Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH:9]([CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[C:15](=[O:33])[CH2:14][S:13]1(=[O:35])=[O:34])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C>[F:44][C:41]1[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH:9]([OH:8])[CH2:10][CH2:11][CH:12]2[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:15](=[O:33])[CH2:14][S:13]2(=[O:34])=[O:35])=[CH:43][CH:42]=1
Reactant: O=C(CCCCCCN1C(=O)CS(=O)(=O)C1CCC(COc1ccc(F)cc1)OCc1ccccc1)OCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCCN1C(=O)CS(=O)(=O)C1CCC(O)COc1ccc(F)cc1

Procedure:
A solution of benzyl 7-{2-[3-benzyloxy-4-(4-fluorophenoxy)butyl]-1,1,4-trioxo-3-thiazolidinyl}heptanoate (1.1 g., 1.76 millimole) in absolute ethanol-ethyl acetate (100:2; v:v; 102 ml.) is magnetically stirred and hydrogenated at 25° C. and atmospheric pressure in the presence of 10% palladium/charcoal until hydrogen consumption ceases (~139 ml. of hydrogen is consumed). After removing the catalyst by filtration, the filtrate is concentrated in vacuo leaving an oily residue which is applied to a silica gel column (20 g.) with chloroform. Impurities are eluted with chloroform-acetic acid (25:1; v:v; 200 ml.); continued elution with the same eluant (375 ml.) affords the title compound as a tlc homogeneous, viscous oil (0.59 g., 75%); pmr (CDCl3) δ2.31 (2H, t), 2.73-3.37 (H, m), 3.60-4.30 (6H, m, containing singlets at 3.80 and 3.90), 4.61 (H, t), 6.67-7.60 (6H, m, containing a broad singlet at 7.30).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[N:7][CH:8]=1.COC(OC)C1N=CC(NC)=CC=1.[CH3:24][C@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH3:24][C@H:25]1[CH2:30][N:29]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][CH3:1])=[CH:8][N:7]=2)[CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32]
Reactant: CNc1ccc(C=O)nc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNc1ccc(C(OC)OC)nc1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(methylamino)-2-pyridinecarbaldehyde and 6-[bis(methyloxy)methyl]-N-methyl-3-pyridinamine (D60) (0.622 g), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.910 g, 4.552 mmol) and triethylamine (0.418 g, 4.139 mmol) in 1,2-DCE (40 mL) was stirred at room temperature overnight. Sodium tri(acetoxy)borohydride (1.14 g, 5.38 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated aq. NaHCO3 solution and water. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-100% EtOAc/petroleum ether gave the title compound as a yellow/brown oil (0.542 g). δH (CDCl3, 400 MHz) 7.96 (1H, d), 7.23 (1H, d), 6.88 (1H, dd), 4.17 (1H, br.s), 3.80 (2H, d), 3.58 (1H, d), 3.45 (1H, d), 3.12 (1H, td), 2.86 (3H, s), 2.76 (1H, m), 2.58 (1H, m), 2.18 (1H, dd), 2.07 (1H, m), 1.45 (9H, s), 1.23 (3H, d). MS (ES): MH+ 321.4
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[CH:32]([NH:35][CH:36]([CH3:38])[CH3:37])([CH3:34])[CH3:33]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:35]([CH:36]([CH3:38])[CH3:37])[CH:32]([CH3:34])[CH3:33])=[O:5]
Reactant: CC(C)NC(C)C
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C(C)C)C(C)C

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and diisopropylamine.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1SC.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1>>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[NH:34][CH2:33][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][N:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH2:26][CH2:27]1
Reactant: NCCCN1CCN(c2ccc3ccccc3n2)CC1
Reactant: CSc1nc2ccccc2c(=O)n1N
Product: Nn1c(NCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2ccccc2c1=O
Temperature: 145 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
