Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10][N:11]=[C:12]=[O:13]>CS(C)=O>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:12](=[O:13])[NH:11][CH3:10])[CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CN=C=O
Solvent: CS(C)=O
Product: CNC(=O)n1cc(F)c(=O)[nH]c1=O
Yield: 86.1 %

Procedure:
10.4 g. (0.08 mole) of 5-fluorouracil and 10.0 g. (0.176 mole) of methyl isocyanate were mixed in 100 ml. of dimethyl sulfoxide and stirred at room temperature. Dimethyl sulfoxide and excess methyl isocyanate were removed from the reaction mixture by distillation. The resultant residue was washed with chloroform and dried in a vacuum oven to give 15.8 g. (86.1% yield) of 5-fluoro-1-methylcarbamoyluracil. The product was recrystallized from ethyl acetate and there were obtained white crystals melting at 277° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:17][C:18]3[CH:19]=[C:20]([NH:25]C(=O)OC(C)(C)C)[C:21]([Cl:24])=[N:22][CH:23]=3)=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)[N:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:17][C:18]3[CH:19]=[C:20]([NH2:25])[C:21]([Cl:24])=[N:22][CH:23]=3)=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)[N:3]=1
Reactant: COc1cnc(Nc2cnc(Cl)c(NC(=O)OC(C)(C)C)c2)c(-c2nc(C)nc(N)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(Nc2cnc(Cl)c(N)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a 20 mL scintillation vial which contained tert-butyl 5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-ylcarbamate (0.210 g, 0.458 mmol) in DCM (5 mL) was added trifluoroacetic acid (Aldrich) (0.170 mL, 2.288 mmol). The resulting mixture was capped and stirred at rt in closed system for 1 h. The reaction mixture was first neutralized with sat. NaHCO3 then extracted with CHCl3 (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using the column chromatography (40 g, 3% to 5% MeOH in DCM) to afford the desired product as a yellow solid (135 mg). MS (ESI pos. ion) m/z: 359.0. Calc'd exact mass for C15H15Cl N8O: 358.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.84 (s, 3H) 5.43 (s, 2H) 7.78 (br. s., 1H) 7.86 (br. s., 1H) 7.89 (d, J=2.35 Hz, 1H) 7.94 (d, J=2.15 Hz, 1H) 8.16 (d, J=3.13 Hz, 1H) 8.40 (d, J=3.13 Hz, 1H) 11.75 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: BrBr.[F:3][C:4]1[CH:10]=[C:8]([NH2:9])[C:7]([CH3:11])=[CH:6][CH:5]=1.C([Br:19])C1C=CC=CC=1>>[F:3][C:4]1[CH:10]=[C:8]([NH:9][Br:19])[C:7]([CH3:11])=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(F)cc1N
Agent: BrBr
Product: Cc1ccc(F)cc1NBr

Procedure:
Bromine (0.5 mole) is added over 1 hour to stirred 5-fluoro-o-toluidine (0.5 mole) at 100° C illuminated with a high wattage lamp. The crude benzyl bromide is used as prepared.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]=[CH:16][CH:17]=[CH:18][C:11]=3[NH:10][C:9]2=S)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]=1
Reactant: O=c1c2ncccc2[nH]c(=S)n1-c1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1c2ncccc2nc(Cl)n1-c1ccc(F)cc1
Temperature: 135 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(4-fluorophenyl)-2-thioxo-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one (2.6 g, 9.5 mmol) in 30 mL of POCl3 is heated to 135° C. and stirred for 2 days. After cooling to RT, the excess POCl3 is removed in vacuo, and the residue is azeotroped twice with toluene. The resulting sticky brown oil/solid mix is dissolved in CH2Cl2 and neutralized to pH 7-8 with saturated NaHCO3. The layers are separated, and the CH2Cl2 layer is dried (Na2SO4), filtered, and evaporated to give a brown sticky solid. Purification by column chromatography (gradient from CH2Cl2 to 20% EtOAc/CH2Cl2) affords the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (1H, m), 8.05 (1H, m), 7.74 (1H, m), 7.28 (4H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=O)[CH:8]=[CH:9][CH:10]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[N:30][OH:31])[CH:8]=[CH:9][CH:10]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2cccc(CCCO)c2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(CCCO)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-[3-(3-hydroxy-propyl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a colorless oil, MS (ESI+): m/z=389.2 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:10][CH2:9][C:7]2[N:6]=[C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1cc(CN)nc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CNS(=O)(=O)c2ccc(F)cc2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A mixture of C-(4-Methoxy-[2,2′]bipyridinyl-6-yl)-methylamine (62.0 mg, 0.29 mmol), triethylamine (55.1 μL, 0.43 mmol), 4-Fluoro-benzenesulfonyl chloride (72.0 mg, 0.371 mmol) and dichloromethane (3 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography on silica gel (0-100% Ethyl acetate in Hexane) to afford 4-Fluoro-N-(4-methoxy-[2,2′]bipyridinyl-6-ylmethyl)-benzenesulfonamide as a white solid (48.1 mg, 38%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16]>C(Cl)Cl.C(N(CC)CC)C>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([O:14][C@@H:12]([C@@:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:11][O:10]1)[CH3:13])=[O:22])([O-:17])=[O:16]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C[C@@H](O)C1(c2ccc(F)cc2F)CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 46.3 %

