Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:6]=[N:7][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Agent: N
Product: c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1

Procedure:
The product of Example 9A (480 mg, 2 mmol) was coupled with 5-indolylboronic acid (Frontier, 403 mg, 2.5 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (240 mg, yield, 38%). 1H NMR (300 MHz, CD3OD) δ 1.49-1.64 (m, 1H), 1.68-1.93 (m, 2H), 2.00-2.15 (m, 1H), 2.28-2.36 (m, 1H), 2.76-3.05 (m, 5H), 3.43-3.55 (m, 1H), 5.26-5.34 (m, 1H), 6.56 (dd, J=3.4, 1.0 Hz, 1H), 7.25 (d, J=9.2 Hz, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.74 (dd, J=8.5, 1.7 Hz, 1H), 8.08 (d, J=9.5 Hz, 1H), 8.14 (d, J=1.4 Hz, 1H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>C(OCC)(=O)C>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1csc(N)n1
Solvent: CCOC(C)=O
Product: Cc1csc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)n1
Yield: 39.2 %

Procedure:
5.0 gm (0.016 mol) of 4-hydroxy-2-methyl-2H-naphtho [2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 2.75 gm (0.025 mol) of 2-amino-4-methyl-thiazole in 200 ml ofxylene analogous to Example 1 and yielded 2.52 gm (40% of theory) of 4-hydroxy-2-methyl-N-(4-methyl-2-thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 177° C (decomp.; from ethyl acetate).
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[CH3:23][O:24]C1C=C(C=CC=1)N>CO>[Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:24][CH3:23])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: COc1cccc(N)c1
Agent: [Cl-]
Solvent: CO
Product: COc1cccc(-[n+]2ccc(C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-carbamoyl-1-(2,4-dinitrophenyl)-pyridinium chloride (43.2 g, prepared in a similar manner to that described in Example 2), 3-methoxyaniline (34 g) and methanol (1500 ml) was stirred at ambient temperature for 16 hours. The mixture was then warmed at 40° C. for 30 minutes, and stirring was continued for 2 hours at ambient temperature, then the solvent was removed in vacuo. Ether was added to the resulting oily solid and the solid collected by filtration. The solid was triturated in hot 2-propanol (11), collected by filtration and dried. The solid was triturated in hot acetone, collected by filtration and dried to give 4-carbamoyl-1-(3-methoxyphenyl)pyridinium chloride as a beige solid (32.4 g), m.p. 272° C. (dec).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:35])([CH2:33][CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:32])([CH3:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:35])([CH2:33][CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:32])([CH3:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 mL, 8 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (192 mg, 0.39 mmol) in methanol (4 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. Chiral HPLC eluting with IPA/heptane afforded the two individual enantiomers. 1H NMR (500 MHz, CD3OD) δ 8.47 (s, 1H), 7.82 (m, 1H), 7.73 (d, J=7 Hz, 2H), 7.64 (m, 1H), 7.07 (d, J=7 Hz, 2H), 6.58 (s, 1H), 3.19 (d, J=11 Hz, 1H), 3.13 (d, J=11 Hz, 1H), 2.40 (s, 2H), 1.61 (s, 3H), 1.62 (q, J=5.5 Hz, 2H), 0.87-0.75 (m, 9H); (M+H) found: 382.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23].C(N(CC)CC)C>ClCCl>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[S:18][C@@H:16]([C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH3:17]
Reactant: CN(C)C(=S)Cl
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](SC(=S)N(C)C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.3 %

