Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH2:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: COc1ccccc1-c1cccn2nc(N)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ccccc1-c1cccn2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc12

Procedure:
8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 0.0047 mol) and 2-methoxybenzeneboronic acid (1.1 g, 0.0070 mol) in a manner analogous to Step 2c. The reactin product was isolated as a brown solid (1.0 g) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.50 (d, J=6.5 Hz, 1H), 7.51 (dd, J=7.6, 1.5 Hz, 1H), 7.43-7.36 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.02 (t, J=7.3 Hz, 1H), 6.91 (t, J=7.0 Hz, 1H), 5.96 (br s, 2H), 3.73 (s, 3H). MS=241 (MH)+. 55b) [8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.312 mmol) and 1-(4-Bromo-phenyl)-4-methyl-piperazine (90.0 mg, 0.353 mmol) with 2,2′-Bis-dicyclohexylphosphanyl-biphenyl (34.0 mg, 0.0622 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a pale yellow foam (0.063 g, 49%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.39 (d, J=6.2 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.45 (d, J=7.5 Hz, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.09 (t, J=7.3 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.95 (d, J=7.6 Hz, 2H), 6.91-6.86 (m, 1H), 6.65 (s, 1H), 3.81 (s, 3H), 3.17-3.12 (m, 4H), 2.61-2.56 (m. 4H), 2.36 (s, 3H). MS=415 (MH)+.
Reaction SMILES: ClCCl.[F:4][C:5]1[C:15]([N:16]2[C:20](=[O:21])[N:19]([CH3:22])[C:18]([CH3:23])=[N:17]2)=[CH:14][C:8]2[N:9]=[C:10]([S:12][CH3:13])[S:11][C:7]=2[CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>O>[F:4][C:5]1[C:15]([N:16]2[C:20](=[O:21])[N:19]([CH3:22])[C:18]([CH3:23])=[N:17]2)=[CH:14][C:8]2[N:9]=[C:10]([S:12]([CH3:13])=[O:29])[S:11][C:7]=2[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2cc(-n3nc(C)n(C)c3=O)c(F)cc2s1
Solvent: O
Solvent: ClCCl
Product: Cc1nn(-c2cc3nc(S(C)=O)sc3cc2F)c(=O)n1C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
10 mL dichloromethane was charged with 0.001 mol 1-(6-fluoro-2-(methylthio)benzo[d]thiazol-5-yl)-3,4-dimethyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred for 10 mins and then 0.0011 mol m-chloroperoxybenzoic acid (MCPBA) were added. After stirring at room temperature for 2 hours, the mixture was poured into 30 mL of water, extracted with 15 mL dichloromethane twice. Organic phases were combined and dried over anhydrous sodium sulfate. Filtration and removal of solvent under vacuum gave the title compound as a white solid in a 93% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:40]=[N+:41]=[N-:42].[Na+]>CS(C)=O>[N:40]([CH2:28][C@H:23]1[O:22][C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@@H:25]([OH:26])[C@@H:24]1[OH:27])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCc3ccccc3)[C@H](NC(=O)OCc3ccccc3)[C@@H](O)[C@@H]2O)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1O[C@H](OCc2ccccc2)[C@H](NC(=O)OCc2ccccc2)[C@@H](O)[C@@H]1O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 32.14 g benzyl 2-benzyloxycarbonylamino-2-desoxy-6-O-(p-tolylsulfonyl)-a-D-glucopyranoside in 75 ml of dimethyl sulfoxide was treated at room temperature with 7.5 g of sodium azide and stirred at 90° C. for 3 hours. The mixture was then poured on to ice/water. Separated crystals were filtered off under suction, washed with water and dried. There was obtained benzyl 6-azido-2-benzyloxycarbonylamino-2,6-didesoxy-a-D-glucopyranoside, [a]+119.60° (c 0.5; dioxan), MS: m/z 428 ([M+H]+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])=[O:5].[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:8]1[CH2:15][CH2:16][O:17][C:7]1([CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: OCCO
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC1(CC(=O)OCC)OCCO1
Yield: 42 %

