Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.C[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:21][CH:22]=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.B(Br)(Br)Br>CCCCCC>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([NH:21][CH:22]=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(C(Cc2ccc(F)cc2)NC=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CNC(Cc1ccc(F)cc1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a -20° C. CH2Cl2 (100 mL) solution of N-[1-(4-methoxyphenyl)-2-(4-fluorophenyl)ethyl]formamide (1.6 g, 5.86 mmol) (for preparation see step A of Example 48) was added 11 mL of 1N BBr3 in hexane. After warming to 0° C. and stirring for one hour, an additional 5 mL of BBr3 solution was added. After 40 minutes, the reaction was complete by HPLC analysis. The reaction was quenched upon transferal into a stirred 4° C. aqueous NaHCO3 solution and extracted with CH2Cl2 (3×). The organic phases were washed with pH 4 NaH2PO4, brine, dried over Na2SO4 and concentrated to yield 1.4 g of N-[1-(4-hydroxyphenyl)-2-(4-fluorophenyl)ethyl]formamide as a yellow solid. To a 50° C. DMF (10 mL) containing benzyl bromide (400 mg, 2.3 mmol) and N-[1-(4-hydroxyphenyl)-2-(4-fluorophenyl)ethyl]formamide (450 mg, 1.7 mmol) under N2 was added 60% NaH (200 mg, 5 mmol). After one hour the reaction was quenched with H2O, extracted with EtOAc (3×). The organic phases were washed with H2O (3×), brine, dried over Na2SO4 and concentrated to yield 1 g of crude product. Flash chromatography on silica gel using 1:1 EtOAc/hexane eluted 300 mg of N-[1-(4-phenylmethoxyphenyl)-2-(4-fluorophenyl)ethyl]formamide. A 1:1 ETOH/H2O solution (10 mL) containing N-[1-(4-phenylmethoxyphenyl)-2-(4-fluorophenyl)ethyl]formamide (300 mg, 0.86 mmol) and NaOH (200 mg, 5 mmol) was refluxed for 40 hours, diluted with H2O and extracted 3× with EtOAc. The organic phases were washed with H2O (3×), brine, dried over Na2SO4 and concentrated to yield 290 mg of α-(4-phenylmethoxyphenyl)-4-fluorobenzeneethanamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:21])([CH3:20])[CH2:15][CH2:16]C[Mg]Br>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:16][CH2:15][C:14]([CH3:21])([CH3:20])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)CCC[Mg]Br
Product: COC(=O)c1ccc(C(O)CCC(C)(C)C)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and 4,4-dimethylpentylmagnesium bromide following the general method of Preparation 1.
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:3]=1[C:4]([OH:14])([C:9]#[C:10][CH:11]1[CH2:13][CH2:12]1)[C:5]([F:8])([F:7])[F:6].C(N(CC)CC)C.[C:28](Cl)(Cl)=[O:29]>C1(C)C=CC=CC=1>[Cl:20][C:16]1[CH:17]=[C:18]([F:19])[C:2]2[NH:1][C:28](=[O:29])[O:14][C:4]([C:9]#[C:10][CH:11]3[CH2:13][CH2:12]3)([C:5]([F:6])([F:7])[F:8])[C:3]=2[CH:15]=1
Reactant: Nc1c(F)cc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1Nc2c(F)cc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a stirred, cooled (−25° C.) solution of 144 mg (0.47 mmol) of (+/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 6 mL of toluene was added 0.28 mL (2.0 mmol) of triethylamine followed by 0.62 mL(1.2 mmol) of a 1.93 M solution of phosgene in toluene over 3 min. The solution was stirred an additional 30 min. at −25° C. after which time it was warmed to ambient temperatue and quenched with 0.5 N aq. citric acid. The mixture was extracted once with ether and once with ethyl acetate, and the combined organic extracts were washed sequentially with sat'd aq. NaHCO3, water, and brine. The solution was dried (MgSO4), and concentrated under reduced pressure to afford a tan solid. The crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether) to afford, after concentration, 90 mg (58%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. 1H NMR (300 MHz, CDCl3) δ7.65(br s, 1H); 7.32-7.34(m, 1H); 7.22(d, 1H, J=2.2 Hz); 1.36-1.43(m, 1H); 0.82-0.98(m, 4H). 19F NMR (282 MHz, CDCl3) δ−132.5(s, 1F), −81.1(s, 3F). High resolution mass spec: calculated for C14H9NO2ClF4(M+H)+: 334.0258, found: 334.0244.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N

