Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1.Cl>C(O)(C)C>[ClH:1].[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:26]([F:31])[CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C)CC1
Yield: 95.8 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (200 mg, 0.62 mmol) and 4-bromo-2-fluoroaniline (142 mg, 0.74 mmol) in isopropanol (3 ml) containing 6N hydrogen chloride in isopropanol (110 μl, 0.68 ml) was heated at reflux for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol followed by ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (304 mg, 90%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH:9]=[C:8]([F:23])[C:7]=1[OH:24].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:24][C:7]1[C:6]([F:5])=[CH:11][C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)=[CH:9][C:8]=1[F:23])(=[O:3])[CH3:2]
Reactant: CCCCC[C@H]1CC[C@H](c2cc(F)c(O)c(F)c2)CC1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2cc(F)c(OC(C)=O)c(F)c2)CC1

Procedure:
8 g of acetyl chloride is added to a solution of 28.2 g of 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-phenol and 20 ml of pyridine in 300 ml of toluene, and the mixture is heated at 80° for 1 hour. Cooling and working up in the usual manner gives 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-phenyl acetate.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1>[C:36]1([C:35]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CCCCC=C(c1ccccc1)c1ccccc1
Yield: 70.6 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.6 g); dimethylsulfoxide (100 mL), (5-carboxypentyl)triphenylphosphonium bromide (37.64 g); benzophenone (18 g) and tetrahydrofuran (100 mL). The acid, isolated in the normal manner, was crystallized from hexane to give 16.3 g of 7,7-diphenyl-6-heptenoic acid, mp 71.5°-72.5° C. A portion was recrystallized from hexane to give the analytical sample, mp 72.5°-73.5° C. Anal. Calculated for C19H20O2 : C, 81.40; H, 7.19. Found: C, 81.61; H, 7.40.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([N:8]([OH:12])[C:9]([NH2:11])=[O:10])[CH3:7])=[CH:2]1.[CH3:13][C@H:14]([C:27](O)=[O:28])[C:15]1[CH:16]=[CH:17][C:18]2[CH:19]=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=2[CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:26][O:25][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[CH:24]=[C:15]([C@H:14]([CH3:13])[C:27]([O:12][N:8]([CH:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH3:7])[C:9]([NH2:11])=[O:10])=[O:28])[CH:16]=[CH:17]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(c1ccoc1)N(O)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)ON(C(N)=O)C(C)c3ccoc3)ccc2c1
Reaction time: 18 h
Yield: 68.3 %

Procedure:
To a solution of N-1-(fur-3-yl)ethyl-N-hydroxyurea (1.00 g, 5.9 mmol), prepared as described in U.S. Pat. No. 5,112,848, in CH2Cl2 (25 mL) was added naproxen (135 g, 5.9 mmol) followed by dicyclohexylcarbodiimide (1.34 g, 6.49 mmol), and a crystal of 4-N,N-dimethylaminopyridine. The reaction was stirred for 18 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (ether), followed by crystallization in ethyl acetate/hexanes to give N-[(S)-2-(6-methoxynaphth-2-yl)propionyloxy]-N-[1-(fur-3-yl)ethyl]urea (1.54 g). m.p. 128.5°-134° C. 1H NMR (300 MHz, DMSO-d6, mixture of diastereomers) δ 0.72 and 1.12 (bm, 3H), 1.48 (bm, 3H), 3.87 (s, 3H), 4.13 (bm, 1H), 5.14 (bm, 1H), 6.79 and 6.94 (bs, 2H), 7.16 (m, 2H), 7.29-7.46 (m, 3H), 7.69-7.86 (m, 3H). MS (DCI/NH3) m/e 383 (M+H)+. Analysis calc'd for C21H22N2O5 : C, 65.95; H, 5.80; N, 7.33. Found: C, 65.39; H; 5.80; N, 7.26.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][P:27]([OH:29])[OH:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][P:27]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:28])[OH:29])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCCCCCCCCCC
Reactant: O=C(NCCCP(O)O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCP(=O)(O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.30 g of dodecene in 6 ml of dry toluene is heated to 80° under an atmosphere of argon. To this solution a suspension of 2.0 g of 3-benzyloxycarbonylaminopropylphosphonous acid in 30 ml of dry toluene containing 0.6 g of t-butylcyclohexylperdicarbonate is added within 15 minutes. The reaction mixture is then stirred at 80° for 2 hours. An additional amount of 0.6 g of the radical initiator is added and stirring at 80° is continued for 2 hours. Then, the reaction mixture is cooled to room temperature and the solvent is removed by means of a rotary evaporator. The residue is triturated with petroleum ether (60°-80°), filtered and dried to give 3-benzyloxycarbonylaminopropyl(dodecyl)phosphinic acid as a white solid, m.p. 115°-6°; 31P-NMR: δ=+58.7 ppm (CDCl3).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]([CH2:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:8]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:7][C:6]=1[OH:36])(=O)C.[ClH:37]>C(O)C>[ClH:37].[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH2:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:8]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:7][C:6]=1[OH:36]
Reactant: CCCCCCCCCCCCCCCCOc1cc(O)c(NC(C)=O)cc1C(C)(CC)CCCC
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1cc(O)c(N)cc1C(C)(CC)CCCC

Procedure:
To 6 g of 2-acetamido-4-(1-ethyl-1-methylpentyl)-5-hexadecyloxyphenol were added 30 ml of ethanol and 25 ml of concentrated hydrochloric acid, and the resulting mixture was heated on a steam bath for 4 hours. Thereafter, the reaction solution was cooled with ice whereupon it separated into two layers. The oil layer was separated and dried under reduced pressure. Yield: 3.5 g.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[S:17][CH:18]=[C:19]([C:21]([N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[O:22])[N:20]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:36]=[CH:37][N:38]=[CH:39][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[S:17][CH:18]=[C:19]([C:21]([N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[O:22])[N:20]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:36]=[CH:37][N:38]=[CH:39][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1csc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)n1)N1CCNCC1

Procedure:
Compound 74 was dissolved in DCM (5 mL) and TFA (1.5 mL) and stirred at 20° C. for 2.5 hrs. The reaction was concentrated in vacuum and purified by preparative HPLC eluting with a gradient 10% MeCN/water/0.1% TFA-50% MeCN/water/0.1% TFA to provide compound 71 (23 mg) as a yellow solid. 1H NMR (500 MHz, CD3OD) δ 9.63 (1H, s), 9.32 (1H, s), 8.68 (1H, d, J=6.1 Hz), 8.63 (1H, d, J=6.4 Hz), 7.84 (1H, s), 5.56 (1H, p, J=8.1), 4.00-4.29 (4H, br s), 3.39 (4H, t, J=5.3 Hz), 2.63 (2H, m), 2.25 (4H, m), 1.98 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 449.2.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](Br)=[C:12]([CH3:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH2:28]CCC.CI>C1COCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([CH3:28])=[C:12]([CH3:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Cc1nc2c(cc1Br)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2nc1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A suspension of 2-anilino-6-bromo-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (203 mg, 0.5 mmol) in THF (10 mL) in an atmosphere of argon was cooled to −78° C. A solution of n-BuLi in hexanes (1.0 mL, 1.6 mmol, 1.6 M) was added and the suspension was stirred for 10 min at 0° C. until it became a clear solution. Excessive MeI (0.2 mL, 3.2 mmol) was added, and the reaction was stirred for another 10 min. The reaction was quenched with saturated aqueous NH4Cl (2.0 mL) and water (10 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford 2-anilino-6,7-dimethyl-1-phenyl-1,8-naphthyridin-4(1H)-one (55 mg, 32%): LCMS RT: 2.33 min, MH+: 342.4, Rf=0.39 (EtOAc). 2-anilino-7-ethyl-1-(3-methylphenyl)-1,8-naphthyridin-4(1H)-one (13.3 mg, 7.5%) was also obtained as a side product: LCMS RT: 2.54 min, MH+: 356.3, Rf=0.40 (EtOAc). Other electrophiles such as aldehydes, carbon dioxide, disulfides, trifluoroacetates acid chlorides and other alkyl halides can also be used to quench the generated aryl lithium.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1.[C:24]([NH:27][CH2:28][CH2:29][NH2:30])(=[O:26])[CH3:25]>CS(C)=O>[C:24]([NH:27][CH2:28][CH2:29][NH:30][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1)(=[O:26])[CH3:25]
Reactant: O=C(CN1CCCCC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CC(=O)NCCN
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCCCC2)nc(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
N-(6-Chloro-2-phenylpyrimidin-4-yl)-2-piperidin-1-ylacetamide (25 mg) was dissolved in DMSO (1 ml) and N-acetylethylenediamine (78 mg) added. A reflux condenser was fitted and the mixture heated to 130° C. with stirring for 16 hrs. The reaction was cooled to room temperature and the solvent removed in vacuo. Purification via flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5, then 93:7 v/v) yielded the title compound (18 mg).
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[C:8]([CH3:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[Cl:6][C:7]1[C:8]([CH3:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[CH2:1]
Reactant: [Li]CCCC
Reactant: Cc1c(Cl)cccc1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1cccc(Cl)c1C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (6.9 g, 0.019M) was suspended in dry tetrahydrofuran (100 ml) at -40° C. under an atmosphere of dry nitrogen. n-Butyllithium (13.5 ml. of a 1.55M solution in hexane, 0.021M) was added dropwise during 10 minutes and the mixture was stirred at -40° C. for 30 minutes. 3-Chloro-2-methylbenzaldehyde (3.0 g, 0.019M) in dry tetrahydrofuran (10 mls) was then added. The mixture was maintained at -40° C. for 30 minutes and then allowed to warm to room temperature. Hexane (150 ml) was added and the mixture was filtered. The hexane was evaporated to give crude 3-chloro-2-methylstyrene which was used directly without further purification.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10]([NH:12][CH:13]1[CH:18]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:17][CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>[Pd].C(OCC)(=O)C.CO>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH:18]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[NH:12][C:10](=[O:11])[O:9][C:5]([CH3:7])([CH3:6])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CNCCC1N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Ammonium formate (419 mg) and 10% Pd/C (84 mg) were added to an ethyl acetate/MeOH (4 ml/4 ml) solution containing benzyl 3-((tert-butoxycarbonyl)amino)-4-(1,3-dioxoisoindolin-2-yl)piperidin-1-carboxylate (419 mg) obtained in the 1st step, followed by stirring at 60° C. for 1 hour. The reaction solution was cooled to room temperature and insoluble matter was removed through Celite. Filter cake was washed with ethyl acetate and water. Subsequently, the filtrate was mixed with wash liquid and sodium chloride was added to the mixture. The organic layers were separated and washed with saturated saline. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. A white solid of tert-butyl (4-(1,3-dioxoisoindolin-2-yl)piperidin-3-yl)carbamate (280 mg) was thus obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:10]1[NH:11][C:12](=[O:28])[C:13](=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:14]=1)[CH2:8][CH3:9].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH:43]2[N:47]([CH3:48])[N:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:45]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[N:44]2[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:33][CH:32]=1>CN(C)C=O.C(Cl)Cl>[C:22]1([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]2[N:14]=[C:10]([CH2:7][CH2:8][CH3:9])[N:11]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[CH:43]4[N:47]([CH3:48])[N:46]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[N:45]([C:55]5[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=5)[N:44]4[C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)=[CH:35][CH:36]=3)[C:12]2=[O:28])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCC1=NC(=C(c2ccccc2)c2ccccc2)C(=O)N1
Reactant: CN1C(c2ccccc2-c2ccc(CBr)cc2)N(c2ccccc2)N(c2ccccc2)N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC1=NC(=C(c2ccccc2)c2ccccc2)C(=O)N1Cc1ccc(-c2ccccc2C2N(C)N(c3ccccc3)N(c3ccccc3)N2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
A mixture of potassium carbonate (83 mg, 2 eq.), 2-propyl-4-(diphenylmethylene)-1H-imidazol-5(4H)-one (90 mg, 0.3 mmol), and 4'-bromomethyl-2-(triphenyl methyl tetrazol-5-yl)biphenyl (0.21 g, 1.2 eq.) in dimethyl formamide (10 mL) was allowed to stir at room temperature for 2 days. The solvent was in vacuo, the residue was dissolved in CH2Cl2 and washed with water and brine. The organic layer was dried over MgSO4 and concentrated. The crude mixture was chromatographed over silica gel eluting with ethyl acetate-hexane (1:4) to give 3,5-dihydro-5-(diphenylmethylene)-2-propyl-3-[(2'-(triphenyl methyl tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl]-4H-imidazol-4-one (100 mg). M.S. m/e 767 (M+ +H) NMR (CDCl3 /TMS) δ0.90 (m, 3H, CH3), 1.65 (m, 2H, CH2), 2.38 (m, 2H, CH2), 4.62 (s, 2H, CH2), 6.88-7.50 (m, 30H, Harom), 7.61 (m, 2H, Harom), 7.90 (d, 1H, Harom). The above compound was detritylated following the procedure described in Example 2C, to give 61 mg of the desired product. M.S. m/e 524 (M+ +H) NMR (CDCl3 /TMS) d 1.01 (t, 3H, CH3), 1.78 (m, 2H, CH2), 2.49 (t, 2H, CH2), 4.75 (s, 2H, CH2), 7.12-7.41 (m, 15H, Harom), 7.58 (m,2H, Harom), 8.10 (d, 1H, Harom).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:25][CH2:26][NH2:27].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:27][CH2:26][CH2:25][N:24]([CH3:23])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: CN(CCN)c1ccccn1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCN(C)c2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.44 mmol), N-methyl-N-(2-pyridyl)-1,2-ethanediamine (326 mg, 2.16 mmol) and triethylamine (0.300 mL, 2.15 mmol) in anhydrous DMSO (6 mL) was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL), the resulting precipitate was collected by filtration and washed with water. The obtained solid was recrystallized from EtOH to give 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[2-[methyl(2-pyridyl)amino]ethylamino]-4-oxoquinoline-3-carboxylic acid (303 mg, 48%) as yellow needles.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30]([NH:33][CH:34]([CH3:36])[CH3:35])[CH2:31][CH3:32])[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:40](=O)[CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[CH:30]([N:33]([CH2:40][CH3:41])[CH:34]([CH3:35])[CH3:36])[CH2:31][CH3:32])[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CCC(NC(C)C)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC(c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)N(CC)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[1-(isopropylamino)propyl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (28.5 mg, 0.0500 mmol) in dichloroethane (1 mL) was added acetaldehyde (2 mL) and NaBH(OAc)3 (excess). The reaction was stirred at room temperature for 16 hours, and then diluted with EtOAc (10 mL) and washed with water and brine (5 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by PTLC (50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2 {1-[ethyl(isopropyl)amino]propyl}-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.53 (50% EtOAc/hexanes). LCMS=599.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.90 (s, 1H), 7.81 (s, 2H), 7.56-7.49 (m, 3H), 5.78-5.74 (m, 1H), 5.02 (d, J=16.4 Hz, 1H), 4.74-4.71 (m, 1H), 4.07-4-04 (m, 1H), 3.90-3.87 (m, 1H), 2.89-2.85 (m, 1H), 2.62-2.52 (m, 2H), 2.00-1.96 (m, 1H), 1.79-1.72 (m, 1H), 1.26-0.69 (m, 15H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[CH2:19][NH:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:7][C:6]([CH2:26][C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C.[OH-].[Na+].Cl>C(Cl)Cl>[C:30]([N:20]([CH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:17])([F:18])[F:16])[CH:13]=[CH:14][C:9]=1[C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([CH2:26][C:27]([OH:29])=[O:28])[CH:7]=1)[CH2:21][C:22]([OH:24])=[O:23])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: COC(=O)CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(CC(=O)O)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{6-Methoxy-2′[(methoxycarbonylmethyl-amino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (0.094 g, 0.23 mmol), acetyl chloride (0.03 mL, 0.46 mmol), and triethylamine (0.08 mL, 0.57 mmol) were combined in CH2Cl2 (1 mL) and stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, aqueous 1N NaOH was added. After stirring at room temperature for 45 minutes, analytical LCMS indicated that both acids had been hydrolyzed to the free acid, and so the mixture was neutralized with aqueous 1N HCl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 440.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])C(OC(C)(C)C)=O)[CH3:2]>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A solution of 2-(5-chloro-2,4-dinitro-phenyl)-malonic acid tert-butyl ester ethyl ester (0.4 g) in a mixture of dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) was heated at 70° C. for 30 minutes in a sealed tube. The reaction mixture was then evaporated under reduced pressure and the residue was purified by flash chromatography (EtOac/hexane, 10/90) to afford 150 mg of (5-chloro-2,4-dinitro-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH3:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1>[C].[Pd].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH:3]=1)[NH2:12]
Reactant: CCCOc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCOc1ccc(F)cc1N
Yield: 85.7 %

Procedure:
4-Fluoro-2-nitro-1-propoxybenzene (2.0 g, 10.0 mmol) and 5% palladium carbon (750 mg) were added to ethanol (30 ml). Catalytic reduction was conducted at room temperature and atmospheric pressure (normal pressure). The catalyst was removed by celite filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 1.45 g of oily red orange 5-fluoro-2-propoxyaniline (yield: 86%).