Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20])=[O:15])=O)(C)(C)C.C1(OC)C=CC=CC=1.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>C(Cl)Cl>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: NCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
The 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-4-fluorobenzamide (570 mg, 0.93 mmol) was mixed with CH2Cl2 (5 mL), anisole (1 mL), and trifluoroacetic acid (2 mL). The mixture was stirred at ambient temperature for 2 hours, concentrated to dryness, mixed with diethyl ether, and sonicated for 5 minutes to give a white fluffy solid which was filtered to give 490 mg (62%) of the desired product as the trifluoroacetate salt.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C1(C)C=CC=CC=1.C(O)(=O)C>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 92 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane and 56 mg of toluene were placed in a glass reaction tube and 0.002 ml of acetic acid was then added. Then, 0.001 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.39%) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 96.6% and n-octyltriethoxysilane was produced at a yield of 92%.
Reaction SMILES: CC1OC[C:5]([CH2:25][O:26][P:27](=[O:38])([O:33]C(C)(C)C)[O:28]C(C)(C)C)([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[N:6]=1.Cl.[CH2:40]([OH:42])[CH3:41]>>[P:27]([OH:38])([OH:33])([OH:28])=[O:26].[NH2:6][C:5]([O:42][CH2:40][CH3:41])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:14]=1)[CH3:25]
Reactant: CC1=NC(CCc2ccc(OCCOc3ccccc3)cc2)(COP(=O)(OC(C)(C)C)OC(C)(C)C)CO1
Reactant: CCO
Agent: Cl
Product: CCOC(C)(N)CCc1ccc(OCCOc2ccccc2)cc1
Product: O=P(O)(O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of (2-methyl-4-{2-[4-(2-phenoxy-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol (200 mg, 0.56 mmol) and tetrazole (197 mg, 2.81 mmol, 5 eq., recrystallized from toluene) in dry THF (5 ml) was added di-tert-butyl-N,N-diisopropylphosphoramide (561 mg, 2.25 mmol, 4 eq.). After stirring under argon at RT for 3 h, H2O2 (30%, 10 eq.) was slowly added at 0° C. with vigorous stirring. The reaction mixture was stirred for further 30 min, followed by addition of saturated sodium thiosulfate solution (5 ml). The organic layer was separated and the aqueous phase was extracted with ether (3×20 ml). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/hexane 1:1) afforded phosphoric acid di-tert-butyl ester 2-methyl-4-{2-[4-(2-phenoxy-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-ylmethyl ester as colorles crystals. Finally, to a solution of phosphoric acid di-tert-butyl ester 2-methyl-4-{2-[4-(2-phenoxy-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-ylmethyl ester (150 mg, 0.27 mmol) in ethanol (5 ml) was added conc. HCl (5 ml). The reaction mixture was stirred at 50° C. for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford mono-(2-amino-4-{4-[2-phenoxy-ethoxy]-phenyl}-2-ethoxy-butan) phosphate as a colorless powder. ESI+ MS: m/z=410.2 (M−H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17]OC)=[O:4].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](N)=[CH:31]C=2)[CH2:24][CH2:23]1.C[N:37](C)C=O>>[CH3:20][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]\[NH:37][C:33]1[CH:34]=[CH:29][C:28]([N:25]2[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]2)=[CH:31][CH:32]=1)=[O:4]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CN(C)C=O
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(=O)N(C)C)cc21
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(C(=O)N(C)C)cc43)cc2)CC1
Yield: 86 %