Procedure:
(2R,3R)-2-(2,4-difluorophenyl)-3-mercapto1-[1H-1,2,4-triazol-1-yl]-2-butanol (0.10 g) was allowed to react with N,N-dimethylthiocarbamoyl chloride (0.13 g) in dichloromethane (3.0 ml) in the presence of triethylamine (49 ml) by the same manner as in Example 2. The compound (32), i.e., [(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl] N,N-dimethyldithiocarbamate (0.08 g) was obtained as colorless oil.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15](Cl)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].F[C:26](F)(F)[CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>C(OCC)(=O)C>[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15]([N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([CH3:26])[CH2:28]2)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: FC(F)(F)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ncnc(N2CCCC(C)C2)c1F
Temperature: 70 °C
Reaction time: 5 h
Yield: 108.6 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 0.2 g of 4-(2-butynyloxy)-5-fluoro-6-chloropyrimidine, 0.28 g of potassium carbonate and 0.15 g of 3-trifluoromethylpiperidine was added therein, and the mixture was stirred for 5 hours at 70° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 4-(2-butynyloxy)-5-fluoro-6-(3-methylpiperidino)pyrimidine (hereinafter, referred to as Compound (26)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:32])([CH:29]([F:31])[F:30])[CH2:20]OS(C(F)(F)F)(=O)=O>CC(C)=O.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:19]([F:32])([F:18])[CH:29]([F:31])[F:30])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (2.0 g, 13.1 mmol) in acetone (40 ml) was treated with potassium carbonate (5.415 g, 39.2 mmol) and trifluoro-methanesulphonic acid 2,2,3,3-tetrafluoropropyl ester. After 4 hours stirring at room temperature the suspension was diluted with diethylether. After filtration the solution was evaporated and the yellow solid purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 30:70 as the eluent. The 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester was obtained as a light yellow solid (3.49 g, 76% of theory). MS (ISP): m/z=468.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[C:7]([N:12]=[C:13]=[O:14])(=[O:11])[C:8]([CH3:10])=[CH2:9]>C(Cl)(Cl)Cl.ClCCCl>[C:7]([NH:12][C:13](=[O:14])[O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: CN(C)CCO
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)OCCN(C)C
Yield: 99.9 %

Procedure:
Dimethylaminoethanol (0.89 g; 10 mmol) was dissolved in dry chloroform (20 ml) under ice-cooling, and a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (5 ml) was dropwise added thereto under nitrogen stream. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give dimethylaminoethyl N-methacryloylcarbamate (2.00 g), which was recrystallized from a mixture of benzene and hexane to give colorless needle-like crystals. M.P., 71°-73° C.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].O=O.[C:7]([OH:10])(=[O:9])[CH3:8]>>[C:7]([O:10][C:1]([O:10][C:7](=[O:9])[CH3:8])=[CH:2][CH2:3][CH3:4])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: C=CC=C
Agent: O=O
Product: CCC=C(OC(C)=O)OC(C)=O

Procedure:
The reactor was maintained at 6 MPa, and 70° C. acetic acid containing butadiene and 70° C. nitrogen gas containing oxygen were continuously introduced into a lower part of the reactor at superficial velocities of 1.8 cm/sec and 1.5 cm/sec, respectively, and passed through the catalyst-packed bed upward. The nitrogen gas containing oxygen was introduced with a sparger so as to form fine bubbles. The liquid and gas introduction was thus continued over 2,700 hours to conduct a reaction for yielding diacetoxybutene. Thereafter, the catalyst was withdrawn through the upper part of the reactor and examined for palladium content. As a result, the palladium content had not decreased at all. Furthermore, the surface of the catalyst withdrawn was examined with an optical microscope (magnification, 50 diameters). As a result, almost no mars formed by friction were observed.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[CH:17]=O)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[CH:17]=[CH:27]/[C:25]#[N:26])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1oc(COc2ccccc2/C=C/C=O)nc1-c1ccccc1
Product: Cc1oc(COc2ccccc2/C=C/C=C/C#N)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 35, (E)-3-[2-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[2-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile. Recrystallization from ethanol-chloroform gave colorless prisms, m.p.128°-129° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1Cl)[CH3:5]>CO>[CH2:4]([O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[O:2][CH3:1])[CH3:5]
Reactant: C[O-]
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cccnc1OC
Temperature: 25 °C
Yield: 79 %

Procedure:
Sodium methoxide (18 mL, 25 wt % in methanol) was added slowly to a solution of ethyl-2-chloronicotinate (11.14 g 60 mmol) in anhydrous methanol (60 mL). The reaction mixture was stirred under reflux for 15 h, then cooled to rt. The methanol was removed in vacuo. The residue was dissolved in EtOAc (200 mL) and sat. ammonium chloride solution (50 mL) was added. The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave ethyl-2-methoxynicotinate (8.58 g, 79%) as yellow oil. Sodium hydride (0.21 g, 60% in mineral oil, 5.16 mmol) was mixed with anhydrous DMF (5 mL). A solution of 3′-bromo-4′-methoxyacetophenone (0.99 g, 4.3 mmol) in anhydrous DMF (3 mL) was added drop-wise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 5 min. and then at rt for 30 min. The mixture was cooled to 0° C. A solution of ethyl 2-methoxy nicotinate (1.81 g, 10 mmol) in anhydrous DMF (3 mL) was added slowly. The ice bath was removed and the stirring continued at rt under nitrogen for 20 h. Water (20 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. Removal of the solvent gave a dark solid. Triturating with ether gave a yellow solid (1.32 g, 84%). The solid (1.31 g, 3.6 mmol) and pyridinium hydrochloride (6.24 g, 54 mmol) were mixed together and stirred at 190° C. for 3 h, The reaction mixture was then cooled to rt, followed by the addition of water (200 mL). The solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was purified by column chromatography (Silica Gel 230-400 mesh; 5:4:1 hexanes, EtOAc and methanol as an eluent) to give 2-(3-bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one (0.453 g, 40%) of as yellow solid. MS (ES) m/z: 317.84, 239.9; Mp. 267-272° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[O:15]>>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:16][C:14](=[O:15])[C:13]([OH:18])=[O:17]
Reactant: CC(=O)C(=O)O
Reactant: COc1cccc(C=O)c1OC
Product: COc1cccc(C=CC(=O)C(=O)O)c1OC

