Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[C:10](=[O:25])[NH:11][C:12](=[O:24])[N:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:16])[CH:14]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:18]([NH:17][C:15]([N:13]1[CH:14]=[C:9]([NH:8][CH3:1])[C:10](=[O:25])[NH:11][C:12]1=[O:24])=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCNC(=O)n1cc(N(C)Cc2ccccc2)c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCNC(=O)n1cc(NC)c(=O)[nH]c1=O
Yield: 26.6 %

Procedure:
5-(Benzyl(methyl)amino)-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide(0.10 g, 0.28 mmol) was dissolved in EtOAc (30 mL) and hydrogenated in an H-Cube apparatus (using 10% Pd/C as catalyst, 1 bar hydrogen pressure, at 40° C.). The reaction mixture was concentrated under reduced pressure. The crude was purified by column chromatography using SI (2 g) cartridge (cyclohexane:EtOAc 85:15) to afford the title compound (0.02 g, 27%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.78-0.99 (m, 3H), 1.17-1.36 (m, 6H), 1.50 (dd, J=14.0, 7.0 Hz, 2H), 2.57 (s, 3H), 3.27 (dd, J=5.7, 6.9 Hz, 2H), 5.01 (s, 1H), 7.05 (s, 1H), 9.32 (t, J=5.7 Hz, 1H), 11.87 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 13.85, 21.96, 25.89, 28.71, 29.70, 30.82, 40.21, 106.74, 126.49, 150.01, 150.68, 160.01. MS (ESI) m/z: 267 [M-H]−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.C1CCN2C(=NCCC2)CC1.[CH2:35]([NH:37][S:38](Cl)(=[O:40])=[O:39])[CH3:36]>C1COCC1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH:1][S:38](=[O:40])(=[O:39])[NH:37][CH2:35][CH3:36])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: CCNS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(N)nc(-c2ccncc2)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNS(=O)(=O)Nc1nc(-c2ccncc2)nc(Cl)c1Oc1ccccc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Amino-6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (100 mg) was dissolved in THF (5 ml) and DCM (5 ml). DBU (46 mg) and DMAP (37 mg) were added followed by the addition of ethyl-sulfamoylchloride (prepared from ethylamine hydrochloride and sulfuryl chloride). The mixture was stirred for 12 h at r.t. The solvent was evaporated. Water and a 10% solution of citric acid were added followed by extraction with EtOAc and DCM. The combined organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure. After purification of the residue by chromatography over silicagel with EtOAc/methanol/ammonia=4:1:0.5, ethyl sulfamic acid-[6-chloro-5-(o-methoxy-phenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (10 mg) was obtained. tR=4.31 min, (LC); [M+H]+=436.14 (ES+).
Reaction SMILES: [CH3:1][N:2]([CH2:5][CH2:6][CH:7]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)OC.[CH3:24]O>[Ni]>[CH3:1][NH:2][CH2:5][CH2:6][C@:7]([CH3:24])([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: CO
Reactant: CON(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: [Ni]
Product: CNCC[C@](C)(Oc1cccc2ccccc12)c1cccs1
Reaction time: 12 h