A mixture of 131 mg of 3-amino-2-methylthio-3H-quinazolin-4-one as synthesized in above Step 6-1-A and 172 mg 3-(4-quinolin-2-ylpiperazin-1-yl)propylamine was heated at 145° C. under stirring for 5 hours. The reaction mixture was cooled and purified on silica gel column chromatography (methanol:methylene chloride=1:19) to provide 198 mg (73%) of 3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylamino]-3H-quinazolin-4-one.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:9]=[C:10]([N:15]2[C:19](=[O:20])[CH:18]([OH:21])S[CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]>O.CO.[Ru](Cl)(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([N:15]2[C:19](=[O:20])[CH:18]([OH:21])[O:2][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: O=C1C(O)SCN1c1ccc(Cl)c(Br)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(O)OCN1c1ccc(Cl)c(Br)c1
Reaction time: 1 h
Yield: 15.2 %

Procedure:
Sodium periodate (14.2 g) was dissolved in water (175 ml) and ruthenium trichloride (0.7 g) added to give a black solution. The solution was stirred during the addition of 3-(3-bromo-4-chlorophenyl)-5-hydroxythiazolidin-4-one (7.85 g) in methanol (35 ml) over 5 min, the reaction vessel was cooled in an ice bath to control the resulting exotherm. The mixture was stirred for 1 hour before quenching with sodium metabisulfite. The mixture was extracted with ethyl acetate and the combined organic extracts washed with aqueous sodium metabisulfite solution and water, then dried (MgSO4). Evaporation of the solvent under reduced pressure gave a gum which was triturated with dichloromethane to give the title compound as a grey solid (1.13 g), m.p. 139-140° C.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[S:31]1[C:35]2[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1>>[S:31]1[C:35]2[CH:36]=[C:37]([S:40]([N:11]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]3)(=[O:41])=[O:42])[CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc3ncsc3c2)c1
Yield: 85.4 %

Procedure:
Using 5-phenyl-1H-pyrrole-3-carbaldehyde (135 mg), sodium hydride (60% in oil, 38.3 mg), 15-crown-5 (0.18 mL) and 6-benzothiazolesulfonyl chloride (206 mg), a procedure as in Reference Example 219 was performed to give the title compound as white crystal (yield 248 mg, 85%).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([OH:32])=O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1.[O:33]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[NH:36][CH:35]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH2:34]1>CCOC(C)=O>[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([N:36]3[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:33][CH2:34][CH:35]3[CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:32])[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: COC(=O)CC1COc2ccccc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: COC(=O)CC1COc2ccccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 75 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
T3P (50% solution in EtOAc, 61.5 g, 96.6 mmol) was added to 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (10.3 g, 53.1 mmol), methyl 3,4-dihydro-2H-1,4-benzoxazin-3-ylacetate (Intermediate 2, 10.0 g, 48.3 mmol) and TEA (26.8 mL, 193.2 mmol) in EtOAc (125 mL) at rt. The resulting mixture was stirred at 75° C. for 16 h. The resulting solution was diluted with 350 mL of EtOAc and washed with sat. aq. NaHCO3 solution (160 mL), 0.5 M HCl solution (160 mL) and brine (160 mL). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by re-crystallization from MeOH to afford the title compound (10.1 g, 55%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[C:26]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 58.1 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess cyclopentanone (1.11 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 36 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-2 M ammonia in methanol afforded 0.31 g (58%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([O:16][CH3:17])[CH2:11][C:10]1=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=O)CCCCCCC>>[C:1]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([O:16][CH3:17])[CH2:11][C:10]1=[O:18])(=[O:8])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:19]
Reactant: COC1CCCN(C(=O)c2ccccc2)C(=O)C1
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)N1CCCC(OC)CC1=O

Procedure:
Synthesized as for N-benzoyl-3-methoxycaprolactam (Example VII) using octanoyl chloride (Aldrich) in place of benzoyl chloride.
