Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]3[CH2:19][CH2:20][CH2:21][N:14]3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1.ClC1C(O)=CC(N2C(=O)N3CCCCN3C2=S)=C(F)C=1>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]3[CH2:19][CH2:20][CH2:21][N:14]3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)cc3n(c2=O)CCC3)c(F)cc1Cl
Agent: O=c1n(-c2cc(O)c(Cl)cc2F)c(=S)n2n1CCCC2
Product: O=c1cc2n(c(=O)n1-c1cc(O)c(Cl)cc1F)CCC2
Yield: 86 %

Procedure:
This was synthesized from 2-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6,7-dihydropyrrolo[1,2-c]pyrimidine-1,3(2H,5H)-dione in 86% yield under similar conditions as described below for the preparation of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)hexa-hydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Example 10.2). 1H NMR (CDCl3, TMS): 2.22(2H, m), 3.06(2H, t, J=7.5 Hz), 3.13(1H, br), 4.01(2H, t, J=6.5 Hz), 5.71(1H, s), 6.87(1H, d, J=6.9 Hz), 7.18(1H, d, J=9.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][CH:31]=[C:32]([CH2:34]Cl)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)[S:30][CH:31]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)(C)C)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 4 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-thiazole (example 4 a]) in acetonitrile in the presence of cesium carbonate to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13]O)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[F:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][Cl:3])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1Oc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Fc1ccc(Oc2ccccc2CCl)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
8.5 g of thionyl chloride are added dropwise over a 10 minutes span to a stirring mixture of 13.0 g of 2-(4-fluorophenoxy)benzyl alcohol in 80 ml of benzene at ambient temperature. After total addition, the reaction mixture is stirred for 16 hours before being carefully poured onto 350 ml of crushed ice containing 8 ml of sodium bicarbonate. The mixture is stirred until the ice melts. The layers separate and the benzene layer is successively washed twice with 40 ml portions of a half saturated sodium bicarbonate solution, washed twice with 40 ml portions of water, washed once with a 25 ml portion of a saturated sodium chloride solution, dried and rotary evaporated to provide a clear liquid. The liquid is distilled at 106°-109° C. and 0.16 mm to provide a clear colorless liquid of 2-(4-fluorophenoxy)benzyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-])=O>C(O)(=O)C.[Zn]>[NH2:13][C:3]1[C:4]([CH3:12])=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[O:6][CH2:7][C:8]#[N:9]
Reactant: Cc1c(OCC#N)ccc(Cl)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c(OCC#N)ccc(Cl)c1N
Temperature: 62.5 °C

Procedure:
A mixture of (4-chloro-2-methyl-3-nitrophenoxy)acetonitrile (9.1 g) and zinc (dust) (10.5 g) in glacial acetic acid (90 mL) was heated at 60-65° C. for 4 hr under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature, then filtered through celite. The filtrate was evaporated under reduced pressure and the residue partitioned between ethyl ether (500 mL) and 10% ammonium hydroxide solution (500 mL). The ethereal solution was separated, washed with saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue flash chromatographed on silica, eluting with ethyl acetate:hexane (1:4) to afford 4.76 g as a light yellow oil which crystallized on standing.
Reaction SMILES: [CH3:1][N:2]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[C:10](=[O:21])[C:4]([C:5]([O:7]CC)=[O:6])=[C:3]1[CH3:22].[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[C:10](=[O:21])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[CH3:22]
Reactant: CCOC(=O)c1c(C)n(C)c(C)c(-c2ccc(Br)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)c(=O)c(-c2ccc(Br)cc2)c(C)n1C

