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (500 mg, 2.874 mmol), dichlorobis(triphenylphosphine)palladium(II) (290 mg, 0.413 mmol), 3-thiopheneboronic acid (500 mg, 3.908 mmol), and a saturated aqueous sodium carbonate solution (4 mL) in ethylene glycol dimethyl ether (8 mL) and ethanol (8 mL) was heated under reflux for 45 min. The reaction mixture was then cooled, diluted with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded 5-thiophen-3-yl-pyrazin-2-ylamine (351.3 mg, 69%) as a light purple solid: EI-HRMS m/e calcd for C8H7N3S (M+) 177.0361, found 177.0358.
Reaction SMILES: C1OC1C.[CH2:5]1[O:7][CH2:6]1.C(OC)=C.[CH3:12][O:13][CH:14]([O:21][CH3:22])[CH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18].COC(OC)CC1OCCO1.COC(OC(OC)CC(OC)OC)C>C(OC)=O>[CH3:22][O:21][CH:14]([O:13][CH2:12][CH2:6][O:7][CH3:5])[CH2:15][CH:16]1[O:19][CH2:20][CH2:18][O:17]1
Reactant: COC(CC(OC)OC)OC
Reactant: C1CO1
Agent: C=COC
Agent: CC1CO1
Agent: COC(C)OC(CC(OC)OC)OC
Solvent: COC=O
Product: COCCOC(CC1OCCO1)OC

Procedure:
The procedure described in Example 4 is followed, but instead of the propylene oxide solution 107 parts by volume/hour of a 50 percent strength by weight solution of ethylene oxide in methyl formate are used. In this example, only 40 parts by volume/hour of the methyl vinyl ether solution are employed. After working up as in Example 4, a mixture of 1,1,3,3-tetramethoxypropane, 2-(2',2'-dimethoxyethyl)-(1,3)-dioxolane, malondialdehyde bis-(ethyleneacetal), 1-methoxyethoxy-1,3,3-trimethoxypropane and 2-(2'-methoxy-2'-methoxyethoxy-ethyl)-(1,3)-dioxolane is obtained as the end product, the composition being as in Example 2.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]([C:22]1[O:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:20]([C:22]1[O:26][CH:25]=[C:24]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:23]=1)=[O:21]
Reactant: CC1(C)OB(c2coc(C=O)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2coc(C=O)c2)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.18 g, 3.60 mmol), 5-formylfuran-3-boronic acid pinacol ester (800 mg, 3.60 mmol), saturated aqueous sodium carbonate solution (15 ml), and tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.102 mmol) in ethylene glycol dimethyl ether (20 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (900 mg, 72.6%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]([CH3:23])=[C:18]([C:20](O)=O)[N:19]=[C:13]2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:30][C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][C:40]=1[O:41][CH:42]([CH3:44])[CH3:43])/[C:34](=[N:36]\[OH:37])/[NH2:35].C(Cl)(=O)C>C(Cl)Cl.N1C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]([CH3:23])=[C:18]([C:20]3[O:37][N:36]=[C:34]([C:33]4[CH:38]=[CH:39][C:40]([O:41][CH:42]([CH3:44])[CH3:43])=[C:31]([Cl:30])[CH:32]=4)[N:35]=3)[N:19]=[C:13]2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nc2n1CCN(C(=O)OCc1ccccc1)C2
Reactant: CC(C)Oc1ccc(/C(N)=N\O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)nc2n1CCN(C(=O)OCc1ccccc1)C2
Temperature: 115 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of 7-(benzyloxycarbony)-3-methy-5,6,7,8-tetrahydroimidazo[1,2-a] pyrazine-2-carboxylic acid (370 mg, 1.173 mmol) in DCM (10m1) was added oxalyl chloride (2.054 ml, 23.47 mmol) and DMF (5 uL). The reaction was stirred for one hour and concentrated. A solution of (E)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (268 mg, 1.173 mmol) in pyridine (10.00 ml) was added and the reaction was stirred at room temperature for 30 minutes. The reaction was treated with acetyl chloride (0.092 ml, 1.291 mmol) and then was heated at 115° C. under nitrogen for 4 hours. The reaction was cooled, concentrated and partitioned between saturated Na2CO3 and methylene chloride. The organic layer was washed with water, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified on silica gel using 80:20/methylene chloride:ethyl acetate as the eluant to yield 2-[3-(3-Chloro-4-isopropoxy -phenyl)-[1,2,4] oxadiazol-5-yl] -3-methyl-5,6-dihydro-8H-imidazo[1,2-a] pyrazine-7-carboxylic acid benzyl ester (173 mg, 29%) as an off-white solid. LCMS (Table 1, Method a) Rl=4.34 min, m/z 508.24 (M+H)+; 1H NMR (400 MHz, DMSO-d6)δ 7.98 (d, 1 H), 7.93 (d,d, 1 H), 7.35 (m, 6H), 5.12 (s, 2H), 4.78 (m, 1 H), 4.66 (s,broad, 2H), 3.99 (m, 2H), 3.88 (s, broad, 2H), 2.57 (s, 3H), 1.31 (d, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:15]1(C)[C:19]2(CS(O)(=O)=O)[C:20](C[CH:16]1[CH2:17]C2)=[O:21]>O1C=CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH:20]2[CH2:19][CH2:15][CH2:16][CH2:17][O:21]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C1=COCCC1
Product: c1ccc(CN2CC[C@@H](OC3CCCCO3)C2)cc1
Reaction time: 14 h
Yield: 120 %

