Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1)[CH3:2].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:21][C:15]1[CH:14]=[C:13]([C:10]2[N:9]=[C:8]([C:6]3[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[O:12][N:11]=2)[CH:18]=[C:17]([CH3:19])[C:16]=1[O:20][CH2:22][CH:24]1[CH2:25][O:26]1
Reactant: CCc1ccc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)s1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: CCc1ccc(-c2nc(-c3cc(C)c(OCC4CO4)c(C)c3)no2)s1
Temperature: 40 °C
Reaction time: 15 h
Yield: 28.3 %

Procedure:
A mixture of 4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (367 mg, 1.22 mmol) and epichlorohydrine (565 mg, 6.10 mmol) in isopropanol (20 mL) and 3 N aq. NaOH (6 mL) is stirred at 40° C. for 15 h. The mixture is diluted with diethyl ether, washed with sat. aq. NaHCO3 and water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazole (123 mg) as a pale yellow oil; LC-MS: tR=1.15 min, [M+1]+=357.11.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][N:16](CC3C=CC=CC=3)[CH2:17][CH2:18][CH:19]=2)=[CH:10][C:9]=1[C:27]([F:30])([F:29])[F:28]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][N:16]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:17][CH2:18][CH:19]=2)=[CH:10][C:9]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)c1cc(C2=CCCN(Cc3ccccc3)C2)ccc1Cl
Product: CCOC(=O)N1CCC=C(c2ccc(Cl)c(C(F)(F)F)c2)C1
Reaction time: 5 h

Procedure:
2.5 ml of distilled ethyl chloroformate were added to a mixture of 5 g of 3-(4-chloro-3-trifluoromethylphenyl)-1-benzyl-1,2,5,6-tetrahydropyridine and 55 ml of anhydrous, distilled benzene and the mixture was refluxed with stirring under an inert atmosphere for 5 hours. The mixture was evaporated to dryness to obtain 5 g of ethyl 3-(4-chloro-3-trifluoromethyl-phenyl)-1,2,5,6-tetrahydropyridine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:26]C)[C:11](=[O:25])[N:12]4[CH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:23])[C:17](=[O:24])[C:13]4=3)[C:8]2=[O:28])=[CH:4][CH:3]=1>Br.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:26])[C:11](=[O:25])[N:12]4[CH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:23])[C:17](=[O:24])[C:13]4=3)[C:8]2=[O:28])=[CH:29][CH:30]=1
Reactant: COc1c2c(c3n(c1=O)CCCCN(C)C3=O)CCN(Cc1ccc(F)cc1)C2=O
Agent: Br
Solvent: CC(=O)O
Product: CN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)cc2)CC3)C1=O

Procedure:
A solution of 11-(4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (27 mg, 0.07 mmol) in 30% hydrobromide in acetic acid was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was concentrated from a solution in toluene twice. The resultant solid was triturated with a mixture of diethyl ether and dichloromethane to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8].C(N(CC)CC)C>C(#N)C>[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8]
Reactant: CCn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 91.9 %

Procedure:
Piperazine (0.06 g, 0.74 mmol) was added to a solution of 1-ethyl-6,7-difluoro-3-hydroxy-1H-quinazoline-2,4-dione (Example D, 0.15 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 20 mL of acetonitrile. The solution was heated to reflux for 23 hours, cooled, and filtered to give 0.17 g of the title compound as a solid, mp 206-208° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][C:17]1[C:16]([N:4]2[CH2:5][CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:2]([CH3:1])[C:3]2=[O:14])=[CH:21][CH:20]=[C:19]([CH3:22])[N:18]=1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: Cc1ccc(Br)c(C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)c(C)n1
Temperature: 25 °C
Yield: 53.8 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 3-bromo-2,6-dimethylpyridine (557 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated at reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane. The residue was dissolved in methanol and applied to a SCX ion exchange cartridge and washed with methanol and then 2M ammonia in methanol. The basic fractions were combined and evaporated to give 1,1-dimethylethyl 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (493 mg, 54%). LC/MS [M+H]+=306. (ii) A solution of 1,1-dimethylethyl 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (0.489 g, 1.6 mmol) in TFA/DCM (1:2, 9 ml) was stirred at room temperature for 16 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt, (assume ˜1.6 mmol) which was used in the next step. LC/MS [M+H]+=250.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10](OC)=[O:11])[N:3]=1.C1COCC1.[Li+].[BH4-].Cl>O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: COC(=O)c1cccc(-c2noc(C)n2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cccc(CO)c2)no1
Temperature: 0 °C

