Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[F:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO.C(OCC)(=O)C.COCCOC>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:7]=2)[CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Fc1cccc(CNc2cc(C(F)(F)F)cc(Cl)n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1cccc(CNc2cc(C(F)(F)F)cc(-c3ccnc(F)c3)n2)c1
Temperature: 105 °C
Yield: 41.7 %

Procedure:
To 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine (70 mg, 0.230 mmol) was added 2-fluoropyridin-4-ylboronic acid (58.3 mg, 0.414 mmol), PdCl2(dppf).CH2Cl2 adduct (22.52 mg, 0.028 mmol), DME (1.2 ml), and 2M sodium carbonate (0.460 ml, 0.919 mmol). The resulting reaction mixture was stirred at 105° C. until completion as indicated by LCMS, about 6 hours. The reaction mixture was cooled, 15 ml of ethyl acetate and 5 ml of methanol was added, filtered and concentrated to yield a crude solid. The solid was purified by prep LC. The product was free-based using 200 ml of ethyl acetate and washed with saturated sodium bicarbonate (1×), water (2×), saturated salt solution (1×), dried sodium sulfate, filtered and concentrated to a constant mass, yielding 35 mg of titled compound as free base. LCMS (m/z): 366.2 (MH+), retention time=1.20 min.
Reaction SMILES: [CH2:1]1COC2(C3C=CC(CC#N)=CC=3C=CC3C=CC=CC2=3)O1.Cl.[CH:24]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29](=[O:39])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH2:40][C:41]([OH:43])=[O:42].C1COC2(C3C=CC(C(C)C#N)=CC=3C=CC3C=CC=CC2=3)O1>O.C(OCC)(=O)C.C(O)(=O)C>[CH:24]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29](=[O:39])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:40]([CH3:1])[C:41]([OH:43])=[O:42]
Reactant: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Reactant: N#CCc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Agent: CC(C#N)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 75 %

Procedure:
23.4 Gm. of 5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl acetonitrile is refluxed for seven hours in 160 ml. of acetic acid and 240 ml. of concentrated hydrochloric acid. The solution is cooled and added to ethyl acetate and water. The organic layer is washed with water then extracted with aqueous sodium carbonate. The extract is acidified with hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated to afford the product which is recrystallized from acetone/hexane to give 9.5 gm., 50%, of 5H-dibenzo[a,d]cyclohepten-5-on-2-yl acetic acid, m.p. 148°-149.5°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionitrile gives a 75% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:4](=[O:17])[C:5]2[C:10]([C:11](=[O:14])[C:12]=1Br)=[CH:9][C:8]([CH3:15])=[C:7]([CH3:16])[CH:6]=2>[N+](C1C=CC=CC=1)([O-])=O>[NH2:1][C:12]1[C:11](=[O:14])[C:10]2[C:5]([C:4](=[O:17])[C:3]=1[Br:2])=[CH:6][C:7]([CH3:16])=[C:8]([CH3:15])[CH:9]=2
Reactant: N
Reactant: Cc1cc2c(cc1C)C(=O)C(Br)=C(Br)C2=O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc2c(cc1C)C(=O)C(Br)=C(N)C2=O
Yield: 86 %

Procedure:
Dry ammonia was passed through a refluxing solution of 2,3-dibromo-6,7-dimethyl-1,4-naphthoquinone (10 g; mp 237°-238° C.) in dry nitrobenzene (65 ml) for 30 mins. and the orange solid which separated on cooling was filtered off and washed with light petroleum. After removal of ammonium bromide with water, 6.96 g. (86%) of material of mp 228° C. was obtained. Recrystallisation from glacial acetic acid gave analytically pure material of the same melting point. ν max(mull) 3400, 3300, 1680, 1610, 1585, 1570 cm-1. δ(DMSO) 2.35 (6H,s); 7.35 (2H, exchangeable broad singlet); 7.74 (2H,s). (Found; C, 51.50; H, 3.38; N, 4.79; C12H10BrNO2 requires; C, 51.45; H, 3.60; N, 5.00%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cccc(Cl)c1