Procedure:
10% Palladium-on-carbon (0.035 g) was added to a stirred solution in methanol (40 ml) of the nitro compound so obtained. (0.28 g) and the mixture was stirred at ambient temperature under 1 atmosphere pressure of hydrogen. After uptake of hydrogen had ceased, the catalyst was removed by filtration and the filtrate was evaporated to give N-(3-amino4-methylphenyl)-3-morpholinobenzamide; NMR Spectrum: (DMSOd6) 2.0 (s, 3H), 3.19 (t, 4H), 3.78 (t, 4H), 4.8 (s, 2H), 6.8 (q, 2H), 7.08 (s, 1H), 7.1 (d, 1H), 7.34 (m, 2H), 7.4 (s, 1H), 9.8 (s, 1H); Mass Spectrum: M+H+ 312.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:27]=[CH:26][C:15]3[CH2:16][CH2:17][N:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:6][CH:5]=1>CO.[OH-].[Na+].O>[CH:21]1([N:18]2[CH2:19][CH2:20][C:14]3[CH:13]=[C:12]([O:11][CH2:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][CH:6]=4)[CH:27]=[CH:26][C:15]=3[CH2:16][CH2:17]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid methyl ester (E88) (3.1 g, 8.1 mmol)) was dissolved in a mixture of methanol (90 ml), 2N sodium hydroxide (12 ml) and water (30 ml). The resulting mixture was stirred at 60° C. for 4 hours and then cooled to room temperature. The mixture was concentrated in vacuo to remove the organic solvents and then acidified to pH 6 (2N hydrochloric acid). The resulting precipitates were filtered, washed with water and dried under vacuum to afford the title compound (E89); MS (ES+) m/e 366 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[OH:13]
Reactant: [H][H]
Reactant: COc1cccc(CC(=O)c2ccco2)c1OC
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CC(O)C2CCCO2)c1OC
Yield: 70.5 %

Procedure:
A solution of 450 mg (1.8 mmol) of 2-(2',3'-dimethoxyphenyl)-1-furanylethanone, from Step 2, and 20% palladium on carbon (225 mg) in 75 mL of methanol was shaken under 4 atmospheres of hydrogen until hydrogen uptake ceased. The solution was filtered and concentrated in vacuo to give 320 mg (69% yield) of the title compound as an oily solid. This product was carried on without purification to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][N:7]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:8]2=[N:9][CH:10]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-bromo-7-azaindole (1, 1.5 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60% in mineral oil, 0.27 g, 11.0 mmol) and triisopropylsilyl chloride (2.6 mL, 12.0 mmol), under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give the compound (2, 1.6 g, 59%). MS (ESI) [M+H+]+=352.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.Cl[CH2:11][CH2:12][N:13]([CH2:21][CH2:22]Cl)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:13]1[CH2:21][CH2:22][C:7]([C:8]#[N:9])([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:11][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1cccnc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccnc2)CC1

Procedure:
Prepare by the method of example 30.2 using 3-pyridylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-butoxycarbonyl-ethanamine (11 mmol).
Reaction SMILES: CO[C:3]1=[N:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]1.[C:10]1([C:16]2[O:17][C:18](=[O:21])[CH2:19][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[OH-].[Li+].O>C1COCC1>[C:10]1([C:16]2[N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:3]3=[C:19]([C:18]([OH:21])=[O:17])[N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1=NCCOCC1
Reactant: O=C1CN=C(c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccccc2)n2c1CCOCC2
Temperature: 150 °C

