Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[C:21]([CH2:29][C:30]([O:32]CC)=[O:31])=[N:20]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[C:21]([CH2:29][C:30]([OH:32])=[O:31])=[N:20]2)=[CH:35][CH:36]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2cc(F)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2cc(F)ccc12
Yield: 85.4 %

Procedure:
Ethyl 2-[1-[4-(2-naphthamido)benzyl]-6-fluoro-1H-indazol-3-yl]acetate (205 mg, 0.426 mmol) was dissolved in tetrahydrofuran (15 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (54 mg, 1.29 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 165 mg, at a yield of 85.4%.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].[N:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:41][C:38]2([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: NC1(c2cnccn2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cnccn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.015 g, 0.011 mmol, 1.2 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.034 g (66%). 1H NMR (400 MHz, CD3OD): δ 8.60 (d, J=1.6 Hz, 1H), 8.52 (m, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.98-7.95 (m, 2H), 7.92 (dd, J=1.6, 7.8 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.36-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.73-1.71 (m, 2H), 1.47-1.43 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ−77.68 (TFA), −112.27, −122.72 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:12]=[CH:11]2
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Clc1nccc2cc[nH]c12
Temperature: -78 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
2-Chloro-3-nitropyridine 22e (5.0 g) was dissolved in dry THF (200 ml). After the solution was cooled down to −78° C., an excess of vinyl magnesium bromide (1.0 M in THF, 100 ml) was added. Then, the reaction was left at −20° C. for eight hours before quenched with 20% NH4Cl (150 ml). The aqueous phase was extracted with EtOAc (3×150 ml). The combined organic layer was dried over MgSO4. After filtration and concentration, the crude product was purified by silica gel column chromatography to afford 1.5 g of 7-chloro-6-azaindole 1e in 31% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-])=O.[C:11](O)(=[O:13])C>O>[NH2:1][C:4]1[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][C:5]1[CH:6]=[C:7]([O:13][CH3:11])[CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: CC(=O)O
Reactant: Cc1ccccc1[N+](=O)[O-]
Solvent: O
Product: COc1ccc(N)c(C)c1
Product: Cc1ccccc1N
Yield: 76.6 %

Procedure:
The same catalytic reduction reaction as in Example 1 was carried out except that o-nitrotoluene was used in an amount of 68.6 g (0.5 mole), and 68.6 g of glacial acetic acid was used instead of distilled water. The reaction required a period of 220 minutes with the absorption of 26.4 liters of hydrogen until its termination. The reaction solution was worked up in the same way as in Example 1 to give 9.0 g of o-toluidine and 53.1 g (yield 76.6%) of 2-methyl-4-methoxyaniline. The 2-methyl-4-methoxyaniline was found to have a purity of 99.0% by gas chromatography.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]>CC(C)=O>[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(C)=O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
The free base was dissolved in acetone and treated with one mole equivalent of L-tartaric acid. This mixture was concentrated and treated with dry ether to give a tartaric acid salt of the title compound as a white solid; mp 160°-163° C.; IR (KBr) 3448, 3064, 3030, 1726, 1664, 1612, 1582, 1518 cm-1 ; MS (FAB) MH+ m/z 1070, (M+Na)+ m/z 1092, (M+K)+ m/z 1108; 1H-NMR (CDCl3) δ 1.085 (s, 3H), 1.156 (s, 3H), 1.586 (s, 3H), 1.683 (m, H), 1.894 (s, 3H), 2.063 (m, H), 2.153 (s, 3H), 2.226 (s, 3H), 2.366 (s, 3H), 2.438 (m, 8H), 3.498 (s, 2H), 3.835 (d, H), 4.132 (d, H), 4.254 (d, H), 4.384 (m, H), 4.911 (m, H), 5.617 (m, 2H), 5.974 (m, H), 6.190 (t, H), 6.225 (S, H), 6.967 (d, NH), 7.200-8.200 (m, 19H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[NH2:54][CH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([NH:54][CH:55]6[CH2:60][CH2:59][O:58][CH2:57][CH2:56]6)=[O:26])=[CH:28][CH:29]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCOCC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.08 h
Yield: 20.5 %

