Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:28][CH3:29])[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)[CH:15]=[C:14]([CH3:27])[N:13]=1.CO>[Fe].C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:28][CH3:29])[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH:15]=[C:14]([CH3:27])[N:13]=1
Reactant: CCN(c1nc(C)cc(-c2ccccc2[N+](=O)[O-])n1)c1ccc(C(C)C)cc1Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(c1nc(C)cc(-c2ccccc2N)n1)c1ccc(C(C)C)cc1Br
Reaction time: 6 h

Procedure:
The product of Example 11 (778 mg), methanol (40.5 mL), acetic acid (13.5 mL) and iron powder (382 mg) were heated at reflux and stirred mechanically for 6 h. More iron powder (1.15 g) was added and the reaction was heated at reflux 2 more hours, after which it was cooled, filtered through celite, and concentrated to a thick black oil. Added ethyl acetate (200 mL) and water (100 mL), stirred, and filtered through celite. The layers were separated and the ethyl acetate dried over MgSO4 and concentrated to a thick yellow oil (754 mg). The oil was chromatographed on silica gel using ethyl acetate/hexane (1:9) as eluent. The title compound was obtained as an off-white solid (526 mg). CI-HRMS calc'd. for C22H26N4Br (M+H)+ : 425.134083. Found: 425.131850.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 3.19 (s, 4H), 3.77 (s, 3H), 4.13 (s, 4H), 6.88-7.02 (m, 4H), 7.23-7.27 (m, 1H), 7.45-7.71 (m, 3H).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([I:13])[CH:7]=[C:8]([Cl:12])[C:9]=2[Cl:11])[C:4](=[O:14])[N:3]1C(C)(C1C=CC=CC=1)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Cl:11][C:9]1[C:8]([Cl:12])=[CH:7][C:6]([I:13])=[C:5]2[C:10]=1[CH2:2][NH:3][C:4]2=[O:14]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)cc(Cl)c(Cl)c2C1O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(Cl)c(Cl)cc(I)c21
Yield: 74 %

Procedure:
In a similar manner to Step 4 of Example 16, 3-hydroxy-4,5-dichloro-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (347 mg, 0.750 mmol) was dissolved in nitromethane (14 mL), and the solution was treated with trifluoroacetic acid (0.867 mL, 11.3 mmol) and triethylsilane (0.240 mL, 1.50 mmol), followed by purification by slurry using chloroform to obtain 4,5-dichloro-7-iodoisoindolinone (182 mg, yield 74%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Cl:25][C:26]1[CH:31]=[C:30](CO)[CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[Br:24][CH2:20][C:30]1[CH:29]=[CH:28][N:27]=[C:26]([Cl:25])[CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccnc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CBr)ccn1
Yield: 73 %

Procedure:
Triphenylphosphine (19 g, 71 mmol) and carbon tetrabromide (29 g, 88 mmol) were added to a solution of 2-chloropyridine-4-methanol (8.5 g, 59 mmol, Reference compound No. 7-1) in methylen chloride (250 mL), then the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 4-bromomethyl-2-chloropyridine. Immediately, 2-mercaptonicotinic acid (9.1 g, 59 mmol) was added to a solution of this bromo intermediate in N,N-dimethylformamide (100 mL) under ice-cooling, then triethylamine (25 mL, 180 mmol) was added dropwise thereto. The reaction mixture was stirred at room temperature for 15 hours, then diethyl ether (100 mL) and water (600 mL) were added thereto, and the organic layer and the aqueous layer were separated. The aqueous layer was adjusted to pH 6 with 2N hydrochloric acid, the precipitated solid was filtered off. The solid was washed with water and diethyl ether, and dried at 50° C. under reduced pressure to give 12 g of the title reference compound as a yellow solid. (Yield 73%)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([O:23][CH2:24][C:25]2[C:30]([F:31])=[CH:29][C:28]([Br:32])=[CH:27][C:26]=2[F:33])=[N:7][S:8][C:9]=1[NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:12])=O.[NH3:34]>CO.O1CCCC1>[Br:32][C:28]1[CH:29]=[C:30]([F:31])[C:25]([CH2:24][O:23][C:6]2[C:5]([C:3]([NH2:34])=[O:2])=[C:9]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:12])[S:8][N:7]=2)=[C:26]([F:33])[CH:27]=1
Reactant: COC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)NCCCCN1CCCC1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)NCCCCN1CCCC1
Temperature: 0 °C
Yield: 76 %