Procedure:
Prepared from a slurry of 81.7 mg (0.298 mmol) of 4-methoxymethylene-1,3-dioxo-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid dimethylamide and 56.9 mg (0.298 mmol) of 4-(4-methylpiperazin-1-yl)methyl-phenylamine in 1.5 mL of N,N-dimethylformamide (DMF) at 100° C. under N2 as described for example 21. After heating for 0.5 h, the reaction is chilled in ice. The solid product is collected, washed with N,N-dimethylformamide (DMF) and Et2O and dried to give 111 mg (86%) of yellow crystals: mp >300° C.; 1H NMR (DMSO-d6) δ 12.55 (d, 1H, J=12.8 Hz), 11.25 (s, 1H), 8.88 (d, 1H, J=12.8 Hz), 8.14 (s, 1H), 8.03 (d, 1H, J=8.07 Hz), 7.46 (d, 2H, J=8.94), 7.16 (d, 1H, J=8.07 Hz), 6.98 (d, 2H, J=8.94 Hz), 3.14 (m, 4H), 3.04 (s, 3H), 2.90 (s, 3H), 2.46 (m, 4H), 2.22 (s, 3H); HRMS (ESI) m/e calcd for C24H27N5O3 432.20411. found 432.20337 (M+H)+1, Analysis for C24H27N5O3, Calcd: C, 66.50; H, 6.28; N, 16.16. Found: C, 66.33; H, 6.43; N, 16.28.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:23])=[CH:9][C:8]1=[O:24].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:23][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[N:7]([CH2:6][CH:2]=[O:1])[C:8](=[O:24])[CH:9]=1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(-c3ccccc3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n(CC=O)c2cc(-c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
, To 94 mg of 1-(1,3-dioxolan-2-ylmethyl)-4-methyl-7-phenylquinolin-2(1H)-one, 3 mL of 80% aqueous trifluoroacetic acid solution was added, and stirred at room temperature for 5 and half hours, thereafter ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (4-methyl-2-oxo-7-phenyl-1,2-dihydroquinolin-1-yl)acetaldehyde as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[OH:13]S(O)(=O)=O.[OH2:18]>[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]([F:12])([F:10])[F:11])(=[O:13])=[O:18])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Agent: [Cr+6]
Agent: [O-2]
Product: O=S(=O)(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chromium trioxide (1.2 g, 11.7 mmol) was added to a solution of (4-bromophenyl)(trifluoromethyl)sulfane (1.5 g, 5.83 mmol), concentrated H2SO4 (6 mL), and H2O (10 mL). After stirring at rt for 2 h, the reaction mixture was poured into ice-water and extracted with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4), concentrated, and purified by column chromatography on silica gel (EtOAc/petroleum ether=1:100) to give 960 mg of 1-bromo-4-((trifluoromethyl)sulfonyl)benzene as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.89 (d, 2H), 7.85-7.81 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 133.4, 132.8, 132.1, 130.4, 119.7 (q, J=320 Hz).
Reaction SMILES: BrC1C=C(N2C3=NC=CC(C4C=NC5C(C=4)=CC=CC=5)=C3C(C)=C2)C=CC=1C#N.C([O:33]CCCN)(C)C.[CH:38]([O:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]1[CH:53]=[C:52]([N:54]2[C:58]3=[N:59][CH:60]=[CH:61][C:62]([C:63]4[CH:64]=[N:65][C:66]5[C:71]([CH:72]=4)=[CH:70][CH:69]=[CH:68][CH:67]=5)=[C:57]3[C:56]([CH3:73])=[CH:55]2)[CH:51]=[CH:50][C:47]=1[C:48]#[N:49])([CH3:40])[CH3:39]>>[CH:38]([O:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]1[CH:53]=[C:52]([N:54]2[C:58]3=[N:59][CH:60]=[CH:61][C:62]([C:63]4[CH:64]=[N:65][C:66]5[C:71]([CH:72]=4)=[CH:70][CH:69]=[CH:68][CH:67]=5)=[C:57]3[C:56]([CH3:73])=[CH:55]2)[CH:51]=[CH:50][C:47]=1[C:48]([NH2:49])=[O:33])([CH3:39])[CH3:40]
Reactant: CC(C)OCCCN
Reactant: Cc1cn(-c2ccc(C#N)c(NCCCOC(C)C)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: Cc1cn(-c2ccc(C(N)=O)c(NCCCOC(C)C)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 38 %

Procedure:
According to Example 1(6), a crude product of 2-(3-isopropoxypropylamino)-4-{(3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile was prepared using compound (40f) instead of compound (1e) and using 3-isopropoxypropylamine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (59) (the second stage yield: 38%) was prepared as a white solid using 2-(3-isopropoxypropylamino)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[N+:25]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[NH2:25])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3c(c2[N+](=O)[O-])CCCC3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3c(c2N)CCCC3)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 94.9 %

Procedure:
tert-Butyl[4-[(1-nitro-5,6,7,8-tetrahydro-2-naphthyl)amino]phenyl]carbamate (7.66 g, 20 mmol) was dissolved in tetrahydrofuran (77 mL) and methanol (77 mL), the solution was added with 10% palladium-carbon (0.77 g), and the mixture was stirred at room temperature for 42 hours under a hydrogen atmosphere. The catalyst was separated by filtration, then the solvent was evaporated under reduced pressure, and the residue was washed with hexane to obtain the title compound (6.71 g, yield 95%) as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14].N[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C(O)CCCC.O=C1C2C(=CC=CC=2)C(=O)N1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[N:8]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH2:20][CH2:19]3)[C:9]2=[O:10])=[CH:11][C:12]=1[S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Reactant: NC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: O=C1NC(=O)c2ccccc21
Solvent: CCCCCO
Product: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3ccc(Cl)cc3)CC1)C2=O