Procedure:
Following General Procedure BG above and using 3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: COc1ccc(C(=O)c2c[nH]c3ncccc3c2=O)cc1C
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)c3)c3ncccc3c2=O)cc1C
Yield: 15.6 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,8]naphthyridin-4-one, and 1-Bromomethyl-3-trifluoromethyl-benzene 53 mg (0.22 mmol), to give 12 mg of desired compound. LCMS (M+H)+: 453.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:5][C:4](=[O:11])[CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C:15]=1[F:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:28][C:15]1[CH:16]=[C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]=1[CH2:13][N:5]1[C:4](=[O:11])[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1nc(C)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 50 °C
Reaction time: 12 h
Yield: 29.5 %

Procedure:
To a solution of 6-methyl-2-propylpyrimidin-4(3H)-one (2.0 g) and 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (4.4 g) in acetonitrile (50 mL) was added potassium carbonate (3.6 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (1.4 g, 29%) as a colorless viscous substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([Cl:17])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nc(Cl)c(C(=O)Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid (2.1 mmol) in CH2Cl2 (20 mL) are added oxalyl chloride (4.2 mmol) and one drop of DMF at 0° C. After stirred at room temperature for 3 h under N2 atmosphere, the reaction mixture is concentrated and dried in vacuo, to give 4,6-dichloro-2-methylsulfanylpyrimidine-5-carbonyl chloride as a yellow crystal.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][NH2:6].CC1C=CC(S(O[CH2:18][C@@H:19]2[O:24][C:23]3[CH:25]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[C:28]([Cl:29])[C:22]=3[O:21][CH2:20]2)(=O)=O)=CC=1.FCCCN>>[Cl:29][C:28]1[C:22]2[O:21][CH2:20][C@H:19]([CH2:18][NH:6][CH2:5][CH2:4][CH2:3][F:2])[O:24][C:23]=2[CH:25]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: NCCCF
Agent: Cl
Product: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CNCCCF)CO2

Procedure:
3-Fluoropropan-1-amine HCl-salt (0.178 g, 1.52 mmol) was basified on a SCX-3 ion exchange column (TEA/MeOH). [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) and 3-fluoropropan-1-amine (0.15 M in MeOH/TEA:4/1, 5 ml) was heated under microwave radiation at 120° C. for 1 h 20 min. MS m/z (rel. intensity, 70 eV) 337 (M+, 0.4), 91 (5), 90 (bp), 85 (3), 70 (17), 63 (3).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([C:22]#[N:23])([CH3:21])[CH3:20])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[Br:25]Br.O>O1CCOCC1.C(Cl)Cl>[Br:25][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([C:22]#[N:23])([CH3:21])[CH3:20])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc(NC(=O)c2cccc(C(C)(C)C#N)c2)ccc1C
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of N-(3-acetyl-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 112 (1.136 mmol, 364 mg) in dioxane (4 mL) and CH2Cl2 (1 mL) at 0° C. was added BROMINE (1.250 mmol, 0.064 mL). The reaction was stirred overnight at room temperature. Water was added and extracted with CH2Cl2. Organic layer was dried and evaporated to give N-(3-(2-bromoacetyl)-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 113 (450 mg, 99%). (m/z)=401 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.Cl>CC(O)(C)C.COCCOC.O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:26]4[O:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: C1COCCO1
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4nc5ccccc5o4)cn3)cc2)CC1
Temperature: 120 °C