Procedure:
(1R)-1-[2-(2,4-Difluorophenyl)-2-oxiranyl]ethanol (31.5 g) and 40 g of 3,5-dinitrobenzoyl chloride were dissolved in 500 ml of methylene chloride and, with ice cooling, 24.1 ml of triethylamine was added dropwise thereinto. The reaction solution was stirred at room temperature for 3.5 hours, washed with 150 ml of water and then with 150 ml of 5% aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The crystals separated out were collected by filtration and washed with methylene chloride. The mother liquor and the washing were combined and distilled off under reduced pressure, then 25 ml of ethyl acetate and 300 ml of methanol were added to the residue and the mixture was cooled with ice. The crystals separated out were collected by a filtration and recrystallized from a mixture of 25 ml of ethyl acetate and 250 ml of methanol to give 28.7 g of [(1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl] 3,5-dinitrobenzoate as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=O)[C:11](=[CH:15]N(C)C)[C:10](=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[NH2:23][C:22]1[N:24]=[CH:15][C:11]2[C:10](=[O:19])[CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][C:12]=2[N:21]=1
Reactant: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ncc2c(n1)CC(c1ccc(Cl)cc1)CC2=O
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (0.8 g, 2.89 mmol) from stage 1, guanidine hydrochloride (551 mg, 5.77 mmol) and sodium carbonate (919 mg, 8.67 mmol) were stirred in ethanol (10 ml) at reflux for 4 h. The reaction mixture was cooled to ambient temperature and water (10 ml) was added to the flask. The resulting precipitate was recovered by filtration, washed with water (15 ml), heptane (15 ml) and air dried.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][CH2:2][CH2:3][O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: C1=COCCC1
Reactant: OCCBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
To a solution of 2-bromoethanol (15 g, 0.12 mol) in DCM (150 mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (10.6 g, 0.126 mol) was added dropwise at 0° C. The mixture was stirred at room temperature for 4 h. It was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give 2-(2-bromoethoxy)tetrahydro-2H-pyran (18.0 g, 72.0% yield) as a light yellow oil.
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C1(C2[O:26]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16]([CH3:17])=[O:26])[N:8]=3)[CH2:2][CH:3]([CH2:5]1)[CH2:4]2
Reactant: CSc1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a stirring solution of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)pyrimidine-5-carboxamide (76 g, 0.304 mol) in chloroform (7 L) was added 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (143 g, 0.547 mol, 1.8 equiv.) and the resulting pale yellow solution was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure to give the crude product as a white solid, which was diluted with ethyl acetate (1.5 L) and the slurry was stirred at room temperature for 1 h. The resulting suspension was filtered, washed with ethyl acetate, and dried under vacuum to afford the desired compound (73 g, 0.274 mol, 90% yield) as a white solid; MS (ESI): m/z 267.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:3]=1[NH:4][S:5]([CH3:8])(=[O:7])=[O:6].C(N(CC)CC)C.[F:23][S:24]([C:27]1[CH:28]=C(S(Cl)(=O)=O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>O1CCCC1>[NH2:1][C:2]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:3]=1[N:4]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[S:5]([C:8]1[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([F:23])(=[O:25])=[O:26])[CH:28]=1)(=[O:7])=[O:6]
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=S(=O)(F)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NN(c1ccc([N+](=O)[O-])cc1N)S(=O)(=O)c1cccc(S(=O)(=O)F)c1
Temperature: 5 °C
Yield: 166.2 %

Procedure:
2'-Amino-4'-nitromethanesulfonanilide (30.4 g; 0.13 mole) was dissolved in dry tetrahydrofuran (ca. 700 ml) and then triethylamine (13.1 g; 0.13 mole) was added and the solution was chilled to 5° C. While stirring and maintaining a temperature <10° C., While stirring and maintaining a temperature <10° C., m-fluorosulfonylbenzenesulfonyl chloride (33.8 g; 0.13 mole) was added dropwise. After the addition, the reaction was kept at the ice bath temperature for one hour and then stirring continued at room temperature for an additional hour. The reaction solution was poured into ice cold water (about 2 liters) while stirring and scratching vigorously. The product was filtered and dried to yield 50.6 g (85 percent) beige solid, m.p. 204° to 209° C. A small sample (1 g) was recrystallized from ethanol (150 ml) to yield a beige solid, m.p. 224° to 226° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:12]12[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH2:17][CH2:18]1)[CH2:15][NH:14][CH2:13]2.C(N(CC)CC)C>C(O)(C)C>[CH3:11][C:10]1[C:3]2[C:2]([N:14]3[CH2:13][CH:12]4[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CC4CCC(C3)N4C(=O)OC(C)(C)C)c12
Temperature: 180 °C
Yield: 71.4 %