Procedure:
Reaction of 4-chloro-5-sulfamoylphthalimide (5.57 g., 0.0214 mole) and 4-amino-1-(4-chlorobenzyl)piperidine (4.8 g., 0.0214 mole) in 85 ml. of n-pentanol according to the procedure of Example 1(a) with heating at 130°-138° for a 48 hr. period afforded 7.07 g. (71%) m.p. 248°-250° (dec.) of the 1,3-dioxoisoindole product. A sample crystallized from dimethylformamide-methanol provided analytically pure 6-chloro-2-[1-[(4-chlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide, m.p. 250°-251° (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1N
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
To the solution of 4-amino-m-cresol (125 mg, 1.01 mmol, 1.0 eq) in 1 mL of NMP was added 4-chloro-N-methylpicolinamide (189 mg, 1.11 mmol, 1.1 eq) and cesium carbonate (658 mg, 2.02 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 75° C. for 12 hours, thereafter the mixture was diluted with water (ca. 50 mL) and aqueous layer extracted with ethyl acetate (ca. 50 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give sufficiently pure crude product which was carried to next step without further purification. LC/MS (m/z) [258.1] (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]=[N:5][OH:6].[Cl:12]N1C(=O)CCC1=O.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[N:5][OH:6])[Cl:12]
Reactant: ON=Cc1c(F)cccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 2-chloro-6-fluorobenzaldehyde oxime (5.13 g, 29.6 mmol) in DMF (50 ml) was added a portion of N-chlorosuccinimide followed by a syringe of HCl gas (5 ml from the vapors of a conc. HCl solution). The temperature increased slightly and the rest of the N-chlorosuccinimide (total of 4.07 g, 30.5 mmol) was added. After stirring at room temperature for 1 h, ice was added and the mixture was extracted twice with diethyl ether. The combined organic fractions were washed (brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, hexane/Et2O gradient) gave 2-chloro-6-fluorobenzoylchloride oxime (4.83 g, 78%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH3:7][N:8]([CH3:11])C=O.[F:12][C:13]1[C:14]([N:23]2[C:27]([CH3:28])=[C:26]([C:29]([OH:31])=O)[CH:25]=[N:24]2)=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1>ClCCl>[F:12][C:13]1[C:14]([N:23]2[C:27]([CH3:28])=[C:26]([C:29]([NH:15][C:14]3[CH:7]=[N:8][C:11]([C:26]4[CH2:25][CH2:2][CH:1]([OH:5])[CH2:28][CH:27]=4)=[C:18]([CH3:17])[CH:13]=3)=[O:31])[CH:25]=[N:24]2)=[N:15][CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C(=O)O)cnn1-c1ncc(C(F)(F)F)cc1F
Reactant: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3F)c2C)cnc1C1=CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.14 ml) and N,N-dimethylformamide (catalytic amounts) were added at room temperature to a solution of 1-(3-fluoro-5-trifluoromethylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (120 mg) described in Reference Example 130 in dichloromethane (5 ml) and stirred at room temperature for two hours. The solvent and an excess amount of oxalyl chloride were evaporated, and toluene (5 ml) was added to the resulted reaction mixture. Next, a solution of 2-(4-hydroxycyclohex-1-en-1-yl)-3-methyl-5-aminopyridine (81 mg) described in Reference Example 111 in pyridine (5 ml) was added thereto and stirred at room temperature overnight. After the reaction, 1N aqueous solution of sodium hydroxide was added under ice-cooling and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with a silica gel column chromatography (chloroform/methanol), washed with ethanol and the resulting solid was collected by filtration and dried at 60° C. in vacuo to give the titled compound (107 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:28](=[O:31])[CH2:29][CH3:30])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: CCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 14 mg, 38 μmol) and propanoyl chloride (10 mg, 114 μmol). Yield 14 mg (90%).
Reaction SMILES: C(ON[C@H]1CN[C@H](C(N)=O)C(C)=C1)C=C.[CH2:16]([O:19][N:20]([C@H:33]1[CH2:38][NH:37][C@H:36]([C:39]([NH2:41])=[O:40])[C:35]([CH:42]([CH3:44])[CH3:43])=[CH:34]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:17]=[CH2:18]>>[CH2:16]([O:19][NH:20][C@H:33]1[CH2:38][NH:37][C@H:36]([C:39]([NH2:41])=[O:40])[C:35]([CH:42]([CH3:44])[CH3:43])=[CH:34]1)[CH:17]=[CH2:18]
Reactant: C=CCON([C@@H]1C=C(C(C)C)[C@@H](C(N)=O)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON[C@@H]1C=C(C)[C@@H](C(N)=O)NC1
Product: C=CCON[C@@H]1C=C(C(C)C)[C@@H](C(N)=O)NC1
Yield: 60.5 %