Procedure:
N-methyl-N-methoxyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine obtained in example 3 was dissolved in 15 mL of methanol with 0.67 g of Raney-nickel were charged in a glass autoclave. The resulting solution was hydrogenated at 50□ for 12 hours. Upon completion of hydrogenation the reaction mixture was filtered and solvent is removed under reduced pressure, and then the desired compound is obtained as an oily compound (12.0 g, 96.4% by HPLC assay). 1H NMR (400 MHz, CDCl3) δ (ppm)=2.2 (m, 1H), 2.4 (m, 1H), 2.4 (s, 3H), 2.8 (m, 2H), 5.8 (m, 1H), 6.8 (d, 1H), 6.9 (m, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 7.3 (d, 1H), 7.4 (m, 1H), 7.5 (m, 2H), 7.8 (m, 1H), 8.3 (m, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][C:23]=1[F:34])[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[CH:24][C:23]=1[F:34])[CH3:19]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1F
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1F
Temperature: 120 °C
Yield: 18.1 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (76 mg, 0.348 mmol), N-ethyl-2-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (100 mg, 0.348 mmol), (cyanomethyl)trimethylphosphonium iodide (127 mg, 0.521 mmol) and N,N-diisopropylethylamine (0.303 ml, 1.738 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 120° C. for 3 h. The reaction mixture became a dark brown suspension. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)—N-ethyl-2-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (28.5 mg, 0.063 mmol, 18.12% yield) as a brownish solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (t, J=7.20 Hz, 3H) 1.83-2.02 (m, 3H) 2.18 (dd, J=6.44, 4.17 Hz, 1H) 2.44-2.49 (m, 4H) 2.81-3.01 (m, 4H) 3.23-3.32 (m, 2H) 3.34-3.44 (m, 3H) 3.52-3.64 (m, 1H) 3.93-4.01 (m, 1H) 6.91 (td, J=8.21, 2.53 Hz, 1H) 6.97 (d, J=1.77 Hz, 1H) 7.00 (dd, J=11.37, 2.53 Hz, 1H) 7.62 (d, J=1.52 Hz, 1H) 7.67 (dd, J=8.46, 7.20 Hz, 1H) 8.86 (t, J=5.43 Hz, 1H) 10.45 (s, 1H). [M+H] calc'd for C24H29FN6O2, 453; found, 453.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:38](=S)=[S:39]>C(O)C>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[CH:3]=[C:2]4[NH:1][C:38](=[S:39])[N:12]([CH2:13][CH3:14])[C:11]4=[CH:10][C:9]=3[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: S=C=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c(=S)[nH]c2cc3c(N4CCN(C(=S)NCc5ccccc5)CC4)ncnc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 502.7 mg (1.19 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 10 ml of ethanol were added 1.66 ml (11.9 mmol) of triethylamine and 10 ml (166 mmol) of carbon disulfide, followed by overnight stirring at room temperature in an atmosphere of argon. After the solvent was evaporated, the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([OH:24])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([CH:23]=1)[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Cc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(Cl)cc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 54.5 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 5-chloro-2-methyl-phenol (26 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(5-chloro-2-methyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (20 mg, 55%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.01 (br. s., 1H), 7.93 (d, J=8.2 Hz, 2H), 7.54-7.64 (m, 3H), 7.18 (d, J=7.8 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.91 (dd, J=8.0, 2.0 Hz, 1H), 5.22 (s, 2H), 2.18 (s, 3H).
Reaction SMILES: O=[C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH2:3][C:4]#[N:5].Cl.[CH3:17][NH2:18].C([O-])(=O)C.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[CH3:17][NH:18][C:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[CH:3][C:4]#[N:5]
Reactant: N#CCC(=O)c1ccc2ccccc2c1
Reactant: CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CNC(=CC#N)c1ccc2ccccc2c1
Yield: 58 %

Procedure:
A solution of β-oxo-2-naphthalenepropionitrile (5.0 g, 0.0256 mol) in toluene is treated with methylamine hydrochloride ()2.6 g, 0.0384 mol), sodium acetate (3.15 g, 0.0386 mol) and a catalytic amount of acetic acid, heated at reflux temperature (fitted with a Dean Stark trap) for 6 hours, cooled, diluted with ethyl acetate and dilute hydrochloric acid. The organic phase is dried over Na2SO4 and concentrated in vacuo to give a residue which is triturated under hexanes to give the title compound as a yellow solid, 3.1 g (58% yield) mp 138° C., identified by IR, 1NHMR and mass spectral analyses.
Reaction SMILES: Cl[C:2]([F:28])([F:27])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:5]([CH:24]([CH3:26])[CH3:25])[N:4]=1.C(N(CC)CC)C>C(O)C.[Pd]>[F:28][CH:2]([F:27])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:5]([CH:24]([CH3:26])[CH3:25])[N:4]=1
Reactant: COC(=O)c1c(C(F)(F)Cl)nc(C(C)C)c(C(=O)OC(C)(C)C)c1CC(C)C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1c(C(F)F)nc(C(C)C)c(C(=O)OC(C)(C)C)c1CC(C)C
Yield: 90.8 %