Procedure:
To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml) HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and triethylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min. 4-Aminotetrahydropyran (0.106 g, 1.04 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.050 g, 20%). M.P.: 202-205° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.99 (m, 4H), 7.85 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 4.04 (m, 1H), 3.89 (d, J=9.7 Hz, 2H), 3.39 (t, J=10.0 Hz, 2H), 1.78 (d, J=10.5 Hz, 2H), 1.63 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[C:12]([F:15])[C:11](F)=[C:10]([F:17])[C:9]=2[F:18])=[C:6]([F:19])[C:5]([F:20])=[C:4](F)[C:3]=1[F:22].[C:23]1([OH:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:34](=[O:37])([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:23]1([O:33][C:4]2[C:5]([F:20])=[C:6]([F:19])[C:7]([C:8]3[C:9]([F:18])=[C:10]([F:17])[C:11]([O:37][C:34]4[C:2]5[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:8]=[CH:9][CH:10]=4)=[C:12]([F:15])[C:13]=3[F:14])=[C:2]([F:1])[C:3]=2[F:22])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Fc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2ccccc12
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Fc1c(F)c(-c2c(F)c(F)c(Oc3cccc4ccccc34)c(F)c2F)c(F)c(F)c1Oc1cccc2ccccc12
Temperature: 140 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
The monomer 4,4'-bis(1-naphthoxy)octafluorobiphenyl (8FNE) was prepared by the following procedure. A 100 mL round bottom flask was charged with decafluorobiphenyl (3.01 g, 0.0090 mole), 1-naphthol (2.60 g, 0.0181 mole), potassium carbonate (2.95 g, 0.0218 mole), and DMAc (40 g). The mixture was heated with stirring at about 140° C. for 2 hr and then cooled to room temperature, filtered, and poured into toluene (100 mL). The toluene solution was washed with 5% sodium hydroxide (50 mL) and then twice with deionized water (2×100 mL). After drying with magnesium sulfate and filtering, it was concentrated by rotary evaporation to yield a red solid. The solid was recrystallized from DMAc/water, filtered, and dried to yield 8FNE (3.9 g, 78.8% yield; m.p. 189°-191 ° C.; GC/MS m+ /e 582).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](NC1C=C2OCOC2=CC=1C(=O)C)=[O:17])(=[O:10])=[O:9].[CH3:32][O:33][C:34](=[O:46])[C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:36]=1[NH2:45]>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:45][C:36]1[CH:37]=[C:38]([O:43][CH3:44])[C:39]([O:41][CH3:42])=[CH:40][C:35]=1[C:34]([O:33][CH3:32])=[O:46])=[O:17])(=[O:9])=[O:10]
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Product: COC(=O)c1cc(OC)c(OC)cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Yield: 13 %

Procedure:
The title compounds were prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) except that methyl-2-amino-4,5-dimethoxybenzoate was used instead of 2'-amino-4',5=-(methylenedioxy)acetophenone. The crude product was purified via HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonylphenyl)aminocarbonyl]thiophene-3-sulfonamide as a yellow powder (13% yield, m.p. 167-168° C.) and N-(4-chloro-3-methyl-5-isoxazolyl)-2-{{2-[(4,5-dimethoxy-2-methoxycarbonyl)phenylaminocarbonyl]-4,5-dimethoxy}phenylaminocarbonyl}thiophene-3-sulfonamide as a dull yellow solid (1% yield, m.p. 228-230° C.).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][N:37]=1)CCC.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][C:2]([C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: [Pd]
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2-c2nccs2)cc1
Temperature: 120 °C
Yield: 3.3 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.2 mmol) in 5 ml of anhydrous DMF was added 2-tributylstannyl thiazole (0.071 g, 0.2 mmol) and degassed the reaction mixture for the 10 minutes. Then added tetraphenylphosphine palladium (0) (0.026 g, 0.2 mmol). The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to rt. 100 ml of water was added into it and extracted the compound with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using ethyl acetate (40:60) as the eluent to provide the title compound as yellow solid (0.003 g, 3%). 1H NMR (DMSO-d6, 400 MHz): δ 3.82 (s, 3H), 5.57 (s, 2H), 7.06 (d, 1H, J=8.4 Hz (o-coupling), 7.13 (dt, 1H), 7.39-7.47 (m, 1H), 7.51 (d, 2H, J=8.4 Hz (o-coupling), 7.52-7.58 (m, 1H), 7.59-7.86 (m, 2H), 7.68 (d, 1 H, J=3.2 Hz), 7.84 (d, 1 H, J=3.2 Hz), 7.89 (broad s, 1H), 8.18 (broad s, 1H), 9.12 (s, 1H); MS ES+ (460.01), HPLC (method 5) Rt=15.64 min.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15](Br)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1.[Li]CCCC.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=[O:32].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15]([CH:31]([OH:32])[C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1
Reactant: O=Cc1cccs1
Reactant: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(O)c3cccs3)c(C3OCCO3)cc21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. tetrahydrofuran (3.0 mL) solution of 2-(1,3-dioxolan-2-yl)-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (253 mg, 0.75 mmol) was added n-BuLi (1.6 M in hexane, 0.49 mL). The reaction mixture gradually thickened over 45 min. A solution of thiophene-2-carboxaldehyde (0.09 mL, 0.94 mmol) in tetrahydrofuran (0.75 mL) was added dropwise to the above slurry. The reaction mixture rapidly became homogeneous and was stirred at −78° C. for 45 minutes. Saturated ammonium chloride and ethyl acetate were added and the layers were separated. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a yellow oil which was purified by preparative thin layer chromatography (15% ethyl acetate/hexane) to give 2-(1,3-dioxolan-2-yl)-3-[1-hydroxy-1-(thiophene-2-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a waxy solid (190 mg, 67%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.CO.[CH3:12][C:13](=[N:15][OH:16])[CH3:14].[CH2:17]1COCC1>CCCCCC>[CH3:17][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7](=[O:9])[CH2:12][C:13](=[N:15][OH:16])[CH3:14]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: C1CCOC1
Reactant: CC(C)=NO
Solvent: CCCCCC
Solvent: CO
Product: CC(CC(=O)[C@@H]1CCC(=O)N1C)=NO