Procedure:
In a 1 Liter autoclave 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 27.0 g) was slurried in methanol (270 mL, 10 volumes) and tetrahydrofuran (270 mL, 10 volumes). The mixture was cooled to 0° C. and stirred at 600 rpm. Anhydrous ammonia gas was charged carefully, keeping the temperature below 10° C. Once a steady pressure of around 10 psi was maintained, the mixture was heated to 40° C. The pressure increased to about 45 psi. The pressure was adjusted to 50 psi and stirred at 600 rpm and 40° C. for 90 hours. The stir rate was then adjusted to 1000 rpm and stirred for an additional 24 hours. The ammonia was removed by vacuum, and the mixture was cooled to 20° C. and transferred out of the reactor. The mixture was filtered to remove insoluble solids (non-product related). The filtrate was diluted with 2-propanol (270 mL, 10 volumes), and the tetrahydrofuran and methanol were distilled atmospherically. Additional 2-propanol (135 mL, 5 volumes) were added, then the mixture was distilled to approximately 250 mL total volume. The slurry was cooled to 20° C. and stirred 18 hours. The solids were filtered and then dried under vacuum to give 19.9 grams of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide (76% yield). 1H NMR (DMSO-d6): δ 10.98 (s, 1H); 8.18 (m, 1H); 7.55 (m, 3H); 6.80 (s, 1H); 5.41 (s, 2H); 3.08 (m, 2H); 2.47 (m, 6H); 1.62 (m, 4H); 1.42 (m, 4H). MS (API-ES pos) 532/534 (M+H)+, base.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]2[O:29][CH:30]=[C:31]([CH2:33]Cl)[N:32]=2)=[C:22]([F:35])[CH:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2[O:29][CH:30]=[C:31]([CH2:33][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:32]=2)=[C:22]([F:35])[CH:21]=1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: Fc1cc(Cl)ccc1C=Cc1nc(CCl)co1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Cl)ccc1/C=C/c1nc(COc2ccc(COCCn3ccnn3)cc2)co1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
380 mg (15 mmol) of 95% sodium hydride were given to a solution of 3.00 g (13.7 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 70 ml N,N-dimethylformamide and stirred for 30 min at room temperature. Then 3.73 g (13.7 mmol) 2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-4-chloromethyl-oxazole were added and stirring continued over night. The mixture was quenched with water, stirred for 1 h and the precipitate isolated by filtration. After washing with water, little methanol, ethyl acetate/heptane 2:1 and ether, and drying at 40° C. in vacuo, 3.34 g (54%) 1-[2-(4-{2-[2-(E)-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzyloxy)-ethyl]-1H-[1,2,3]triazole were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Br)[N:7]=1)=[O:5])[CH3:2].[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:21][C:18]2[CH:19]=[CH:20][C:15]([I:14])=[CH:16][CH:17]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: Oc1ccc(I)cc1
Reactant: CCOC(=O)c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(COc2ccc(I)cc2)n1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
6-Bromomethyl-pyridine-2-carboxylic acid ethyl ester (1:1.72 g, 48 mmol; from Step 1 above) was dissolved in acetone (250 mL) and 4-iodophenol (11.61 g, 52.8 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added, followed by potassium carbonate (7.55 g, 54.6 mmol). The mixture was heated overnight at 65 degrees, and it was then cooled and filtered. The solid was washed with small portions of acetone and the filtrate was concentrated to approximately 100 mL by evaporation. The solution was warmed and then diluted with water (approximately 70 mL). The resulting brown solution was cloudy and started to precipitate an oily solid. The mixture was scratched with a spatula and allowed to cool to room temperature. The off-white precipitate was filtered off, washed with several portions of acetone/water (1:1), and then dried in vacuo over phosphorus pentoxide to give 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid ethyl ester (13.72 g, 75%) as an off-white crystalline solid. MS (MH+) 384. 1HNMR (CDCl3): δ 1.47 (t, 3H, J=7 Hz), 4.52 (q, 2H, J=7 Hz), 5.33 (s, 2H), 6.78 (d, 2H, J=9 Hz), 7.58 (d, 2H, J=9 Hz), 7.74 (d, 1H, J=7.8 Hz), 7.91 (dd, 1H, J=7.8, 7.8 Hz), 8.09 (d, 1H, J=7.8 Hz).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:21]=[CH:20][CH:19]=[C:18](I)[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:8]>CO>[Cl:4][C:5]1[N:21]=[CH:20][CH:19]=[C:18]([O:2][CH3:1])[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:8]
Reactant: C[O-]
Reactant: O=C(Nc1ccc(F)cc1F)c1c(I)ccnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(Cl)c1C(=O)Nc1ccc(F)cc1F
Temperature: 60 °C
Yield: 27.3 %