Procedure:
A solution of 17 g (40 mmol) of crude 3-methyl 5-(1,1-dimethylethyl) 2-(chlorodifluoromethyl)-6-(1-methylethyl)-4-(2-methylpropyl)-3,5-pyridinedicarboxylate and 7 mL of triethylamine in 160 mL of ethanol was subjected to hydrogenolysis at ambient temperature and 2 atom pressure in the presence of 3 g of 5% palladium on charcoal for 18 hours. The suspension was filtered through celite and concentrated. Water and CH2Cl2 were added. The CH2Cl2 layer was separated, washed with H2O, dried and concentrated. Column chromatography on silica gel (2% ethyl acetate/cyclohexane) gave 14 g (91%) of 5-(1,1-dimethylethyl) 3-methyl 2-(difluoromethyl)-6-(1-methylethyl)-4-(2-methylpropyl)-3,5-Pyridinedicarboxylate as colorless oil, nD25 1.4713.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[CH:5][N:4]=1>CO.[Pd]>[F:16][C:2]([F:1])([F:15])[C:3]1[N:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][N:8]=1
Reactant: COC(=O)/C=C/c1cnc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A mixture of methyl (2E)-3-[2-(trifluoromethyl)-5-pyrimidinyl]-2-propenoate (870 mg, 3.75 mmol) and Pd/C (39.9 mg, 0.375 mmol) in methanol (4 mL) was stirred at room temperature for 1 h under hydrogen. After cooling, the mixture was filtered through silica gel. The filtrate was concentrated to afford the title compound (577 mg, 2.47 mmol, 65.8% yield). LCMS: rt=2.47 min, [M+H+]=235
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].O>C(Cl)Cl>[O:1]=[CH:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Solvent: ClCCl
Solvent: O
Product: O=CCN1C(=O)c2ccccc2C1=O
Yield: 74 %

Procedure:
The preparation from N-(2-hydroxyethyl)phthalimide was carried out as in example 2; cooling was carried out by means of tap water. Yield: 74%, m.p. 114° C. (from methylene chloride).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CO.CCOCC.CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cn1
Yield: 90 %

Procedure:
To a solution of 5-bromo-2-formylpyridine (4.6 g, 25 mmol) in methanol (30 ml) was added sodium borohydride (0.93 g, 25 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 1 hour. After evaporating the solvent in vacuo, the residue obtained was diluted with ether, poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained and imidazole (3.4 g, 49 mmol) in N,N-dimethylformamide (30 ml) was added t-butyldimethylsilyl chloride (4.1 g, 27 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was poured into water (50 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:49 to 1:9) as the eluent to afford the title compound (6.8 g) in a yield of 90% as a white crystalline solid.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH2:18][OH:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Compound 13 (2.08 g, 7.04 mmol) was dissolved in chloroform (100 mL), and Manganese(IV) oxide (9.20 g, 0.106 mol) was added to the solution, followed by stirring at room temperature overnight. The unsoluble material was filtered out through Celite, and the filtrate was combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:1) to obtain 3-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)benzaldehyde (2.04 g, quantitative yield).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)[CH2:7][CH2:8][CH2:9][CH3:10].[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:16]2[CH:12]([O:11][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][C:15]2=[O:17])=[O:27])=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCCCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCOC1CCC(=O)N1C(=O)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
15.57 cm3 of a 1.5M solution of n-butyllithium in n-hexane is added at -70° C. to a solution of 4 g of 5-(1-pentyloxy) pyrrolidin-2-one in 80 cm3 of tetrahydrofuran. Agitation is carried out for 15 minutes at -70° C. then while maintaining this temperature, a solution of 3.98 g of para-anisoyl chloride at 58% in toluene is added. After allowing to return to ambient tempera-ture and evaporating under reduced pressure, the residue is chromatographed on silica (eluent: n-hexane-ethyl acetate 2-1). 5.1 g of sought product is obtained.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]>>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])([O-:18])=[O:17]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=C(O)[C@H]1CCCN1c1ccccc1[N+](=O)[O-]
Yield: 82.3 %

Procedure:
The same procedures used in Reference Example 1 were repeated except for using D-proline and 1-fluoro-2-nitrobenzene to give the title compound. Yield 82.3%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[CH3:12])=[O:6]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(O)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(O)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure D from 2-fluoro-4-hydroxy-benzoic acid and 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (Intermediate 11). MS (ES+) 307.3.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](O)[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].[NH4+]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:15])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: Cc1ncc([N+](=O)[O-])c(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ncc([N+](=O)[O-])c(Cl)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,3-Dimethyl-4-hydroxy-5-nitropyridine (26.8 g, 0.16 mol) prepared in Step 3 was added to 85 ml of phosphorus oxychloride. Phosphorus pentachloride (33.3 g, 0.16 mol) was added to the reaction mixture, which was then refluxed under stirring for 2 hours. The reaction mixture was left overnight at room temperature, added to ice water, brought to pH 5 with 28% ammonium hydroxide, and then extracted with ether. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated to give 28.3 g of the titled compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]12([CH2:30][C:31](Cl)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([CH2:30][C:31]([NH:1][N:2]3[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]4[C:4](=[CH:5][C:6]([C:15]([F:18])([F:16])[F:17])=[CH:7][CH:8]=4)[C:3]3=[O:19])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)c1nn(N)c(=O)c2cc(C(F)(F)F)ccc12
Product: CC(C)c1nn(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(=O)c2cc(C(F)(F)F)ccc12