Procedure:
3.46 g of methyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate (15.86 mmol) are dissolved in 50 ml of abs. THF in a 250 ml three-necked flask, and 0.691 g of LiBH4 (31.71 mmol) is subsequently introduced in portions with stirring at 0° C. under a nitrogen atmosphere, and the mixture is stirred without cooling for a further 20 h. For work-up, the reaction mixture is adjusted to pH 7 by slow dropwise addition of 1 N HCl with stirring, diluted with 100 ml of water and extracted 3× with 50 ml of dichloromethane. The combined organic phases are washed 1×100 ml of water, dried over sodium sulfate and evaporated to dryness in a rotary evaporator. The purification is carried out by chromatography (50 g of silica gel/DCM+0-1% of MeOH). The product is crystallised from diethyl ether/petroleum ether; m.p. 57-58° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1CO
Temperature: -10 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (9.50 g, 41 mmol) was dissolved in anhydrous THF (50 mL) under nitrogen and cooled to −10° C. A 1M solution of borane (82 mL, 82 mmol) was added dropwise whilst maintaining the temperature below 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to −5° C. and water (10 mL) was added cautiously followed by Na2CO3 (9.5 g) in water (20 mL). After stirring for 30 min at room temperature the THF was removed in vacuo, water was added and the reaction mixture was extracted with diethylether (×3). The combined organic extracts were dried (MgSO4) and the solvent was evaporated in vacuo to give 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (8.9 g, 100%) as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:28]>CO>[CH2:26]([O:25][CH2:24][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH3:23])[CH:19]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:28])[C:11]=2[N:12]=1)[CH3:27]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCCc1cc(C)no1
Reactant: N
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCc1cc(C)no1

Procedure:
4-Chloro-2-(ethoxymethyl)-1-[3-(3-methylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (1.87 g, 4.86 mmol) was treated with a solution of 7 M ammonia in methanol (20 mL) according to the procedure described in Part C of Example 5. The crude product was purified by flash chromatography (silica gel, gradient elution from 5% to 20% CMA in chloroform). The appropriate fractions were combined and concentrated to yield a solid that was triturated with 9:1 dichloromethane/methanol. The final material was dried under vacuum to yield 2-(ethoxymethyl)-1-[3-(3-methylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.29 mg) as a white powder, mp 163.0-164.0° C.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C=O)C>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Clc1cccc2nccn12
Reactant: Nc1ccc(S)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(Sc2cccc3nccn23)cc1
Yield: 69.9 %

Procedure:
A solution of 5-chloroimidazo[1,2-a]pyridine (2.0 g), 4-aminothiophenol (2.46 g) and triethylamine (1.7 ml) in DMF (10 ml) was stirred for 5 days at 90° C. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 2:1→ethyl acetate), to give 5-(4-aminophenylthio) imidazo[1,2-a]pyridine (2.21 g) as pale yellow crystals.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([C:15]1[C:16]([NH:30][C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:17]([OH:29])[C:18]([F:28])=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:20]=1[CH3:21])#[N:14].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:32]([C:31]1[O:29][C:17]2[C:16](=[C:15]([C:13]#[N:14])[C:20]([CH3:21])=[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:18]=2[F:28])[N:30]=1)([CH3:34])([CH3:33])[CH3:35]
Reactant: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(F)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)C)nc2c1C#N
Yield: 90.7 %

Procedure:
Toluene (67 ml), p-toluenesulfonic acid monohydrate (98 mg, 515 μmol) were added to N-(5-cyano-2-fluoro-3-hydroxy-6-methylbiphenyl-4-yl)-2,2-dimethylpropionamide (I-73) (1.68 g, 5.15 mmol), followed by refluxing with a Dean-Stark condenser for 4 hours. After cooling, saturated sodium bicarbonate water (50 ml) was added to the reaction liquid, the product was extracted with ethyl acetate (200 ml). The organic layer was washed with saturated brine (50 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (1.44 g, 91%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](/[C:17]([OH:19])=[O:18])=[CH:15]\[CH3:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](/[C:17]([OH:19])=[O:18])=[CH:15]/[CH3:16])[N:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C=C(/C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C(\C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.25 h