Procedure:
To a solution of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (25 mg, 0.15 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.14 mmol) in isopropanol (2 ml) was added triethylamine (36 μL, 0.26 mmol). The reaction was heated at 180° C. for 30 min in the microwave, then concentrated under vacuum. The residue was purified by prep HPLC (Sunfire C18 30×50 mm, 10-90% H2O/MeOH w/0.01% TFA, 15 min, 35 ml/min, 220 nm) to give tert-butyl 3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.10 mmol, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](Cl)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2].[CH2:18]([NH:25][CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:12][C:11]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([N:25]([CH2:26][CH3:27])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=[C:7]([CH3:17])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCNCc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(N(CC)Cc2ccccc2)c([N+](=O)[O-])c1Cl
Reaction time: 24 h

Procedure:
279 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester are dissolved in 700 ml. of alcohol. 150 g. of triethylamine are added and at reflux temperature 135 g. of benzyl(ethyl)amine are slowly dropped in. After the addition is completed, the heating is continued for another hour. After this time, the solvent is removed in vacuo, 300 ml. of water are added and the mixture extracted three times with 200 ml. portions of ether. The organic layers are combined, dried with calcium chloride and the solvent is distilled off. The resulting oil is distilled in vacuo, b.p.0.05 210°-220°. The crude product is dissolved in 300 ml. of ether and cooled to about -50°. After 24 hours, the isomeric compound 6-chloro-4-[ethyl(phenylmethyl)amino]-2-methyl-5-nitro-3-pyridinecarboxylic acid ethyl ester precipitates, is filtered off and the filtrate evaporated to dryness. The resulting 4-chloro-6-[ethyl(phenylmethyl)amino]-2-methyl-5-nitro-3-pyridinecarboxylic acid, yield 215 g. (56%) is used without further purification.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:19]1[CH:20]=[CH:21][C:22]([N+:34]([O-:36])=[O:35])=[C:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=1.[H-].[Na+]>CN(C)C=O>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:19]4[CH:20]=[CH:21][C:22]([N+:34]([O-:36])=[O:35])=[C:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH:24]=4)=[CH:15][CH:16]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1[N+](=O)[O-]
Yield: 90 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-(1-adamantyl)phenol (2.28 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.44 g) and anhydrous N,N-dimethylformamide (40 ml) and the reaction mixture was purified to give the title compound (4.30 g).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:21](=[O:37])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([OH:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([C@@H:21]([OH:37])[C@H:22]([N:24]2[CH2:25][CH2:26][C:27]([OH:36])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:28][CH2:29]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:19])[CH3:20])([CH:12]([CH3:13])[CH3:14])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)[Si](Oc1ccc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccccc3)CC2)cc1F)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 9.9 %

Procedure:
A mixture of sodium borohydride (0.12 g, 3.17 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-one (1.41 g, 2.82 mmol in 25 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The white precipitate which formed was collected by filtration to afford 0.14 g (10%) of (1R*,2R*)-1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-ol which had: mp 140-141° C. Analysis calculated for C29H44FNO3Si: C, 69.42; H, 8.84; N, 2.79. Found: C, 69.30; H, 9.06; N, 2.84. The filtrate was quenched with water and stirred overnight. The resulting precipitate was collected, washed with water and air dried (1.5 g). This material was recrystallized from ethanol to afford 0.72 g of additional product for a total yield of 0.86 g (61%).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([F:25])=[C:6]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:7]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([F:25])=[C:6]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
The whole of the diethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylmalonate [(XIV), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] [prepared as described in step (a) above] was dissolved in 200 ml of dioxane, and then 4.52 g (0.0238 moles) of p-toluene-sulfonic acid monohydrate were added to the resulting solution. The mixture was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. 100 ml of water and 2.52 g (0.03 moles) of sodium bicarbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 5.66 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylacetate as a reddish brown liquid.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]3[CH2:30][O:29]C(C)(C)[O:27]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.O1CCOCC1.Cl.C(=O)([O-])O.[Na+]>CO>[F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]([OH:27])[CH2:30][OH:29])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCc1ccccc1C1COC(C)(C)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCc1ccccc1C(O)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a mixture of 273 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)benzyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, 3 ml of dioxane, and 3 ml of methanol was added 6 ml of 1 M hydrochloric acid under ice-cooling, followed by stirring at room temperature for 16 hours. The reaction mixture was ice-cooled and 0.6 g of sodium hydrogen carbonate was added thereto in small portions to make the mixture weakly basic. The precipitated solid was collected by filtration and washed with water to obtain 236 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2-(1,2-dihydroxyethyl)benzyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)[CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccnc(F)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (300.0 mg, 1.02 mmol) in dioxane (5 mL) was added 2-fluoropyridin-4-ylboronic acid (289.0 mg, 2.06 mmol), K3PO4 (435.0 mg, 2.05 mmol), Pd(PPh3)4 (60 mg, 0.05 mmol) and three drops water under an inert atmosphere of nitrogen. The resulting solution was stirred for 1 h at 90° C. and then quenched by the addition of water (50 mL). The resulting solution was extracted with dichloromethane (5×20 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford methyl 2-(2-fluoropyridin-4-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (250 mg, 69%).