Procedure:
The product from Example 173A and 2-(adamantan-1-yl)acetyl chloride were treated as in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.19-11.28 (m, 1H), 8.58 (s, 1H), 8.28-8.40 (m, 2H), 3.58-3.70 (m, 1H), 2.04 (s, 2H), 1.93-1.98 (bs, 3H), 1.55-1.75 (m, 12H), 1.27 (d, J=6.7 Hz, 6H); MS (ESI+) M/Z 448 (M+H)+.
Reaction SMILES: CN(C)CCN(C)C.[CH:9]#[C:10][CH3:11].[Li]CCCC.Br[CH2:18][CH2:19][CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[Cl-].[NH4+]>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1.C1COCC1>[CH3:30][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:19][CH2:18][C:9]#[C:10][CH3:11]
Reactant: CCCCCCCCCC(C)CCBr
Reactant: C#CC
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC#CCCC(C)CCCCCCCCC
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Tetramethylethylenediamine (TMEDA) (15 ml) was added to a THF (80 ml) solution of propyne (about 4 g, 0.1 mol) under argon. To the mixture, n-BuLi (1.55 M, 64.5 ml, 100 mmols) was added dropwise at −78° C. With the temperature being raised gradually to 0° C., the mixture was stirred for 1.5 hours, and then cooled again to −78° C. Thereto, an HMPA-THF (20 ml+20 ml) solution of the 1-bromo-3-methyldodecane (5″) (13.2 g, 50 mmols) was added dropwise, and with the temperature of the mixture being raised gradually to room temperature, stirring was continued overnight. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and extracted with hexane. The resulting organic layer was washed (water, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride), dried (magnesium sulfate), and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6-methyl-2-pentadecyne (6″) (12.1 g, 97%). 1H-NMR (90 MHz, CDCl3) 0.84 (3H,d,J=7,6-Me), 0.88 (3H,t,J=7,15-H), 1.0-1.6 (19H,m,5˜14-H), 1.77 (3H,t,J=2.5,1-H), 2.12 (2H,m,4-H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)c4ccncc4)ccc32)n1)c1ccccc1
Yield: 23 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and isonicotinoyl chloride hydrochloride (20 mg, 0.11 mmol) furnished the product (10 mg, 23%) after chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH:23]([CH2:25][CH:26]=[CH:27][CH3:28])[C:11]3=[C:12]4[C:17](=[CH:18][CH:19]=[C:10]3[C:6]=2[C:7]=1[O:8][CH3:9])[NH:16][C:15]([CH3:21])([CH3:20])[CH:14]=[C:13]4[CH3:22].[I-].[CH:30]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH:23]([CH2:25][CH:26]=[C:27]([CH3:30])[CH3:28])[C:11]3=[C:12]4[C:17](=[CH:18][CH:19]=[C:10]3[C:6]=2[C:7]=1[O:8][CH3:9])[NH:16][C:15]([CH3:20])([CH3:21])[CH:14]=[C:13]4[CH3:22]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC=CCC1Oc2ccc(O)c(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Agent: [I-]
Product: COc1c(O)ccc2c1-c1ccc3c(c1C(CC=C(C)C)O2)C(C)=CC(C)(C)N3

Procedure:
The intermediate aldehyde from Example 282 and isopropyltriphenylphosphonium iodide were processed according to Example 282 to give the desired compound. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.91 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 6.46 (d, J=9 Hz, 1H), 6.14 (s, 1H), 5.60 (dd, J=9, 3 Hz, 1H), 5.43 (s, 1H), 5.15 (m, 1H), 3.64 (s, 3H), 2.45-2.18 (m, 2H), 2.15 (s, 3H), 1.63 (s, 3H), 1.32 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); MS (APCI) m/e (M+H)+ 392, (M−H)− 390.