Reaction SMILES: [CH3:1][NH2:2].O.Br[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1>C1COCC1>[CH3:1][NH:2][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a stirred solution of 40 wt % methylamine in H2O (50 mL, 581 mmole) in THF (50 mL) at 0° C. was added 2-(bromomethyl)naphthalene (10 g, 43 mmole) in one portion. The reaction was allowed to warm to RT and stirred for 16 hr, then was then concentrated under vacuum. The residue was taken up in Et2O and washed with 1.0 N NaOH then with brine, dried (Na2SO4), and concentrated to dryness. Purification by flash chromatography on silica gel (98:2 to 9:1 CHCl3/methanol containing 5% NH4OH) gave the title compound (3.95 g, 54%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 3 H), 7.79 (s, 1 H), 7.49 (m, 3 H), 3.94 (s, 2 H), 2.53 (s, 3 H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=[O:18])[CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH:8]=2)[CH3:2].[C:28](OCC)(=[O:30])[CH3:29].CC(C)([O-])C.[K+].Cl>O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=[O:18])[CH2:17][C:28](=[O:30])[CH3:29])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH:8]=2)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCn1c2ccc(C(C)=O)cc2c2cc(C(=O)c3ccccc3C)ccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCn1c2ccc(C(=O)CC(C)=O)cc2c2cc(C(=O)c3ccccc3C)ccc21
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A one liter four-necked flask equipped with a stirrer, a nitrogen inlet tube, a reflex condenser, and a thermometer was charged with 35.54 g of 1-[9-ethyl-6-(2-methylbenzoyl)-9H-carbazol-3-yl]ethanone, 264.33 g of ethyl acetate, and 33.66 g of potassium t-butoxide, and the mixture was refluxed in a nitrogen atmosphere for 5 hours. After cooling to room temperature, 100 ml of ion exchanged water and 100 ml of 6N hydrochloric acid were successively added, followed by stirring. The organic phase was separated and washed with a sodium chloride aqueous solution until neutral. A hundred fifty milliliters of n-hexane was added thereto, followed by cooling with ice for crystallization. The solid precipitated was collected by filtration by suction and dried under reduced pressure to give 17.29 g (43%) of pale yellow crystals, which had a melting point of 148° C. and was identified by various analyses to be β-diketone compound No. 3 having a carbazolyl group.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][N:8]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CNCC1c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
A stirred solution of 4-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (7.5 g, Reference Example 4) in methylene chloride (100 ml), at 23° C., was treated dropwise with triethylamine (5.8 ml). After stirring for 15 minutes the mixture was treated dropwise with a solution of benzoyl chloride [prepared in a separate vessel by treating a stirred solution of benzoic acid (5 g) in methylene chloride (15 ml), at 23° C., with oxalyl chloride (5 ml) and after stirring for 2 hours evaporating the reaction mixture] in methylene chloride (3.5 ml). The resulting dark brown mixture was stirred for 1.5 hours at 23° C. then filtered. The filtrate was successively washed with water (100 ml), then twice with hydrochloric acid (100 ml, 1N), then with brine (100 ml), then water (100 ml), then dried over magnesium sulphate and then evaporated (40° C. and 2.7 kPa) affording the title compound (10 g) as a viscous oil. 1H-NMR [400 MHz, (CD3)2SO at 383° K.] δ 1.13 (t, J=7 Hz, 3H); 3.49 (m, 1H); 3.65 (m, 1H); 3.75 to 3.90 (m, 2H); 3.90 to 4.20 (m, 2H); 4.09 (m, 2H);7.40 to 7.65 (m, 5H); 7.66 (d, J=8.5 Hz, 2H); 8.19 (d, J=8.5 Hz, 2H). MS [DCI (reactant gas, ammonia)]: 369[M+H]+, 386[M+NH4]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[CH3:32][C@@H:33]1[CH2:37][O:36][C:35](=[O:38])[NH:34]1>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:34]2[C@H:33]([CH3:32])[CH2:37][O:36][C:35]2=[O:38])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: C[C@@H]1COC(=O)N1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 89.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 180 and (R)-4-methyloxazolidin-2-one (121 mg) described in Preparation Example 25, the title compound (474 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Li]C(C)(C)C.CN([CH:20]=[O:21])C.Cl>C1COCC1.C(OCC)C>[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([CH:7]=1)[CH:20]=[O:21])([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(C)C)cc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(C)C)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-isopropyl-1-methyl-benzene (863 mg, 4.0 mmol) in 10 mL of THF is added a solution of t-BuLi (1.7 M in pentane, 4.7 mL) dropwise at below −70° C. After addition, the reaction mixture is stirred at −78° C. for one hour. A solution of DMF (0.46 mL) in 1 mL of THF is added at the same temperature and stirred for additional one hour. The reaction mixture is allowed to warm to room temperature then poured into a mixture containing ice (50 g) and concentrated HCl (2 mL) and stirred for 15 minutes. To the mixture, ethyl ether (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with ethyl ether. The organic solutions are combined, washed with brine, dried and concentrated to give 600 mg of 5-isopropyl-2-methyl-benzaldehyde. 1H NMR: (CDCl3) 10.27 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.17 (d, 1H), 2.94 (m, 1H), 2.63 (s, 3H), 1.24 (d, 6H).