Procedure:
(E)-5-methoxy-2,3,6,7-tetrahydro-1,4-oxazepine (50 mg, 0.387 mmol) was dissolved in THF (1 mL) in a screw-cap vial and 2-phenyloxazol-5(4H)-one (62.4 mg, 0.387 mmol) was added to give a orange solution. The reaction was heated to 150° C. for 5 minutes. LCMS shows two peaks of the corresponding product mass (tautomers of the condensation), Rt 0.73 and 0.78 minutes. The reaction was concentrated under reduced pressure and the residue was dissolved in 1 mL MeOH and treated with lithium hydroxide monohydrate (81 mg, 1.936 mmol) and water (200 μL). The reaction was heated at 120° C. for 5 minutes using microwave irradiation to provide a new desired product (same MW as intermediate) with Rt=0.50 minutes. The reaction was concentrated to remove MeOH and then diluted with water (1 mL). The solution was acidified to pH2 with 5N HCl. The solution was extracted with DCM (3×2 mL). The combined organic extracts were dried and evaporated to provide the title compound as a brown oil (23 mg). Additional material was recovered by concentrating the aqueous layer and repeated extraction with DCM. The combined material (45 mg, 45%) was used without further purification. LCMS (+ESI) m/z: 130.2 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>C(#N)C>[NH2:11][C:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:10]
Reactant: NC(=O)Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CC(N)=O
Temperature: 80 °C

Procedure:
2-Hydroxyphenyl acetamide (1.2 g, 7.93 mmol) was dissolved in acetonitrile (10 mL), and potassium carbonate (5.5 g, 39.6 mmol) was added to the solution. Subsequently, to the mixture, tert-butyl 2-bromoisobutyrate (8.9 g, 39.6 mmol) was added, followed by stirring at 80° C. After completion of reaction, water was added to the mixture. The resultant mixture was extracted with ethyl acetate, followed by washing the organic layer with water. The mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=40/1), whereby the target compound was obtained (1.4 g, 4.87 mmol, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])[C:10]2=[O:35])=[CH:5][CH:4]=1.[OH-:36].[Na+].OO>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]([NH2:31])=[O:36])[C:10]2=[O:35])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(N2C(=O)N(c3cccc(C(N)=O)c3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (±)-3-[3-(4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.11 g; 0.22 mmol) (from Example 5b supra) in dimethyl sulfoxide (1.5 mL) was cooled in an ice-water bath. Aqueous sodium hydroxide (1.0 M; 0.38 mL; 0.38 mmol) was added, followed by aqueous hydrogen peroxide (30% solution; 70 μL; 0.69 mmol). The cooling bath was removed following the additions and the mixture was stirred at room temperature for 3 hours. The solid was collected and washed with water and hot dichloromethane. This crude material was purified by flash chromatography (Biotage; 12M; 99:1 to 80:20 ethyl acetate-methanol gradient) and the pure product crystallized out of solution upon concentration to give (±)-3-[3-(4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzamide as a white solid. (Yield 64.6 mg; 57.9%). Melting Point: 268–273° C. (discolored on melting).
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]1[CH:6]=[C:7]([CH2:11][C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH3:3].S(Cl)([Cl:23])=O>>[CH3:1][N:2]([CH:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]1[CH:6]=[C:7]([CH2:11][C:12]([Cl:23])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CN(C)C(c1ccccc1)c1cccc(CC(=O)O)c1
Product: CN(C)C(c1ccccc1)c1cccc(CC(=O)Cl)c1

Procedure:
1.5 g of 3-(dimethylaminophenylmethyl)phenylacetic acid are heated at reflux temperature for 1/2 an hour in 15 ml of thionyl chloride with stirring. Thionyl chloride not consumed in the reaction is distilled off. The residue is taken up in toluene and the solvent is distilled again.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[O:13]>C(Cl)Cl>[CH3:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:18]2[CH:17]=[CH:16][S:15][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:20])=[O:21])=[O:24])[N:3]=1
Reactant: Cc1nc(C)nc(N)n1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(C)n1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To 1.23 g of 2-amino-4,6-dimethyl-1,3,5-triazine in 30 ml of anhydrous methylene chloride was added with stirring 2.7 g of 2-methoxycarbonyl-3-thiophenesulfonylisocyanate. The mixture was heated to the boiling point and allowed to cool and stir at ambient temperature for sixteen hours. The solid thus obtained was removed by filtration to yield 2.3 g of the crude desired product melting at 158°-178°. The product showed peaks at 1720 and 1700 cm-1, by infrared absorption spectroscopy, consistent for the desired product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([C:14]4[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH3:21])[CH:15]=4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([O:26]CC)=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([C:14]4[CH:15]=[C:16]([CH3:21])[N:17]=[C:18]([CH3:20])[CH:19]=4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Solvent: O
Product: Cc1cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)cc(C)n1
Yield: 73.1 %