Procedure:
65 mg of {4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester and 0.3 Ml of 2-chlorobenzoxazole were dissolved in 1.5 Ml of t-BuOH/DME (1:1) in a 5 Ml microwave tube with a stirring bar. 0.1 Ml of 4N—HCl in dioxane was added and the reaction vessel was sealed and heated at 120° C. for 2 hours by microwave. The reaction was diluted with ethyl acetate and the resulting precipitates were filtered and washed with ethyl acetate. The filter cake was dried by air in the suction funnel and analyzed by 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.2 (s, 3H) 1.5 (s, 2H) 1.8 (s, 6H) 2.3 (d, J=6.8 Hz, 2H) 3.6 (s, 4H) 7.2 (m, 1H) 7.3 (m, 1H) 7.3 (d, J=8.3 Hz, 2H) 7.5 (d, J=13.9 Hz, 2H) 8.0 (m, 3H) 8.4 (m, 1H) 8.9 (d, J=2.3 Hz, 1H) 11.0 (s, 1H); (M+H)+442.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH:12]=O)=[CH:7][CH:6]=2.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([NH2:19])=[O:18].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[NH:19][C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([O:24][CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])[N:14]=1)=[CH:7][CH:6]=2
Reactant: O=Cc1ccc2[nH]c(CO)cc2c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CO)cc4c3)nc2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 2-hydroxymethyl-1H-indole-5-carbaldehyde (90 mg, 0.51 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.15 g, 0.77 mmol) in N,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt %) (0.14 g, 0.77 mmol) and p-toluenesulfonic acid (20 mg, 0.10 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen, cooled to room temperature, and concentrated under reduced pressure. Water (20 mL) was added. The separated solid was filtered, washed with water (20 mL) and ether (20 mL), and dried under vacuum. Crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent), to give the title compound as an off-white solid. Yield: 0.06 g (33%). MP 264-265° C. 1H NMR (400 MHz, DMSO-d6): δ 11.85 (br s, 1H), 11.36 (s, 1H), 8.39 (s, 1H), 7.93 (dd, J=8.6 and 1.6 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 6.41 (s, 1H). 5.34 (t, J=5.8 Hz, 1H), 4.63 (d, J=5.5 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:17])=[O:28])([CH3:25])[CH3:24]
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and isopropyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1cc(Br)ccn1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
Under a stream of nitrogen, 5.0 g (29.07 mmol) of 4-bromo-2-picoline and 10.2 g (60.95 mmol) of ethyl 4-fluorobenzoate are placed in a round-bottomed flask and dissolved in 50 mL of anhydrous tetrahydrofuran. The mixture is cooled to 0° C. and 70 mL (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours, cooled to 5° C., and 100 mL of water are then gradually added. The medium is then diluted with 250 mL of ethyl acetate and 100 mL of water. The organic phase is separated out and the aqueous phase is extracted twice with 100 mL of ethyl acetate. The organic phases are then combined, dried over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, and the resulting mixture is stirred and then concentrated under reduced pressure. The powder obtained is used as a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 7.5 g (88%) of compound are obtained in the form of a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2].[C:23]([O:27][C:28]([CH2:30][NH:31][C@H:32]1[C@H:36]([O:37][CH3:38])[CH2:35][NH:34][CH2:33]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:34]3[CH2:35][C@@H:36]([O:37][CH3:38])[C@H:32]([NH:31][CH2:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:33]3)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CO[C@@H]1CNC[C@H]1NCC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@@H](NCC(=O)OC(C)(C)C)[C@H](OC)C3)ccc2c1=O

Procedure:
With use of 7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester obtained in Example A-1 (4) and (-)-trans-3-(N-t-butoxycarbonylmethylamino)-4-methoxypyrrolidine obtained in Example B-3, there was obtained (+)-7-[trans-3-(N-t-butoxycarbonylmethylamino)-4-methoxy-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (amorphous) in the same manner as in Example C-1 (1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.O>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.8 %