Procedure:
To a stirred solution of (R)-(+)-1-benzyl-3-pyrrolidinol (5.00 g, 28 mmol) and D-camphor-10-sulfonic acid (6.97 g, 30 mmol) in CH2Cl2 (10 ml) was added 3,4-dihydro-2H-pyran (20 ml) at rt and the reaction mixture was stirred for 14 h (in most cases, the reaction was completed after exothermic reaction subsided). The reaction mixture was diluted with CH2Cl2 (100 ml), washed with saturated NaHCO3 aqueous solution, dried (Na2SO4), and concentrated to give brown oil. This was purified by column chromatography (silica gel: 200 g, CH2Cl2 /MeOH: 40/1 as eluent) to give 8.78 g (97.6%) of desired compound as brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[CH2:16][C@H:15]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].[Br:36]Br.[OH-].[Na+]>C(O)(=O)C>[Br:36][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:17]2[C:12]=1[CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:30])[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16]2
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(Br)c3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
(R)-N-[8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide (80 mg, 0.19 mmol) and sodium acetate (200 mg) were dissolved in acetic acid (3 mL) and the mixture was stirred at room temperature. Bromine (34 mg, 0.21 mmol) was added dropwise to the reaction mixture and the mixture was stirred for 2 h at ambient temperature. A 2 M sodium hydroxide solution (100 mL) was added and the mixture was extracted with diethyl ether (2×50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification on a silica gel column using methylene chloride/ethanol saturated with NH3 (94:6) as the eluent gave 80 mg (85% yield) of the title compound as a white solid: mp 229-230° C.; [α]21D -5.4° (c=1, chloroform); EIMS (70 eV) m/z (relative intensity) 495 and 497 (3, M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1COCC1.O>[OH:10][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1)([OH:13])[CH2:11][OH:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C(O)(CO)CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(C(O)(CO)CO)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a stirred solution of 2-(4-aminophenyl)propane-1,2,3-triol (900 mg, 4.918 mmol, 1.0 eq) in THF/H2O/sat. NaHCO3 (4 mL: 2 mL: 4 mL) was added phenyl chloroformate (0.68 mL, 5.367 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 0.5 h, then the THF was evaporated, the residue was diluted with EtOAc (20 mL), washed with water (20 mL) followed by brine and the solvent evaporated. The resulting residue was purified by CC using MeOH/CHCl3 (1:19) as eluent to get phenyl 4-(1,2,3-trihydroxypropan-2-yl)phenylcarbamate (900 mg, 60%, white solid; TLC system: MeOH/CHCl3 (1:9), Rf: 0.4).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]O>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CO)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: COc1cccc(COc2ccnn2-c2cc(C#N)ccn2)c1
Yield: 13 %

Procedure:
The title compound was prepared in 13% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-methoxybenzyl alcohol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C17H14N4O2, 307; Found, 307.
Reaction SMILES: O1CCCC1.[CH2:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(NCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(NCc3ccccc3)cc2)no1
Temperature: 50 °C
Reaction time: 7 h
Yield: 11.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-benzylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Manufacturing Example 68-1-4 and 3-ethynyl-pyridin-2-ylamine (41 mg, 0.348 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (190 μL, 1.37 mmol) at room temperature, which was stirred for 7 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (14 mg, 7%).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])(=O)[CH2:2][CH2:3][CH3:4].Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][NH2:30])=[CH:25][CH:24]=1.CC([O-])=O.[Na+]>CCO>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:6]([C:1](=[N:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH2:2][CH2:3][CH3:4])[CH:11]=1
Reactant: CCCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCC(=NOc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 62.2 %