Procedure:
The condensation reaction between 2,3-dimethoxy-benzaldehyde and pyruvic acid in the presence of a base to yield 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid is well known.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=[O:2]
Reactant: NCCCCO
Reactant: CCOC(=O)c1ccnc(C=O)c1
Product: CCOC(=O)c1ccnc(C(=O)NCCCCO)c1

Procedure:
By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and 4-aminobutan-1-ol. Purification by column chromatography (5% MeOH/DCM) gave the target compound as greenish oil. 1H-NMR (300 MHz, CDCl3): δ 8.60 (d, 1H), 7.80 (s, 1H), 7.70 (d, 1H), 4.40 (q, 2H), 4.05 (s, 1H), 3.60 (m, 2H), 2.80 (m, 2H), 1.70 (m, 4H), 1.40 (t, 3H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][OH:13])=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][N:8]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.[H-].[Na+]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:23]2[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:9][N:8]=1
Reactant: OCc1c(-c2ccccn2)noc1/C=C/c1ccccc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2c(-c3ccccn3)noc2/C=C/c2ccccc2)nc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of [3-pyridin-2-yl-5([E]-styryl)-isoxazol-4-yl]-methanol (1.5 g, 5 mmol) in DMF (30 mL) was added 6-chloro-3-pyridine-carbonitrile (0.82 g, 6 mmol) and sodium hydride (0.26 g of a 55% dispersion in mineral oil, 6 mmol). The mixture was stirred at 70° C. for 3 h. Then the temperature was raised to 90° C. for 1 h. After evaporation of the solvent the residue was partitioned (ethyl acetate/brine) and the organic phase was dried (Na2SO4) and filtered. Evaporation of the solvent followed by trituration with diisopropylether afforded the title compound (1.8 g, 88%) as a light brown solid. MS: m/e=381.3 [M+H]+.
Reaction SMILES: [N:1]1([C:16]([O:18][CH:19]2[CH:26]3[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:28][CH:20]2[CH2:21]4)[CH2:25]3)=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30]>>[CH:29]([S:32]([N:8]1[CH2:7][C:4]2([CH2:5][CH2:6][N:1]([C:16]([O:18][CH:19]3[CH:20]4[CH2:28][CH:24]5[CH2:23][CH:22]([CH2:27][CH:26]3[CH2:25]5)[CH2:21]4)=[O:17])[CH2:2][CH2:3]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(=[O:34])=[O:33])([CH3:31])[CH3:30]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Product: CC(C)S(=O)(=O)N1Cc2ccccc2C2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)C1

Procedure:
The title compound was prepared from 2-adamantyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate following a procedure analogous to that described in Example 34 using isopropylsulfonyl chloride in place of methanesulfonyl chloride. LC-MS Method 1 tR=2.31 min, m/z=487; 1H NMR (CDCl3) δ=7.36 (d, 1H), 7.26 (t, 1H), 7.20 (t, 1H), 7.05 (d, 1H), 4.88 (s, 1H), 4.56 (br s, 2H), 4.18 (d, 2H), 4.35 (m, 1H), 2.99 (m, 4H), 1.42 (d, 6H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)CN
Solvent: Cc1ccccc1
Product: CC(C)CNCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To an ice-cooled solution of benzyl bromoacetate (17.1 g, 74.6 mmol) in toluene (200 ml) was added isobutylamine (14.8 ml, 150 mmol) with stirring. The reaction mixture was allowed to warm to room temperature then heated at reflux for 1.5 h before leaving to cool to room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with brine. The organic phase was dried (anhydrous MgSO4), filtered and evaporated to an oil which was purified further by column chromatography (silica gel, 25% ethyl acetate in hexane) to give the title compound as a yellow oil (8.96 g, 54%). 1H-NMR; δ (CDCl3), 7.35 (5H, m), 5.18 (2H, s), 3.45 (2H, s), 2.41 (2H, d, J=6.8 Hz), 1.75 (2H, m) and 0.92 (6H, d, J=6.8 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[O:4].[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[O:25][CH3:26].C(O)C>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:22][C:21]2[CH:23]=[CH:24][C:18]([OH:17])=[C:19]([O:25][CH3:26])[CH:20]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: COc1cc(N)ccc1O
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)C2C(=O)N(C)C(=O)N(C)C2=O)ccc1O
Temperature: 25 °C