Procedure:
2.7 g. of crude ethyl 1,2,6-trimethyl-5-(4'-bromophenyl)-4-oxonicotinate was suspended in 27 g. of 5% NaOH in 1:1 methanol/water. The reaction mixture was refluxed for 21/2 hours, cooled and acidified. Filtration of the resulting solid provided 2.2 g of 1,2,6-trimethyl-5-(4-bromophenyl)-4-oxonicotinic acid. m.p.=228°-230° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([C:13](OCC)=[O:14])[C:9]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][OH:14])[C:9]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1c[nH]c(-c2cccnc2F)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CO)c[nH]c1-c1cccnc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
A solution of ethyl 5-(2-fluoropyridin-3-yl)-4-methyl-1H-pyrrole-3-carboxylate (5.01 g) in tetrahydrofuran (50 mL) was cooled to −78° C., a 1.5 mol/L toluene solution (45 mL) of diisobutylaluminum hydride was added dropwise, and the mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture, insoluble materials were filtered off, and the filtrate was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound as colorless crystals (yield 1.72 g, 41%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:23]2[CH:22]=[C:21]([N:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20]([O:37][CH3:38])=[CH:19][C:18]=2[O:17][C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH:15]=2)([OH:3])=[O:2].[C:44](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C)C(=O)C>[CH3:44][O:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:23]2[CH:22]=[C:21]([N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:20]([O:37][CH3:38])=[CH:19][C:18]=2[O:17][C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])[CH:15]=2)=[O:3]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(OC)c(N(c3ccccc3)c3ccccc3)cc1C2c1ccccc1C(=O)O
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCN(CC)c1ccc2c(c1)Oc1cc(OC)c(N(c3ccccc3)c3ccccc3)cc1C2c1ccccc1C(=O)OC
Reaction time: 1 h

Procedure:
The carboxylic acid thus obtained and 10 parts of potassium carbonate were mixed in 200 cc of N,N-dimethylacetamide, to which 6.5 parts of dimethyl sulfate was added dropwise at 45° C. followed by stirring at the same temperature for one hour. The resulting reaction mixture was poured into 2 λ of water. Then, the deposited crystals were filtered off and recrystallized with methanol-ethylacetate to obtain 25.7 parts of 9- ( 2-methoxycarbonylphenyl ) -2-diphenylamino-3-methoxy-6-diethylaminoxanthene having a melting point of 117° to 119° C.
Reaction SMILES: O[C:2]1([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CC([O-])(C)C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C1COCC1>[C:9]([O:8][C:6]([N:4]1[CH2:5][C:2]2([O:15][CH2:14][C:13]2([CH3:17])[CH3:16])[CH2:3]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(O)(C(C)(C)CO)C1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCC2(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)azetidine-1-carboxylate (0.20 g, 0.82 mmol) in THF (4 ml) was added in rapid succession, KOtBu (0.19 g, 1.72 mmol) and p-toluenesulfonylchloride (0.16 g, 0.82 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes to give the title compound as a colorless oil 0.13 g, 70%. 1H NMR (CDCl3, 400 Mhz) 1.25 (6H, s), 1.45 (9H, s), 3.89 (2H, d), 4.12 (2H, d), 4.20 (2H, s).
Reaction SMILES: C(Cl)(C(Cl)=O)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[C:18][CH:19]([OH:22])[CH2:20][CH3:21])[CH:12]=1.C(N(CC)CC)C>C(Cl)Cl.O>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[C:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:12]=1
Reactant: CCC(O)C#Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)C#Cc1cccnc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a solution of (COCl)2 (7.9 mL, 91.0 mmol) in CH2Cl2 (300 mL) was added DMSO (11.0 mL, 151 mmol) at −78° C., followed by 1-(3-pyridinyl)-1-pentyn-3-ol (12.2 g, 75.6 mmol) in CH2Cl2 (100 mL). The mixture was stirred at −78° C. for 1 hr, and then quenched with triethylamine (32 mL, 227 mmol). After being warmed to 0° C., the mixture was diluted with water and the layers were separated. The organic phase was dried over MgSO4 and concentrated to give 1(3-pyridinyl)-1-pentyn-3-one (12.2 g, 99%) as an oil. 1H NMR (CDCl3, 400 MHz) 8.81 (bs, 1H), 8.68 (bs, 1H), 7.87 (m, 1H), 7.32 (m, 1H), 2.73 (q, J=7.4Hz, 2H), 1.24 (t, J=7.4 Hz, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[S:9][C:10]2[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7].Cl.N1C=CC=CC=1>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[S:9][C:10]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:7]
Reactant: COc1cccc(C(=O)c2sc3cc(OC)ccc3c2-c2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(c1cccc(O)c1)c1sc2cc(O)ccc2c1-c1ccccc1
Yield: 91 %