Procedure:
reacting the starting material, (S)-pyroglutamic acid, of formula (5), ##STR17## with methanol as the esterifying reagent at from -10° C. to 60° C. for from 4-to-48 hours, to prepare the (S)-pyroglutamic add ester of formula (6), ##STR18## wherein R1 is methyl; (b) reacting the compound of formula (6) with an excess of a salt of the dianion of acetone oxime in a solution of THF:hexane, at a temperature of from -10° C. to ambient temperature, with vigorous mixing of the reagents, to form the intermediate product, 1-(1-methyl-5-oxo-2(S)-pyrrolidinyl)-1,3-butanedione-3-oxime, which is not isolated, but which is cyclized and dehydrated by reaction with a strong acid at ambient-to-reflux temperature for from 0.5-to-3 hours, to produce the novel 5(S)-(3-methyl-5-isoxazolyl)-2-pyrrolidinone compound of formula (7), ##STR19## (c) reducing the compound of formula (7) with a reducing agent known to reduce lactams to cyclic amines, particularly an agent selected from the group consisting of lithium aluminum hydride, NaBH4 /BF3, NaBH4 /CH3SO3H, NaBH4 /camphor sulfonic acid, borane/dimethyl sulfide, and borane/THF, to give the 3-methyl-5-(2(S)-pyrrolidinyl)isoxazole compound of formula (8), ##STR20## which is not isolated; then (d) immediately treating the reaction product from step (c) with the N-alkylating agent formaldehyde and formic acid at ambient or an elevated temperature, and isolating the desired product of formula (1), wherein Alk is methyl, in high chiral purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][NH:13][CH2:12][CH:9]3[O:8][C:7]4[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[O:11][CH2:10]3)[CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Reactant: BrCCCOc1ccc2cccnc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)OC(CNCCCOc1ccc3cccnc3c1)CO2
Temperature: 80 °C
Yield: 28.2 %

Procedure:
2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine (2.7 g, 14 mmole), 7-(3-bromopropoxy)quinoline (3.86 g, 14 mmole), and diisopropylethylamine (6.5 g, 50 mmole) were combined in 100 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 500 ml of dichloromethane. The mixture was washed with 250 ml each of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 200 g of silica gel using 4% methanolchloroform as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue recrystallized from 50 ml of ethanol with the addition of 8 ml of 4N isopropanolic HCl to give 1.5 g of the title compound as a yellow solid dihydrochloride monohydrate, m.p. 135°-142° C.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=[C:2]2[O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)=[CH:13][CH:14]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (240 mg, 0.649 mmol, intermediate 8) in dimethyl formamide (5 mL) was added 3-(trifluoromethyl)phenol (105 mg, 0.649 mmol) followed by potassium carbonate (107 mg, 0.779 mmol). The resulting mixture was stirred at 80° C. for 6 h. The mixture was diluted with ethyl acetate (15 mL) and extracted with brine and saturated aqueous ammonium chloride solution. Then the organic phase was dried and concentrated to give a crude solid product which was collected and washed with ethanol to give 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (237 mg, 81.1% yield) as white solid. 1H-NMR (DMSO-d6) δ 11.24 (s, 1H), 7.77 (s, 1H), 7.69-7.71 (m, 3H), 7.43 (s, 4H), 5.42 (s, 2H), 3.22 (s, 3H). LCMS retention time 2.306 min; LCMS MH+ 451.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 4-(trifluoromethyl)benzoyl chloride (179 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the title compound (171 mg, 62%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C([O:19][C:20](=[O:34])[C@@H:21]([O:30][CH2:31][CH2:32][CH3:33])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)C.C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][C@H:21]([O:30][CH2:31][CH2:32][CH3:33])[C:20]([OH:34])=[O:19])=[CH:28][CH:27]=2)=[CH:6][CH:7]=1
Reactant: BrCCOc1ccc(-c2ccccc2)cc1
Reactant: CCCO[C@@H](Cc1ccc(O)cc1)C(=O)OCC
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: CCCO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 4-(2-bromo-ethoxy)-biphenyl (Example 377, Step 1) and (2S)-3-(4-hydroxy-phenyl)-2-propoxy-propionic acid ethyl ester (Example 377, Step 4) via the same procedure used for the preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3) to produce a white solid. MS (ES) for C26H28O5 [M+H]+: 421.0, [M+NH4]+: 438.0, [M+Na]+: 443.0, [M−H]−: 3239.2.
Reaction SMILES: [OH:1][CH2:2][P:3]([CH2:6][OH:7])(=[O:5])[OH:4].[OH-].[CH2:9]([N+:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]>O.CC(O)C>[OH:1][CH2:2][P:3]([CH2:6][OH:7])(=[O:4])[O-:5].[CH2:22]([N+:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24][CH3:25]
Reactant: O=P(O)(CO)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=P([O-])(CO)CO

Procedure:
To a flask were added 0.48 g bis(hydroxymethyl)phosphinic acid, 1.6 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 10 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 10 ml of 2-propanol were added and removed by distillation under reduced pressure. An oil was obtained.