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6]1)(=O)C.C(O)C.[Na].[Cl-].[NH4+]>C(OC(=O)C)(=O)C.O1CCCC1>[OH:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6]1
Reactant: CCOC(=O)C1Cc2cccnc2C(OC(C)=O)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2cccnc2C(O)C1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
At 0° C. 1.04 kg of metachloroperbenzoic acid was added to chloroform (6 L) solution of 689 g of the compound obtained in the above, and stirred at room temperature for 3 hours. 1:1 mixed solution of aqueous saturated sodium hydrogencarbonate solution and aqueous saturated sodium sulfite solution was added to the reaction liquid, and extracted with chloroform. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure to obtain ethyl 5,6,7,8-tetrahydroquinoline-6-carboxylate 1-oxide. The obtained compound was dissolved in 2 L of acetic anhydride, and stirred at 130° C. for 1 hour. The reaction liquid was distilled under reduced pressure, and diluted with aqueous saturated sodium hydrogencarbonate solution, and extracted with chloroform. The solvent was evaporated off under reduced pressure to obtain a mixture of ethyl (6RS,8SR)-8-acetoxy-5,6,7,8-tetrahydroquinoline-6-carboxylate and ethyl (6RS,8RS)-8-acetoxy-5,6,7,8-tetrahydroquinoline-6-carboxylate. At 0° C., ethanol (3.36 L) solution of 77.2 g of sodium was added to tetrahydrofuran (3 L) solution of the resulting mixture, and stirred at 0° C. for 1 hour. Aqueous saturated ammonium chloride solution was added to the reaction liquid, then extracted with chloroform, and the organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 336 g of ethyl (6RS,8SR)-8-hydroxy-5,6,7,8-tetrahydroquinoline-6-carboxylate as a brown oily substance. This compound contained impurities.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[NH2:62][C:63]1([C:66]([NH:68][CH3:69])=[O:67])[CH2:65][CH2:64]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:62][C:63]2([C:66](=[O:67])[NH:68][CH3:69])[CH2:65][CH2:64]2)=[O:19])[CH:8]=1)=[O:5]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: CNC(=O)C1(N)CC1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(NC(=O)c2cc(NC(=O)c3cc(-c4ncccc4F)c(Cl)cc3Cl)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.1 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 107, 961 mg, 2.04 mmol) in DMF (20 mL), were added N,N-diisopropylethylamine (0.8 mL, 5.5 mmol) and TPTU (848 mg, 2.85 mmol) and the mixture stirred at room temperature for 5 minutes. 1-Amino-N-methylcyclopropanecarboxamide (PCT Int. Appl., 2008051547) (300 mg, 2.65 mmol) was then added and the mixture stirred for 30 minutes. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous brine solution, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography over silica gel, eluting with EtOAc to afford the title compound as a white solid (916 mg, 79%). Crystallisation by vapour diffusion using methanol as the solvent and acetonitrile as the anti-solvent also afforded the title compound as crystalline colourless needles.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH:15]1([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:19]2=[O:34])[CH2:17][CH2:16]1.[H-].[Na+]>CN(C=O)C.CO>[CH:15]1([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:29][CH:28]=3)[C:19]2=[O:34])[CH2:17][CH2:16]1
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C1CC1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c(=O)n(C4CC4)c4cccnc43)cc2)nc2cccnc21
Temperature: 180 °C
Yield: 53.7 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (79 mg) was added to a solution of 1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and NaH (17.96 mg) in DMF (2 ml) at 100° C. The mixture was so heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-cyclopropyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals.