Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([CH2:16][CH2:17]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C([O-])(=O)C([O-])=O.[Sn+4].C([O-])(=O)C([O-])=O>[CH:1]1([C:7]([O:9][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCC1
Reactant: OCCc1ccccc1
Agent: O=C([O-])C(=O)[O-]
Agent: [Sn+4]
Product: O=C(OCCc1ccccc1)C1CCCCC1
Temperature: 180 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A 1-L, 4-neck, round-bottom flask, fitted with a thermometer, mechanical stirrer, nitrogen inlet tube and Liebig condenser/receiving flask, was charged with 320.4 g (2.50 mol, 1.00 equiv) of cyclohexanecarboxylic acid, 335.9 g (2.75 mol, 1.10 equiv) of 2-phenylethanol, and 1.20 g (0.2 wt. %) of tin oxalate (Fascat® 2001). The system was heated gently with slow stirring (<50 rpm) until all the cyclohexanecarboxylic acid was in solution. The air was removed with three cycles of evacuation/nitrogen-fill using a mechanical vacuum pump (50-100 torr). The rate of stirring was increased to ca. 200 rpm, the nitrogen sparge was set at 0.1 scfh, and the reaction mixture was heated to 180° C. After a 1-h hold, 36.7 g of distillate had been collected. The alcohol (9.6 g) was separated and returned to the reaction mixture. The temperature was increased to 190° C. and held for 1 h; an additional 14.0 g of distillate was collected. The alcohol (2.5 g) was separated and returned. The temperature was increased to 200° C. and held for 1 h; an additional 4.9 g of distillate was collected. The alcohol (1.0 g) was separated and returned. The temperature was increased to 210° C. and held for 1 h, and an additional 2.1 g of distillate was collected; 0.3 g of alcohol was separated, but not returned. The temperature was increased to 220° C. and held for 2 h, and an additional 1.3 g of distillate was collected; 0.4 g of alcohol was separated, but not returned. The reaction mixture was cooled to room temperature and sampled for analysis. The acid number was 1.04 mg KOH/g (99.5% conversion). Triisodecylphosphite (0.58 g) was added to the reaction mixture, and the excess 2-phenylethanol (3.9% by GLC) was removed by vacuum distillation at 165-170° C. (10 torr, 0.5 scfh nitrogen sweep) for 1 h. Activated carbon (17.4 g, 3 wt. %) was added, and the mixture was heated at 75-80° C. under vacuum (80 torr, 0.5 scfh nitrogen sweep) for 1 h. The product was cooled to room temperature and filtered through Celite® to afford 470 g (81%) of 2-phenylethyl cyclohexanecarboxylate (99.5% pure by GLC): residual alcohol, 0.06% (GLC); APHA color, 89; acid number, 0.21 mg KOH/g; saponification number, 237 mg KOH/g (theor. 241 mg KOH/g).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:35])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}acetate (0.34 g, 1.00 mmol) was dissolved in chloroform (20 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10 ml) was added thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.30 g, 75%) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[S:12]([OH:15])(=O)=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:17].Cl>>[Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[S:12]([Cl:17])(=[O:15])=[O:13]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1c(F)c(F)c(F)c(F)c1Br
Agent: Cl
Product: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1Br
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
1-Bromo-2,3,4,5-tetrafluorobenzene (5.0 g, 21.8 mmol) was mixed at ambient temperature with 20% fuming sulfuric acid (20 mL). The mixture was heated at 40° C. for 3 h and at 110° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature and poured onto 12 g of crushed ice. The mixture was acidified dropwise with concentrated HCl (2 mL) until a solid, consisting mostly of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid was formed. The solid was filtered, washed with 12N HCl, and dried under high vacuum to afford 5.3 g of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid as a white hygroscopic solid that was used without further purification. To the sulfonic acid (3.0 g, 9.7 mmol) was then added phosphorous pentachloride (8.0 g, 38.4 mmol) in small portions, at ambient temperature (Caution: exothermic reaction with significant evolution of HCl). The reaction was allowed to stir for 20 minutes after the final addition of phosphorous pentachloride. The reaction mixture was then poured onto crushed ice and the white solid that formed was filtered and dried to afford 2.8 g of the title compound, which was used without further purification. MS (EI): 328 (30, M+), 293 (70), 229 (30), 148 (100).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].S(=O)(=O)(O)O.[CH3:16][C:17](=[CH2:19])[CH3:18].[OH-].[Na+]>C(OCC)(=O)C.O1CCOCC1>[C:17]([O:7][C:6](=[O:8])[C@H:4]([CH2:3][C:2]([CH3:10])([CH3:9])[CH3:1])[NH2:5])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@H](N)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a pressure bottle were added 1.5 gm (10.3 mMol) 4-methyl-(L)-leucine, 25 mL dioxane, 1.5 mL concentrated sulfuric acid and 25 mL isobutylene. The pressure bottle was stoppered and the reactants were shaken together for 18 hours. The reaction mixture was then treated with 60 mL cold 1N sodium hydroxide and 100 mL ethyl acetate. To this mixture was added sufficient 1N sodium hydroxide until the pH of the mixture was 8.5. The layers were separated and the aqueous phase was extracted well with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate and concentrated under reduced pressure to provide an oil which gradually crystallized to provide 1.05 gm (50.5%) of the title compound.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(SC)=CC=1.[C:19]1([CH:25]=[N+]=[N-])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.ClCCl>[C:19]1([CH:25]2[O:8][CH:1]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: [N-]=[N+]=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(SC)cc1
Solvent: ClCCl
Product: c1ccc(C2OC2c2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a mixture of rhodium (II) acetate (0.0021 g), dichloromethane (4 ml) and benzaldehyde (0.051 ml) was added 1-methoxy-4-methylthiobenzene (0.0036 ml). To this mixture was added, with stirring, a solution of phenyldiazomethane (1 mmol in tert-butylmethyl ether (8 ml)) over 19 hours. The reaction mixture was stirred or a further 5 hours after which the mixture was allowed to stand at room temperature for 2 days. The solvent was removed in vacuo and the residue chromatographed on silica using dichloromethane:hexane 2:3 as eluant. The title compound was obtained as a colourless oil (0.0713 g, 22.6% yield).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][C@@H:7]1[CH2:11][S:10][C:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:8]1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:23]1([NH:22][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]3[C:14]=2[NH:13][C:12]([C:9]2[S:10][CH2:11][C@@H:7]([CH2:6][CH2:5][C:4]([OH:28])=[O:3])[N:8]=2)=[CH:20]3)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)CC[C@@H]1CSC(c2cc3cc(C)cc(NC4CCCC4)c3[nH]2)=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCC(=O)O)CS3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
The compound (300 mg, 0.75 mmol) prepared in Example 157 was dissolved in tetrahydrofuran (25 ml) and methanol (25 ml). 1N aqueous sodium hydroxide solution (4.0 ml, 4 mmol) was added thereto, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (235 mg, Yield 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:28])[C@@H:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([CH3:19])[CH:12]=3)[C:4]=2[CH:3]=1.ClC1C=CC2NC(=O)[C@@H](CC3C=CC=CC=3Cl)N=C(C3C=CC(OC)=C(C)C=3)C=2C=1>>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[NH:6][C:7](=[O:28])[C@@H:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:19])[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](Cc3ccccc3Cl)N=C(c3ccc(OC)c(C)c3)c3cc(Cl)ccc32)cc1
Agent: COc1ccc(C2=N[C@H](Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)cc1C
Product: Cc1cc(C2=N[C@H](Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)ccc1O

Procedure:
Physical Characterization Data for Synthetic Intermediate Compounds: (R)-7-Chloro-3-(2-chlorobenzyl)-5-(4-methoxy-3-methylphenyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. MS (m/z): 559.3 (M+1)+; and (R)-7-Chloro-3-(2-chlorobenzyl)-5-(4-methoxy-3-methylphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. MS (m/z): 439.2 (M+1)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8](Cl)[N:7]=1)[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.[CH2:27]([CH2:29][NH2:30])[OH:28]>CC(N(C)C)=O>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]([NH:30][CH2:29][CH2:27][OH:28])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCO
Reactant: CCCCNc1nc(Cl)nc(NCCCC)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNc1nc(NCCO)nc(NCCCC)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 500-ml eggplant-shaped flask were placed 77.8 millimoles of N,N′-dibutyl-6-chloro-[1,3,5]triazine-2,4-diamine, 100 ml of dimethylacetamide, 233.5 millimoles of diisopropylethylamine, and 155.6 millimoles of ethanolamine and the mixture was heated at 160° C. with stirring. After 1.5 hours, the mixture was cooled to room temperature and the solvent was distilled off. A white precipitate in the residue was filtered and the filtrate was purified by silica gel column chromatography to give N,N′-dibutyl-N″-hydroxyethyl-[1,3,5]triazine-2,4,6-triamine.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)(=[O:13])=[O:12])=[O:9])=[N:4][C:3]=1[CH3:21].C[S-].[Na+].[CH3:25][OH:26]>>[CH3:25][O:26][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)(=[O:13])=[O:12])=[O:9])=[N:4][C:3]=1[CH3:21]
Reactant: Cc1cccc(S(=O)(=O)NC(=O)Nc2nc(C)c(Br)s2)c1
Reactant: CO
Agent: C[S-]
Agent: [Na+]
Product: COc1sc(NC(=O)NS(=O)(=O)c2cccc(C)c2)nc1C

Procedure:
N-[(5-Bromo-4-methyl-1,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide (41 mg, 0.11 mmol) was treated with sodium methanethiolate (31 mg, 0.42 mmol) in methanol (3.1 ml) at 80° C. for 4 days. After purification on preparative HPLC, 9 mg of the title compound were unexpectedly obtained as a white, amorph, freeze-dried solid. MS (ES): m/e 340.1 (M−H)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[N:18]1([C:23]2[C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[C:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:28]1[C:23]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:24][C:25]([C:34]([F:37])([F:35])[F:36])=[CH:26][CH:27]=1)#[CH:17]
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1N1CCCC1
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N2CCCC2)cc(F)c1NS(C)(=O)=O
Yield: 79.2 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (94 mg, 0.327 mmol) was reacted with 3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (78 mg, 0.272 mmol) to give the title compound (110 mg, 80%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:15])[CH:12]=[CH:13][CH3:14]>>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH:13]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH3:14]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CC=CC(=O)OC
Product: COC(=O)CC(C)n1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was reacted with methyl-3-methylacrylate to provide the title compound: 1H NMR (400 MHz, CDCl3) 1.62 (d, 3H, J=7.0 Hz), 2.81 (d, 2H, J=7.0 Hz), 3.66 (s, 3H), 4.78 (m, 1H), 7.53 (d, 1H, J=1.6 Hz), 7.82 (d, 1H, J=1.6 Hz); MS m/z 214.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH3:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[C:15](OC(=O)C)(=O)[CH3:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CN(C1C=CN=CC=1)C>[CH2:15]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:3]([CH3:12])[C:2]([F:13])([F:14])[F:1])=[CH:10][CH:9]=1)[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Product: CCNc1ccc(OC(C)C(F)(F)F)cc1

Procedure:
This material was prepared from (rac)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine by, first a standard acetylation reaction (acetic anhydride, DMAP as base) followed by reduction with LiAlH4 using standard literature procedures.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]3)=[CH:17][CH:16]=1
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: COc1ccc(-c2cccc3c2C(=O)C(C)C3)cc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
Using a method similar to Example 16d), 3.84 g (0.021 mol) of (1), 3.58 g (0.024 mol) of 4-methoxyphenylboronic acid, 4.98 g (0.047 mol) of sodium carbonate were placed in 60 ml of ethylene glycol/10 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 23.9 mg (0.106 mmol) of palladium acetate and 0.12 g (0.21 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 60 ml of water, the aqueous phase was extracted 4 times with 60 ml each time of ether, the combined ether phases were washed with 60 ml of water and 60 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 3.75 g of (20) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10]CC)=[O:9])=[N:3][CH:2]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[N:3][CH:2]=1
Reactant: CCOC(=O)Cc1ccncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccncn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-(pyrimidin-4-yl)acetate (Example 33b, 450 mg. 2.71 mmol) in ethanol (5 mL) was added 2N NaOH (2 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 24 hours, concentrated under reduced pressure and suspended in ethanol. The solid was removed by vacuum filtration, and the filtrate was concentrated under reduced pressure, triturated with ethanol, concentrated again and carried onto the next step without further purification. MS139 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[Br:13]N1C(=O)CCC1=O>CC#N.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Br:13])=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1ncc(F)cc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1nc(Br)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of methyl 3-amino-5-fluoropyridine-2-carboxylate (3.6 g, 21 mmol) in MeCN (60 mL), N-bromosuccinimide (4.1 g, 23 mmol) was added portionwise. After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc (200 mL), washed with a saturated aq. NaHCO3 (200 mL) and brine (200 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (4.0 g, 76%) LCMS calc. for C7H7BrFN2O2 (M+H)+: m/z=249.0. found 249.0.
Reaction SMILES: CC(NC(C1C=CC2C(=CC=CC=2)C=1OCC1C=NC(OCC(F)(F)F)=CC=1)=O)(C)C(O)=O.C[O:35][C:36](=[O:68])[C:37]([CH3:67])([NH:40][C:41]([C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]=1[O:53][CH2:54][C:55]1[CH:56]=[N:57][C:58]([O:61][CH2:62][C:63]([F:66])([F:65])[F:64])=[CH:59][CH:60]=1)=[O:42])[CH2:38][CH3:39]>>[CH3:67][C:37]([NH:40][C:41]([C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]=1[O:53][CH2:54][C:55]1[CH:56]=[N:57][C:58]([O:61][CH2:62][C:63]([F:66])([F:65])[F:64])=[CH:59][CH:60]=1)=[O:42])([CH2:38][CH3:39])[C:36]([OH:68])=[O:35]
Reactant: CCC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1)C(=O)OC
Agent: CC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1)C(=O)O
Product: CCC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1)C(=O)O

Procedure:
2-Methyl-2-({1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphtha-lene-2-carbonyl}-amino)-butyric acid was prepared in similar manner as 2-methyl-2-({1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carbonyl}-amino)-propionic acid (example 150) via 2-methyl-2-({1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carbonyl}-amino)-butyric acid methyl ester (C25H25F3N2O5 (490.48), LCMS (ESI): 491.15 (MH+)).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH2:21]Cl)[CH:14]=1)[CH:9]=2.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]3[C:17]([CH:18]=2)=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH2:21][N:16]4[CH2:17][CH2:8][CH2:9][CH2:10][CH2:15]4)[CH:14]=2)[CH:9]=3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Product: c1cc2cc3ccc(OCCN4CCCCC4)cc3nc2cc1OCCN1CCCCC1

Procedure:
In accordance with the above flowchart, a 3,6-bis(2-chloroethoxy)acridine (1), where R1 is as described hereinabove, is reacted with piperidine in a steel bomb at about 60° to about 1000° C. for about 18 to about 36 hours, giving a 3,6-bis(2-piperidinoethoxy)acridine (3) which is then dissolved in methanol, treated with excess 30% hydrogen peroxide for about 12 to about 48 hours, then with platinum catalyst to destroy the excess peroxide and is purified by dry column chromatography on silica gel using the developing system methanol:triethylamine (20:1, v/v). The length of reaction time with hydrogen peroxide is the determining factor in whether a mono-oxide (4) or dioxide (5) is produced.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:17]=[CH:16][C:7]2[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:9][O:10][C:6]=2[CH:5]=1.[CH3:18]I>O1CCCC1>[F:3][C:4]1[CH:17]=[CH:16][C:7]2[C:8]([CH:11]([CH3:18])[C:12]([O:14][CH3:15])=[O:13])=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: COC(=O)Cc1noc2cc(F)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1noc2cc(F)ccc12
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.32 g, 57.9 mmol, 60% in oil) is added portionwise to a solution of methyl 6-fluoro-1,2-benzisoxazole-3-acetate (12.07 g, 57.7 mmol) in tetrahydrofuran at -2° C. The mixture is stirred for 30 minutes at 2° C., treated with methyl iodide (10.65 g, 75.0 mmol), stirred at 5° C. for 50 minutes and poured onto ice. The aqueous mixture is extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as an oil which is identified by NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26](OCC)=[O:27])=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1.[C:31]([Li])([CH3:34])([CH3:33])[CH3:32].[Cl-].[NH4+]>C1COCC1.CCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[CH:12][C:11]=1[C:26](=[O:27])[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: [Li]C(C)(C)C
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)C(C)(C)C)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carboxylate (524 mg) in THF (10 mL) was added a solution (1.6 M, 1.6 mL) of tert-butyllithium in pentane at −78° C., and the mixture was stirred at −78° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (268 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:4]=2[CH:3]=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[C:14]([O:13][C:11]([N:9]1[CH2:10][C:4]2[CH:3]=[C:2]([NH:1][C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])[CH:24]=[CH:23][C:5]=2[CH:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7][CH2:8]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)Cc2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)Cc2cc(NC(=O)OCc3ccc([N+](=O)[O-])cc3)ccc21
Reaction time: 5 h

Procedure:
To a stirring solution of methyl 2-{8-amino-2-[(tert-butyl)oxycarbonyl]-1H,3H,4H,5H-benzo[e]azepin-5-yl}acetate (1 eq) in methylene chloride (0.1 M) was added 4-nitrobenzyl chloroformate (1.1 eq) and triethylamine (5 eq) at room temperature. After stirring for 5 hr, the reaction mixture was diluted with methylene chloride. The organic phase was washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/Hexane). EI-MS m/z 514 (M+H)+.