Procedure:
A suspension of 12.4 g ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 320 ml water containing 3.5 g sodium hydroxide was heated at reflux for 2.5 hours. The reaction mixture was then decolorized with charcoal, filtered and brought to pH 5-5.5 with acetic acid. The solid that precipitated was collected, dried in vacuo and recrystallized from dimethylformamide to give 8.4 g 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 300°-302° C. (decompn.).
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[CH:11]=O.C1(P(=[CH:32][C:33]([O:35][CH3:36])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:32]/[C:33]([O:35][CH3:36])=[O:34]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc2ccccc2c1
Yield: 88.2 %

Procedure:
A mixture of 2-naphthaldehyde (6.00 g) and methyl (triphenyl-phosphoranylidene)acetate (13.0 g) in toluene (100 ml) was refluxed for 14 hours. After removal of the solvent, the residue was chromatographed on silica gel (hexane:ethyl acetate:CH2Cl2=4:1:4) followed by recrystallization from hexane-cyclohexane to give the titled compound (7.19 g) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1.C(O)C>[Pd].O1CCOCC1>[NH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CNc1nc(-c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1nc(-c2ccccc2)ccc1N
Yield: 98.9 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 5.7 g of 2-methylamino-3-nitro-6-phenylpyridine (prepared as described in Preparation 108) were hydrogenated in 200 ml of a 1:1 by volume mixture of ethanol and 1,4-dioxane in the presence of 1.14 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.9 g of the title compound having Rf=0.08 (on silica gel thin layer chromatography using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent) were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][O:19][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc3c(N)ncnc32)[C@](C)(O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
To a solution of the compound from Step F (457 mg, 1.63 mmol) in anhydrous pyridine (3.5 mL) was added tert-butyldimethylsilyl chloride (370 mg, 2.45 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then diluted with ethyl acetate (40 mL) which was washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to an oil that was subjected to chromatography on silica gel eluting with 10% MeOH in CH2C2. The appropriate fractions were collected, evaporated, and dried under high vacuum to furnish the title compound as a colorless foam (516 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:4][CH:5]([CH3:6])[CH2:8][S:9][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: CCOC(=O)c1sc(-c2ccc(F)c([N+](=O)[O-])c2)nc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2ccc(SCC(C)C)c([N+](=O)[O-])c2)nc1C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A reaction mixture solution prepared by suspending 155.2 mg of ethyl 2-[4-fluoro-3-nitrophenyl]-4-methyl-1,3-thiazole-5-carboxylate and 244.4 mg of cesium carbonate in 1.5 mL of N,N-dimethylformamide and adding 49.6 mg of 2-methylpropylthiol was heated under stirring at 80° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, 3 mL of water was added and extraction was performed using ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate. (2) The crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate obtained above was reduced using palladium carbon under a hydrogen atmosphere to obtain ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate. (3) A reaction mixture solution prepared by suspending ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate obtained above in 2.0 mL of acetic acid and adding 65 mg of sodium azide and 148 mg of triethyl ortho formate was heated at 70° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, water was added and extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduce pressure, followed by purifying by a conventional method to obtain 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate. (4) A reaction mixture solution prepared by adding 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate to 2 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.5 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 3 hours. After the addition of 0.5 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using ethyl acetate. The organic phase was concentrated, followed by purifying by a conventional method to obtain 67.9 mg of 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CS(C)=O.[Cu]>[F:16][C:10]([F:17])([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Fc1ccc(Br)nc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(F)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a mixture of 2-bromo-5-fluoropyridine (2 g, 11.36 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.6 mL, 12.5 mmol) in DMSO (4 mL) was added copper powder (1.6 g, 24.98 mmol) and the mixture was stirred at 50° C. overnight in a sealed flask. The mixture was diluted with DMSO (10 mL) and filtered through Celite. Then water and EtOAc were added and the mixture was shaken and again filtered through Celite. The organic layer was washed with water (1×) and brine (1×) and dried over sodium sulfate, and concentrated to afford ethyl 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate as a yellow oil (1.5 g, 60%). 1H NMR (300 MHz, CDCl3) δ 1.34 (t, 3H), 4.38 (q, 2H), 7.56 (dt, 1H), 7.77 (dd, 1H), 8.50 (d, 1H).