Procedure:
A solution of N-(2-butyryl-4-chlorophenyl)trifluoromethanesulfonamide 29A (333 mg, 1.0 mmol), O-(4-chlorophenyl)hydroxylamine hydrochloride (200 mg, 1.10 mmol) and anhydrous NaOAc (91 mg, 1.10 mmol) in EtOH (30 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:4) and the solvent removed under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19 to 3:7) to afford N-{4-chloro-2-[1-(4-chlorophenoxyimino)butyl]phenyl}trifluoromethanesulfonamide 166 (283 mg, 62%), as a yellow solid. M.p. 62.5-64.5° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.27, br s, 1H, 7.72, d, J=8.8 Hz, 1H; 7.57d, J=2.4 Hz, 1H, 7.41, dd, J=2.4 and 8.8 Hz, 1H; 7.35, d, J=8.8 Hz, 2H, 7.11, d, J=8.8 Hz, 2H; 2.98, m, 2H, 1.71, sextet, 2H, 1.09, t, J=7.4 Hz,
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C(O)=O.[CH2:19]([NH:21][NH2:22])[CH3:20]>C(O)(=O)C>[CH2:19]([N:21]1[C:9]([CH2:10][CH3:11])=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:22]1)[CH3:20]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)n(CC)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.3 %

Procedure:
A solution of ethyl 2,4-dioxohexanoate (˜0.345 mol), prepared as described in Part A of Example 10, in glacial acetic acid (350 mL) was cooled to 0° C. Ethylhydrazine oxalate (41.43 g, 0.276 mol) was added over a period of 20 minutes. The reaction was allowed to warm to ambient temperature, stirred for 20 hours, and concentrated under reduced pressure. The residue was adjusted to pH 10 with the addition of 2 M aqueous sodium carbonate, and chloroform was added. The mixture was filtered to remove a solid. The aqueous filtrate was extracted with chloroform (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 29.4 g of ethyl 1,5-diethyl-1H-pyrazole-3-carboxylate as an orange oil, which was used without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:11]([O:10][C:9](=[O:15])[NH:8][CH2:7][CH:3]1[O:4][CH2:5][CH2:6][N:1]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:2]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CN(c2ccc(C(F)(F)F)cc2)CCO1
Temperature: 105 °C
Reaction time: 4 h
Yield: 43.7 %

Procedure:
tert-Butyl morpholin-2-ylmethylcarbamate (1.0 g, 4.62 mmol), 1-bromo-4-(trifluoromethyl)benzene (1.04 g, 4.62 mmol), Pd(dba)2 (133 mg, 0.23 mmol), X-Phos (220 mg, 0.46 mmol) and sodium tert-butoxide (533 mg, 5.55 mol) were combined in 10 mL of dry toluene in a sealed tube. The mixture was degassed with argon and then stirred at 105° C. for 4 h. The mixture was filtered through a layer of Celite and rinsed with THF. Solvents were evaporated and the residue was extracted with water and ethyl acetate. The organic layer was dried and concentrated. The residue was purified by ISCO flash column chromatography (50 g silica gel, ethyl acetate in hexanes 0% to 80%) to give the desired compound (727 mg, 44%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15](=[O:23])(=[O:22])[N:14]=2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:38][C@@H:39]([CH2:51][CH3:52])[CH:40]([C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1)[OH:41].CN1CCOCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(OCC)(=O)C.C([O-])(O)=O.[Na+].ClCCl>[O:43]1[C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=[C:42]1[C:40]([C@@H:39]([NH:38][C:9](=[O:10])[C@@H:8]([NH:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15](=[O:23])(=[O:22])[N:14]=1)[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:51][CH3:52])=[O:41]
Reactant: CC[C@H](N)C(O)c1nc2ccccc2o1
Reactant: O=C(O)[C@H](CC1CCCCC1)NC1=NS(=O)(=O)c2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)[C@H](CC1CCCCC1)NC1=NS(=O)(=O)c2ccccc21)C(=O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
(S)-3-Cyclohexyl-2-(1,1-dioxo-benzo[d]isothiazol-3-ylamino)-propionic acid (150 mg, 0.45 mmol) was combined with EDC (250 mg, 1.3 mmol), HOBt (250 mg, 1.6 mmol), and (2S)-2-amino-1-benzoxazol-2-ylbutan-1-ol (250 mg, 1.2 mmol). Dichloromethane (4 mL) was added and then 4-methylmorpholine (0.5 mL). The reaction mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (150 mL), the solution was washed with 1N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in dry dichloromethane (10 mL) and Dess-Martin Periodinane (500 mg, 1.2 mmol) was added. After stirring at ambient temperature for 1 h, the reaction mixture was diluted with ethyl acetate (150 mL) and treated with 0.26M Na2S2O3 solution in saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried with MgSO4 and evaporated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate 2:1) to yield the title compound (120 mg).