Procedure:
Employing the procedure of Example 7, 5.0 g. (0.0134 mole) of the product from Example 11 was demethylated by treatment with 25 g. of pyridine hydrochloride for three hours in a 220° C. oil bath. Yellow crystals, obtained from ethyl acetate, were recrystallized from a mixture of 20 ml. of methanol and about 12 ml. of water to give 4.184 g. (91 percent) of the title compound as yellowish-brown crystals. Melting point 202.0°-202.5° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH2:17][N:18]3[C@@H:22]([CH3:23])[C@@H:21]([C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=4)[O:20][C:19]3=[O:38])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].N(OCCCCC)=O.[I:47]I>C(Cl)(Cl)Cl.C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:26]1[CH:25]=[C:24]([C@H:21]2[O:20][C:19](=[O:38])[N:18]([CH2:17][C:10]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([I:47])[CH:3]=4)=[CH:14][N:13]=[C:12]([S:15][CH3:16])[N:11]=3)[C@H:22]2[CH3:23])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=1
Reactant: CSc1ncc(-c2ccc(F)c(N)c2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: II
Agent: CCCCCON=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CSc1ncc(-c2ccc(F)c(I)c2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of the title compound from Step A (2.1 g, 3.75 mmol), n-pentyl nitrite (0.66 g, 5.62 mmol) and I2 (1.24 g, 4.87 mmol) in chloroform (20 mL) was stirred at 80° C. for 1 h. The mixture was cooled, and the solvent was diluted with CH2Cl2. The mixture was washed with Na2S2O3 (5 mL), and with brine (5 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/hexane (10/90) to give the title compound as a yellow gum. 1H NMR (CDCl3, 500 MHz) δ 8.41 (s, 1H), 7.92 (s, 1H), 7.78 (s, 2H), 7.77 (m, 1H), 7.35 (m, 1H), 7.22 (m, 1H), 5.76 (d, J=8.5 Hz, 1H), 4.91 (d, J=17 Hz, 1H), 4.45 (m, 1H), 4.06 (d, J=17.5 Hz, 1H), 2.64 (s, 3H), 0.76 (d, J=7 Hz, 3H). LCMS=672.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9](I)=[CH:8][N:7]3[C:13]=2[CH3:14])[CH2:3][CH2:2]1.[O:15]=[C:16]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][NH:17]1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:17]4[CH:18]=[CH:19][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][C:16]4=[O:15])=[CH:8][N:7]3[C:13]=2[CH3:14])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc(I)cn12
Reactant: COC(=O)c1cc[nH]c(=O)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccn(-c2ccc3nc(C4CC4)c(C)n3c2)c(=O)c1
Temperature: 110 °C
Yield: 26.7 %

Procedure:
To a mixture of 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (1.9 g), methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (1.0 g), potassium carbonate (901 mg) and dioxane (30 ml) were added CuI (248 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (308 mg), and the mixture was heated at 110° C. in a sealed tube for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with a mixture of DCM and MeOH. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (550 mg) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[F:20])[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cc(Br)ccc2F)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Br)ccc1F)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a mixture of 4-{[1-(5-bromo-2-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.76 g, 7.9 mmol) and ytterbium(III) triflate hydrate (0.49 g, 0.79 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.72 mL, 7.9 mmol) and water (0.14 mL, 7.9 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(5-bromo-2-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.33 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21BrFNO3 M+: 422.3, observed: 404.2, 406.2.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17][CH2:16]2)=[CH:10][CH:9]=1>C(O)C>[CH3:5][O:6][C:7](=[O:28])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc(NC2CCNCC2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Ammonium formate (4.2 g, 66 mmol) was added to a solution of 46 (2.3 g, 6.9 mmol) in 100 mL of absolute ethanol. The mixture was purged with argon then palladium (0.8 g, 5% on activated carbon) was added. The resulting mixture was heated to 80° C. and maintained at that temperature for 12 h. After cooling to 25° C., the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was cooled to 0° C., saturated NaHCO3 (100 mL) was added and the resulting mixture was stirred for 30 min. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give 1.53 g (94%) of the title compound: TLC (Rf =0.20; 15% MeOH/CH2Cl2); 1H NMR (CDCl3) δ 7.85 (d, 2H, J=8.8), 6.54 (d, 2H, J=8.8), 4.08 (d, 1H, J=7.6), 3.85 (s, 3H), 3.47 (m, 1H), 3.13 (d, 2H, J=12.8), 2.72 (t, 2H, J=11.9), 2.07 (d, 2H, J=2.1), 1.37 (m, 2H); 13C NMR (CDCl3) δ 167.3, 150.7, 131.6, 118.0, 111.7, 51.5, 49.9, 45.4, 33.6; Anal. (C13H18N2O2 ·1/4 H2O·1/2 CH3OH) C, H, N.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH:21](Br)([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH:21]([CH3:23])[CH3:22])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reactant: CC(C)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Oc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 35.9 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.035 g, 0.099 mmol) in dichloromethane (1 mL) was treated with isopropyl bromide (0.037 g, 0.297 mmol), DBU (0.048 g, 0.205 mmol) and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.014 g of a clear oil. MS calculated for C16H19BrF3NO2+H: 394, observed: 394.
Reaction SMILES: C(OC(=O)NC1CC(=O)OC1OC1CCCC1)C=C.NC1C=CC(C(NC(C)C(N2CCCC2C(O)=O)=O)=O)=CC=1Cl.[O:43]=[C:44]1[O:48][CH:47]([O:49][CH2:50][CH2:51][C:52]2C=CC=[CH:54][CH:53]=2)[CH:46]([NH:58][C:59]([CH:61]2[CH2:65][CH2:64][CH2:63][N:62]2[C:66](=[O:80])[CH:67]([NH:69][C:70](=[O:79])[C:71]2[CH:76]=[CH:75][C:74]([NH2:77])=[C:73]([Cl:78])[CH:72]=2)[CH3:68])=[O:60])[CH2:45]1>>[CH:50]1([O:49][CH:47]2[CH:46]([NH:58][C:59]([CH:61]3[CH2:65][CH2:64][CH2:63][N:62]3[C:66](=[O:80])[CH:67]([NH:69][C:70](=[O:79])[C:71]3[CH:76]=[CH:75][C:74]([NH2:77])=[C:73]([Cl:78])[CH:72]=3)[CH3:68])=[O:60])[CH2:45][C:44](=[O:43])[O:48]2)[CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OC1CCCC1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OC1CCCC1
Yield: 51 %