Procedure:
To a solution of sodium methoxide (0.023 g, 0.43 mmol) in anhydrous methanol (3 mL) was added 2-chloro-N-(2,4-difluorophenyl)-4-iodonicotinamide (0.17 g, 0.43 mmol). The mixture was heated at 60° C. for 12 hours then allowed to cool to ambient temperature. Concentration of the reaction mixture resulted in a residue that was triturated with methanol and water. Isolation by vacuum filtration afforded the desired compound (0.035 g) as an off-white solid. The filtrate was concentrated in vacuo to a residue that was purified by flash column chromatography (SiO2, eluting with 25-100% EtOAc in hexane) to afford an additional amount desired compound (0.049 g, overall yield 65%) that was spectroscopically consistant with the initially isolated material. 1H NMR (DMSO-d6) δ 10.48 (s, 1H), 8.38 (d, 1H, J=5.8 Hz), 7.85-7.96 (m, 1H), 7.33-7.40 (m, 1H), 7.27 (d, 1H, J=5.8 Hz), 7.05-7.20 (m, 1H), 3.92 (s, 3H); MS(ESI+) m/z 299 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1>CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:23][CH2:13][CH2:14][O:15]2)[CH2:17][CH2:18]1
Reactant: Brc1ccccn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ccccn2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 2-bromopyridine (14 g, 88.6 mmol) in anhydrous ether (300 mL) cooled at −78° C. was slowly added a solution of 2.5 M n-butyl lithium (36 mL). After the addition, stirring was continued at −78° C. for 1 hour. To it was slowly added a solution of 1,4-cyclohexanedione mono-ethylene ketal (15 g, 96 mmol) in anhydrous ether (300 mL). When the addition was complete, the mixture was allowed to warm to 0° C. and stirring was continued for 1 hour. The reaction was quenched by the addition of an aqueous solution (100 mL) of ammonium chloride (4.5 g). The organic phase was separated and the aqueous phase was extracted with methylene chloride 4 times. The combined organic phases were dried over MgSO4 and concentrated. Crystallization from EtOAc provided 7 g of the desired product. The mother liquid was purified on silica gel eluting with 10% MeOH/EtOAc to give 3 g of the desired product. MS (M+H)+ 236.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[F:20][C:17]([F:18])([F:19])[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:16]
Reactant: [H][H]
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CCNCC1)C(F)(F)F

Procedure:
A suspension of 92 g of 1-benzyl 4-trifluoromethylcarbonylamino piperidine (X) and 9 g of wet 10% palladium on charcoal in 1000 ml of methanol is left under agitation for 8 days in a hydrogen atmosphere at room temperature. Then it is filtered, the filtrate is evaporated and the residue chromatographed on a silica column (M.P.L.C.). By eluting with pure methanol, 44 g of the expected product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25](Br)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]1[CH:45]=[N:46][CH:47]=[N:48][CH:49]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25]([C:44]3[CH:45]=[N:46][CH:47]=[N:48][CH:49]=3)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Product: CC(C)(C)OC(=O)N(Cc1cc(-c2cncnc2)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
From cis-3-[(5-bromobenzofuran-7-ylmethyl)tert-butoxycarbonyl-amino]-2-phenyl-piperidine-1-carboxylic acid tert-butyl ester (600 mg) and 5-tributylstannanyl-pyrimidine (458 mg)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:19])=[CH:5][CH:4]=1>C1COCC1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:24][CH:25]=2)=[O:19])=[CH:5][CH:4]=1
Reactant: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3ccccc23)cc1
Yield: 71 %

Procedure:
By essentially following the procedure outlined in Example 1, part D, the title compound was prepared in 71% yield from 4-[2-(diethylamino)ethoxy]phenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone (Part A) as an orange foam following flash chromatography (SiO2; 5% TEA in THF).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.CN.Cl.[BH3-][C:23]#[N:24].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][CH3:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 92 %