Procedure:
(2S,5R)-5-(allyloxyamino)-3-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (55.0 mg, 61.0%) was prepared a similar manner as described in Intermediate 85 as an off-white solid, using (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 95, 160 mg, 0.38 mmol) as a starting material.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([CH3:20])=[N:17][NH:18][CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([CH3:20])=[N:17][N:18]([C:24]4[N:23]=[C:22]([NH2:21])[C:27]([CH3:28])=[CH:26][N:25]=4)[CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: Cc1n[nH]cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1cnc(Cl)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1N
Temperature: 165 °C

Procedure:
A mixture of 3-methyl-1H-pyrazole-4-carboxylic acid (adamantan-1-ylmethyl)-amide (1.6 g, 5.85 mmol), 4-amino-2-chloro-5-methylpyrimidine (924 mg, 6.4 mmol) and potassium carbonate (1.6 g, 11.7 mmol) in DMSO (10 mL) is heated at 165° C. for 14 h. The mixture is cooled to RT and partitioned between EtOAc and water and separate the layers. The aqueous layer is extracted twice with further EtOAc. The extracts are combined, dried and evaporated. Purification by flash chromatography eluting with a mixture of 7% MeOH and 1% TEA in DCM affords the title compound.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.C[K].[C:12](Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[C:19]1([NH:18][C:3](=[O:5])[CH:2]2[O:1][CH:6]2[C:7]([O:9][CH3:12])=[O:8])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1OC1C(=O)O
Reactant: Nc1ccccc1
Agent: C[K]
Solvent: CCOCC
Product: COC(=O)C1OC1C(=O)Nc1ccccc1
Yield: 70.7 %

Procedure:
To a suspension of monomethyl potassium epoxysuccinate (1.0 g) in ethyl ether (30 ml), oxalyl chloride (0.75 g) in ethyl ether was added dropwise with stirring under ice-cooling and the mixture was stirred for an hour at room temperature. To the reaction mixture, aniline (1.02 g) in ethyl ether was added dropwise with stirring under ice-cooling, and the mixture was stirred for an additional hour at room temperature. The precipitate produced was filtered off and the filtrate was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The crude product was purified by chromatography using silica gel as an absorbent and benzene as an eluent to give 0.84 g of methyl N-phenyl-2,3-epoxysuccinamate (Compound No. 50) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5](C)[C:4]=1[N+:11]([O-:13])=[O:12].[C:14](=[O:17])([O-])[O-:15].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>C(OC(=O)C)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]([OH:15])=[O:17])[C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc[n+]([O-])c(C)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: COc1ccnc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxy-2-methyl-3-nitropyridine-N-oxide (mixture with the positional isomer, 10.97 g, 48.5 mmol) was stirred in acetic anhydride (100 mL) at 80° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and in methanol (100 mL), potassium carbonate (33 g, 0.243 mol) was added to the resulting residue at room temperature and stirred at that temperature for 2 hours. The solvent was evaporated off under reduced pressure, and the resulting residue was diluted with ethyl acetate, and washed with water. The resulting organic layer was dried with magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was suspended in water (100 mL), and potassium permanganate (23 g, 0.145 mol) was added thereto at room temperature. The reaction solution was stirred at 90° C. for 16 hours, then potassium permanganate (20 g, 0.126 mol) was added thereto and stirred at 90° C. for 3 hours. The reaction solution was cooled to room temperature, methanol was added thereto, and stirred at room temperature for 2 hours. The reaction liquid was filtered, concentrated, and 2 N hydrochloric acid was added to the resulting residue, and the solution was controlled to have a pH of 2. The reaction solution was stirred at 0° C. for 1 hour, then the resulting milky white solid was taken out through filtration and dried to obtain the intended compound (1.35 g, 3 steps, 14%).