Procedure:
8.3 g (29 mMol) of E-1-(5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)propene-1-carboxylic acid were dissolved in 40 ml of DMF and the solution was added to a solution of 10 g of potassium t-butylate in 30 ml of DMF at 0° C., whereupon the internal temperature rose to 30° C. The mixture was stirred for 15 minutes, 300 ml of water were poured in and the pH was adjusted to 2 with 1N HCl. The mixture was extracted 2×ethyl acetate and the combined organic phases were washed with water, dried over MgSO4 and evaporated in vacuo. 8.0 g (96%) of E/Z mixture~1:2.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([O:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[C:3]1[C:4]([O:9][N:10]([C:11]([O:12][CH2:13][CH3:14])=[O:15])[C:22](=[O:23])[NH:21][CH2:18][CH2:19][CH3:20])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCN=C=O
Reactant: CCOC(=O)NOc1ncccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCNC(=O)N(Oc1ncccc1C(F)(F)F)C(=O)OCC
Temperature: 45 °C
Reaction time: 40 h
Yield: 84.7 %

Procedure:
Ethyl N-(3-trifluoromethyl-2-pyridyloxy)-carbamate (2.30 g; 9.19 mmoles) was dissolved in 50 ml of toluene, and 2.34 g (27.6 mmoles) of n-propyl isocyanate and 0.2 g (2.0 mmoles) of triethylamine were added, and the mixture was stirred at 45° C. for 40 hours. The toluene and the excess of n-propyl isocyanate in the reaction mixture were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane) to give 2.61 g (yield 85 %) of the desired compound as a colorless liquid.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(OC(=O)C)(=O)C>S(=O)(=O)(O)O>[CH2:3]1[C:1]2([C:7](=[O:9])[O:8][C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[O:5][C:4]2=[O:6])[CH2:2]1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: O=C1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC2(CCCCC2)OC(=O)C12CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12843.3 %

Procedure:
A mixture of cyclopropane-1,1-dicarboxylic acid (13.0 g, 0.10 mmol), cyclohexanone (10.8 g, 0.11 mol), acetic anhydride (11.2 g, 0.11 mol) and concentrated sulphuric acid (5 drops) was stirred at room temperature 0.5 h. The mixture soon became a wine-red solution which later darkened to purple. The reaction mixture was partitioned between water (100 ml) and ether (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4), filtered and evaporated to leave a purple oil plus some solid material. This mixture was purified by column chromatography on silica [eluent=ether/hexane (4:1)] to give the title compound as colourless crystals (2.70 g, 13%), m.p. 134.5°-135° C.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.C([O:29][C:30](=[O:57])[CH2:31][N:32]([C:42](=[O:56])[C@@H:43]([NH:47]C(=O)C1C=CC=CC=1)[CH:44]([CH3:46])[CH3:45])[CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)(C)(C)C>>[CH3:24][O:23][C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([O:11][CH3:10])[C:20]=1[O:21][CH3:22])[C:15]([NH:47][C@@H:43]([CH:44]([CH3:46])[CH3:45])[C:42]([N:32]([CH2:31][C:30]([OH:57])=[O:29])[CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)=[O:56])=[O:17]
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: O=C(O)c1ccccc1
Product: COc1cc(C(=O)N[C@H](C(=O)N(CC(=O)O)C2Cc3ccccc3C2)C(C)C)cc(OC)c1OC