Procedure:
To a solution of 6-chloro-3-pyridinecarboxylic acid (10 g, 63.5 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (11.3 g, 69.8 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled and monoethyl malonate magnesium salt (10 g, 34.9 mmol) was added. The mixture was stirred at room temperature for 30 min. To the reaction solution was added water (200 ml) and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(6-chloro-3-pyridyl)-3-oxopropionate (9.28 g, 64%) as a brown oil.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.Cl.[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1.[Cl-].[NH4+].[Cl-].[Zn+2].[Cl-].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>[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Brc1ccncc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2cnccc2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A solution of LDA (2.86 mL, 5.14 mmol) in THF (2.5 mL) was transferred to a solution of 4-bromopyridine hydrochloride (500 mg, 2.57 mmol) in THF (5 mL) at −78° C. and stirred for 30 min. Zinc chloride (350 mg, 2.57 mmol) in THF (2.5 mL) was added to the above reaction mixture. A precipitate was formed and the mixture was allowed to warm to room temperature. Next, 1-bromo-4-nitrobenzene (1039 mg, 5.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (149 mg, 0.129 mmol) were added, and the reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The resulting reaction mixture was diluted with saturated solution of ammonium chloride (25 mL) and extracted with EtOAc (2×25 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (40 g ISCO column, eluting with 0% to 50% EtOAc in CH2Cl2) to afford Intermediate 13A (300 mg, 1.023 mmol, 10.47% yield) as a pale yellow solid. MS (ES): m/z=280.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (s, 1 H) 7.87 (s, 1 H) 7.97 (d, J=5.29 Hz, 1 H) 8.41 (s, 1 H) 8.43 (s, 1 H) 8.57 (d, J=5.29 Hz, 1 H) 8.66 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:42])[F:43])=[CH:38][CH:37]=2)=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(C(F)(F)F)cc4)nc3n2)CC1

Procedure:
6-(2, 6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 36 was reacted with trifluoro-p-tolyl isocyanate according to the general procedure of Example 37. Chromatography, eluting first with ethyl acetate:methyl alcohol:triethylamine (90:10:1) then switching to ethyl acetate:ethanol:triethylamine (9:2:1) gave 0.8650 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(4-trifluoromethyl-phenyl)-urea, ESMS (20/80 MeOH/CH3CN +0.1% AcOH): M+ +H=633; mp 145.5-151° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@H:16]([NH2:22])[CH2:15]2.[OH-].[Na+]>S(Cl)(Cl)=O.C(Cl)Cl.C(OCC)(=O)C>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@H:16]([NH:22][C:11]([C:10]1[CH:9]=[N:8][N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=13)=[O:13])[CH2:15]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Cc1cccc2c(C(=O)O)cnn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc2c(C(=O)N[C@@H]3CN4CCC3CC4)cnn12
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A solution of 880 mg (5 mmol) of 7-methyl-3-pyrazolo[1,5-a]pyridinecarboxylic acid in 10 ml of thionyl chloride was heated under reflux for 30 minutes. Thionyl chloride was distilled off under reduced pressure and the residue was dissolved in 30 ml of methylene chloride. The resultant solution was added dropwise under ice cooling to a solution of 644 mg (5.1 mmol) of (S)-(-)-1-azabicyclo[2.2.2]octan-3-amine, which had been prepared in accordance with the procedure disclosed in Japanese Patent Application Laid-Open No. 196583/1988, in 30 ml of methylene chloride. The resultant mixture was stirred for 30 minutes under ice cooling and for additional 40 minutes at room temperature. 2N aq. NaOH solution was added to the reaction mixture and, after the mixture so obtained was stirred for 10 minutes, the organic layer was collected. Further, the water layer was extracted with methylene chloride and the extract was dried over anhydrous potassium carbonate. Methylene chloride was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column (chloroform:methanol=10:1, 5:1). An oily substance thus obtained was dissolved in ethyl acetate. The solvent was distilled off under reduced pressure, and crystals thus obtained were washed with ether, whereby 1.2 g (4.2 mmol) of the title compound were obtained as white crystals (yield: 84.5%).