Procedure:
6.85 g of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 4.2 g of 4-hydroxy-3-methoxyaniline are suspended in 60 ml of toluene, and the suspension is heated under reflux for 3 hours, whereupon ethanol escapes. On cooling to room temperature a precipitate forms which is isolated by filtration, washed with ethanol and dried. Yield: 8.3 g (86% of theory). Melting point: 252°-253° C.
Reaction SMILES: C[O:2][C:3]([CH:5]([N:7]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9](OCC2C=CC=CC=2)[C:8]1=[O:25])[CH3:6])=[O:4].C([OH:28])C>[Pd]>[OH:28][C@@:5]([C:3]([OH:2])=[O:4])([CH3:6])[NH:7][C:8](=[O:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)N1C(=O)C(OCc2ccccc2)C1c1ccccc1
Reactant: CCO
Agent: [Pd]
Product: C[C@](O)(NC(=O)CCc1ccccc1)C(=O)O
Reaction time: 12 h
Yield: 90.5 %

Procedure:
According to the same procedure as in Example 1, Diastereomer A (700 mg.) of 1-(1-methoxycarbonylethyl)-3-benzyloxy-4-phenylazetidin-2-one, which had been obtained in Example 5, was subjected to hydrogenolysis at room temperature in ethanol (40 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (220 mg.). The reaction was completed in 12 hours. The same after-treatment as in Example 1 was followed to give methyl ester of α-hydroxy-β-phenylpropionylalanine (468 mg., yield: 90.5%), which was an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[C:25]([O:29][C:30]([NH:32][C@H:33]1[C:37]2([CH2:39][CH2:38]2)[CH2:36][NH:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CS(C)=O>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:35]2[CH2:34][C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:37]3([CH2:38][CH2:39]3)[CH2:36]2)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CC2
Solvent: CS(C)=O
Product: CC(=O)Nc1c(F)c(N2C[C@@H](NC(=O)OC(C)(C)C)C3(CC3)C2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
A mixture consisting of 5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (51.2 mg), (7S)-7-tert-butoxycarbonylamino-5-azaspiro(2.4)heptane (48.2 mg) and dimethyl sulfoxide (0.25 ml) was stirred at an outer temperature of 95° C. for 20 hours. When quantitative analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed amount of the compound of interest 5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid corresponded to 68.9 mg. The formation ratio was 85.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[Br-].[Mg+2].[Br-].[CH:20](=[O:22])[CH3:21]>O1CCCC1>[OH:22][CH:20]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)[CH3:21]
Reactant: CC=O
Reactant: COc1cccc2ocnc12
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1cccc2oc(C(C)O)nc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
4-Methoxybenzoxazole (6.0 g) was dissolved in tetrahydrofuran (225 ml) and cooled to −78° C. under nitrogen. n-Butyllithium (26.5 ml of a 1.6M solution in hexanes) was added, and the mixture stirred at −78° C. for 30 minutes before addition of magnesium bromide etherate (11.5 g). The resulting heterogeneous mixture was stirred at −45° C. for 15 minutes, and then cooled to −78° C. A solution of acetaldehyde (2.3 ml) was added from a pre-cooled syringe. The mixture was stirred at −78° C. for 3 h, then allowed to warm to room temperature and stirred overnight. It was quenched with aqueous sodium bicarbonate (50 ml, gradually) and the tetrahydrofuran evaporated in vacuo. The residue was extracted with dichloromethane (3×150 ml). The combined organic phases were dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 30%-50% ethyl acetate in hexane to afford the title compound as a brown solid (6.25 g).