Procedure:
1-Benzylpiperidin-4-one (5.0 g, 26.315 mmol, 1.0 eq.) was dissolved in MeOH (78 ml); AcOH (0.2 ml) and CH3NH2.HCl (2.6 g, 39.47 mmol, 1.5 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (3.3 g, 52.63 mmol, 2.0 eq.) was then added in portions at 0° C. and the mixture was stirred for 16 hours at RT. The reaction mixture was concentrated under reduced pressure. The residue was taken up in sat. sodium hydrogen carbonate solution (150 ml) and extracted with DCM (2×200 ml). The combined org. phases were dried over sodium sulfate, concentrated and used in the next stage without being purified further. Yield: 92% (5.0 g, 24.509 mmol)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:27]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: Clc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)c(F)c2c1=O
Yield: 21.1 %

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 120 mg of 4-chloroisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 64 mg of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of 2-(benzyloxy)biphenyl-3-carbaldehyde (14.4 g, 50 mmol) in anhydrous tetrahydrofuran (180 mL) was stirred on an ice bath under nitrogen and 1M phenylmagnesium bromide in tetrahydrofuran (60 mL, 60 mmol, 1.2 equiv.) was added over 20 min. Stirring was continued for 3 hr at room temperature. The reaction mixture was poured on saturated ammonium chloride (600 mL) and extracted with ethyl acetate (800 mL). The organic extract was washed with water (2×400 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. Crude 24 (19.2 g, 105%) was used in the next step without purification.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[OH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=2)[N+:14]([O-])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][S:2]([O:5][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[OH:10])=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:25])[F:23])[CH:16]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: [O-][n+]1ccc(O)c2ccc(OC(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cnc2cc(OC(F)(F)F)ccc2c1O
Reaction time: 2.5 h

Procedure:
Methanesulphonic anhydride (1.55 g) was added to a stirred mixture of 4-hydroxy-7-trifluoromethoxy-quinoline-1-oxide (2.0 g), potassium carbonate (1.2 g) and dichloromethane (100 ml) at 0°. After stirring at 0° for a further 2.5 hours, the reaction mixture was washed with saturated aqueous sodium carbonate (60 ml) and the dichloromethane phase separated. The aqueous phase was extracted with dichloromethane (2×50 ml) and the combined dichloromethane phase and extracts were dried over magnesium sulphate. The solvent was removed by evaporation and water (100 ml) followed by saturated aqueous sodium bicarbonate (5 ml) at 10° was added. The solid was collected by filtration to give the novel compound 4-hydroxy-7-trifluoromethoxyquinol-3-yl methanesulphonate, m.p. 125°-127°.
Reaction SMILES: CCOP(OCC)([CH:6]1[NH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])=O.C(N(CC)CC)C.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH2:32][CH:6]2[NH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CC2NC(=O)NC2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a stirred solution of diethyl 5-hydantoylphosphonate (10 g, 42.3 mmol) and triethylamine (5.70 g, 56 mmol), in dry acetonitrile (100 ml), at room temperature was added a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (8 g, 36.3 mmol) in dry acetonitrile (75 ml), dropwise over 30 minutes. The resulting mixture was stirred at room temperature overnight, after which volatiles were removed in vacuo. The residue was diluted with 0.05N HCl (120 ml) and the precipitate collected by filtration. Recrystallization of this material with methylene chloride/methanol/diethyl ether afforded the title compound as a pale yellow solid (8.54 g). m.p. 220-222° C.
Reaction SMILES: [CH:1]1([CH:6]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:6]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCC2)oc2ccc(F)cc12
Yield: 94.2 %

Procedure:
To a mixture of methyl 4-{[cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}benzoate (1.19 g) synthesized above, tetrahydrofuran (6 mL) and ethanol (6 mL) was added 1N aqueous sodium hydroxide solution (6 mL), and the mixture was stirred with heating under reflux for 3.5 hr. 1N Aqueous sodium hydroxide solution (6 mL) was additionally added to the mixture, and the mixture was stirred with heating under reflux for 14 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (11 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.08 g, 94%) as a colorless amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[C:19]([CH3:34])[CH:18]=1)[NH:5]C(OCC1C=CC=CC=1)=O.C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[C:19]([CH3:34])[CH:18]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1
Yield: 71.9 %

Procedure:
A mixture of N-(benzyloxycarbonyl)-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.145 mmol, 70 mg), cyclohexene (1 mL) and 10% palladium on carbon (100 mg) in ethanol (2 mL) was heated to reflux for 15 h. Then, it was filtered through a pad of celite and the pad was washed with ethanol (10 mL). The combined filtrate was concentrated under reduced pressure. The residue was dried under high vacuum to afford 36 mg (72% yield) of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as a light yellow solid. ES-HRMS m/e calcd for C18H23N3O4 (M+Na) 368.1327, found 368.1321.