Procedure:
Compound 730 was prepared by a method similar to the method used to prepare compound 724, except benzoic acid is replaced with 3,4,5-trimethoxybenzoic acid in the preparation of 723. ##STR109##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH3:18][C:19]1([CH3:27])[O:23][C@:22]([CH2:25]O)([CH3:24])[CH2:21][O:20]1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:24][C@@:22]1([CH3:25])[CH2:21][O:20][C:19]([CH3:27])([CH3:18])[O:23]1)=[O:15])[CH:7]=[CH:6]2
Reactant: CC1(C)OC[C@](C)(CO)O1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@@]3(C)COC(C)(C)O3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 32.2 g, 0.14 mol) and ((4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)methan-l-ol (15 g, 0.113 mol) in anhydrous dichloromethane (750 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC) (23 g, 0.12 mol) and N,N-dimethylaminopyridine (DMAP, 7.5 g, 61 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and solvent was evaporated under reduced pressure. The product was purified by column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give the title compound (37.5 g, 96.5% yield) as a white solid, mp 65-66° C. 1H NMR (CDCl3) δ7.75 (d, J=8.7 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.46 (dd, J=8.4 and 1.7 Hz, 1H), 7.15 (m, 2H), 4.27 (m, 1H), 4.19 (m, 2H), 4.03-3.92 (m, 2H), 3.96 (s, H), 3.69 (dd, J=8.4 and 6.0 Hz, 1H), 1.64 (d, J=7.1 Hz, 3H), 1.40 (s, 3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 135.3, 133.7, 129.2, 128.8, 127.1, 126.1, 125.9, 119.0, 109.7, 105.5, 73.4, 66.2, 64.8, 55.2, 45.2, 26.5, 25.3, 18.4; LRMS (APIMS) m/z 362 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][C:3]=1[C:14]([O:16]C)=[O:15].[H-].[Na+].[CH2:20]([O:27][C:28]1[C:33]([CH2:34]Cl)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:20]([O:27][C:28]1[C:33]([CH2:34][N:9]2[C:8](=[O:13])[C:7]3[C:2]([CH3:1])=[C:3]([C:14]([OH:16])=[O:15])[CH:4]=[CH:5][C:6]=3[O:12][CH2:11][CH2:10]2)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc2c(c1C)C(=O)NCCO2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CN2CCOc3ccc(C(=O)O)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a solution of methyl 6-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxylate (130e, 0.10 g, 0.45 mmol) in DMF (8 mL) was added NaH (54 mg, 1.36 mmol, 60% in oil) at 0° C. After stirring at 0° C. for 10 minutes, 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 0.20 g, 0.77 mmol) was added. The mixture was stirred at room temperature overnight. To the reaction mixture was added H2O (30 mL). The mixture was extracted with EtOAc (2×20 mL). The aqueous layer was acidified with conc. HCl to pH 3 and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (4×30 mL), dried over Na2SO4, and concentrated under vacuum to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxylic acid (130f, 0.17 g, 84.7%) as an off-white solid.
Reaction SMILES: ClC1C=CC(CC2C(=O)OC(C)(C)OC2=O)=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl.[CH3:40][S:41]([C:44]1[CH:60]=[CH:59][C:47]([CH2:48][CH:49]2[C:54](=[O:55])[O:53]C(C)(C)[O:51][C:50]2=[O:58])=[CH:46][CH:45]=1)(=[O:43])=[O:42]>>[CH3:40][S:41]([C:44]1[CH:45]=[CH:46][C:47]([CH2:48][CH:49]([C:50]([OH:58])=[O:51])[C:54]([OH:55])=[O:53])=[CH:59][CH:60]=1)(=[O:42])=[O:43]
Reactant: CC1(C)OC(=O)C(Cc2ccc(S(C)(=O)=O)cc2)C(=O)O1
Agent: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: CS(=O)(=O)c1ccc(CC(C(=O)O)C(=O)O)cc1

Procedure:
The title compound was prepared by substituting 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a) with 5-(4-methylsulfonylbenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 8: step a) then following the procedure described for the preparation of 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([O-:9])=O.[Li+].Cl.[NH2:29][C:30]1([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:29][C:30]1([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C([O-])c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4ccc(C(F)(F)F)cc4)C3)CC2)cc1
Yield: 12.9 %

Procedure:
The title compound (D199) (24 mg) was prepared according to the experimental procedure described in Description 148 starting from lithium 5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinate (D136) (130 mg, 0.331 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (75.36 mg, 0.331 mmol).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH:12]2[OH:17])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13][CH:12]2[OH:17])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C2CCNCC2O)cc1
Reactant: O=COCc1ccccc1
Product: C=CCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1

Procedure:
Analogously to Example 10f, 29.45 g of 4-(4-allyloxyphenyl)piperidin-3-ol and 26.8 g of benzyl formate are reacted. The title compound is obtained as a white solid. Rt=4.62.