Procedure:
Prepared from (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a to give the title compound (280 mg, 51% yield). 1H-NMR (500 MHz, CD3OD) δ 1.38 (d, 0.5H), 1.44 (d, 2.5H), 1.49-2.35 (m, 12H), 2.47 (dd, 0.7H), 2.56 (dd, 0.3H), 2.75 (dd, 0.3H), 2.81-2.88 (m, 0.1H), 2.97 (dd, 0.6H), 3.47-3.76 (m, 0.2H), 3.82-3.96 (m, 1H), 4.10-4.40 (m, 2H), 4.40-4.46 (m, 1H), 5.44 (d, 0.5H), 5.50 (d, 0.2H), 5.65 (d, 0.3H), 6.79 (d, 1H), 7.54-7.64 (m, 1H), 7.78 (d, 1H), 8.21-8.31 (m, 1H). Analytical HPLC 15.02, 15.34 min. LC-MS (ES+) m/e=507.3 (MH+)
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[N:22]1([C:28]2[CH:29]=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:34][C:31]3[N:30]=[CH:29][C:28]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:33][CH:32]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: Nc1ccc(N2CCCCC2)cn1
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCCCC4)cn3)ncc12
Temperature: 25 °C
Yield: 27.4 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 6-bromo-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a brown solid (0.358 g, 27.3%). 1H NMR δ (400 MHz, CDCl3) 8.79 (s, 1H), 8.27 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.01 (s, 1H), 7.38 (d, J=6.8 Hz, 1H), 5.98 (m, 1H), 3.1 (m, 4H), 2.60 (s, 3H), 2.30 (m, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.57–1.75 (m, 8H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2].[CH3:26]OS(OC)(=O)=O>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([N:17]([CH3:26])[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1cc(NS(=O)(=O)CC)ccc1OC
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCCC1CNC(=O)c1cc(N(C)S(=O)(=O)CC)ccc1OC
Yield: 26.8 %

Procedure:
To a solution of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-ethanesulfonamidobenzamide (266 mg) in dry acetone (7 ml), potassium carbonate and dimethylsulfate (100 mg) are added, and the resultant mixture is refluxed for 30 minutes. After evaporating the acetone, the residue is mixed with water and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is dissolved in methylene chloride, and the resultant mixture is chromatographed on a column of alumina, which is eluted with methylene chloride. After evaporating the eluate to remove the methylene chloride, the residue is washed with isopropyl ether and recrystallized from ethyl acetate/isopropyl ether in that order to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-(N-methylethanesulfonamido)benzamide (74 mg) as crystals melting at 85° to 87° C.