Procedure:
A solution of diethyl 1,3-acetonedicarboxylate (12 g, 59.3 mmol), ethyleneglycol (9.93 mL, 178 mmol), and p-toluenesulfonic acid monohydrate (564 mg, 2.97 mmol) in benzene (80 mL) was refluxed under heating removing water for 10 h by Dean-Stark trap. The benzene layer was washed with a saturated aqueous sodium bicarbonate solution and brine. The solvent was distilled away and the residue obtained was purified by flash chromatography (10 to 40% EtOAc in heptanes) yielding diethyl 2,2′-(1,3-dioxolane-2,2-diyl)diacetate (42%). LCMS (m/z): 247.2 (MH+), 0.65 min; 1H NMR (400 MHz, CDCl3) δ ppm 4.17 (q, J=7.04 Hz, 4H) 4.03 (s, 4H) 2.95 (s, 4H) 1.27 (t, J=7.24 Hz, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH2:11](Br)[C:12]#[CH:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C1(C)C=CC=CC=1>[CH2:13]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[N:5][CH:6]=1)[C:12]#[CH:11]
Reactant: C#CCBr
Reactant: CC(=O)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCNc1ccc(C(C)=O)nc1
Temperature: 25 °C

Procedure:
2-Acetyl-5-aminopyridine, (Journal of Heterocyclic Chemistry, Vol. 10, pp. 1047-1049 (1973)), 25 g (0.161 mol), is dissolved in 600 ml of dry acetone. To this solution is added an 80% solution of propargyl bromide in toluene, 32 ml, and finely powdered potassium carbonate, 27 g. The solution is heated under reflux for thirty-six hours and then allowed to cool to room temperature. The reaction mixture is concentrated in vacuo and the residue is partitioned between dichloromethane and water. The organic portion is separated and the water layer extracted several times with dichloromethane. The combined organics are concentrated in vacuo to a semi-solid residue consisting of a mixture of starting material and a small amount of the monoalkylated product. The residue is triturated with a mixture of toluene and diethyl ether. The solid is removed by filtration and the filtrate is concentrated to an oil. Chromatography of the oil on silica gel with dichloromethane gives the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14]CC2C=CC=CC=2)[C:10]([F:23])([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[C:10]([F:23])([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)(F)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)C(F)(F)C1
Reaction time: 14 h

Procedure:
A suspension of 4-benzylamino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (830 mg, 2.54 mmol), Pd/C (81.2 mg, 76.3 μmol) in MeOH (30 mL) was hydrogenated at room temperature for 14 hours. The catalyst was filtered off, washed thoroughly with MeOH and the solvents were evaporated. The title compound was obtained as colorless oil (601 mg, 100%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([N:16](C(C)C)[CH2:17]C)(C)C.C(Cl)(=O)C(C)(C)C.CNC>ClCCl.O>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:13])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(I)cc(F)c1F
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1cc(I)cc(F)c1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
2,3 Difluoro-5-iodobenzoic acid (10.8 g, 38 mmol) was suspended in 80 mL of dry dichloromethane under nitrogen. Di-iso-propylethylamine (6.6 mL, 38 mmol) was added and the mixture was cooled to 0° C. Pivaloyl chloride (4.7 mL, 38 mmol) was added and the solution was stirred at 0° C. for 1.5 hrs. Dimethylamine was added (40% wt. solution in water, 10.6 mL, 83 mmol) and the reaction mixture was stirred for 5 hrs. The reaction was quenched with sodium bicarbonate and diluted with dichloromethane (50 mL). The layers were separated, the organic phase was washed with 1 N hydrochloric acid and brine. The organic phase was dried over magnesium sulfate and concentrated to give 10.3 g (33 mmol, 87%) of 2,3-difluoro-5-iodo-N,N-dimethyl-benzamide as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 7.95 (ddd, J=10 Hz, J2=7.5 Hz, J3=2 Hz, 1H), 7.57 (dt, J=10 Hz, J2=2 Hz, 1H), 2.98 (s, 3H), 2.84 (s, 3H); MS: m/z 312 [MH+]
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>ClCCl>[CH3:23][S:20]([O:10][CH2:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A flask was charged with 3-morpholinopropan-1-ol (1.0 g, 6.9 mmol), DIEA (2.4 mL, 14 mmol) and dichloromethane (100 mL). Mesylchloride (0.64 mL, 8.3 mmol) was added in a drop wise fashion to the dichloromethane mixture and the reaction mixture was stirred at room temperature for 15 hours. Concentration of the reaction mixture gave rise to a quantitative yield of 3-morpholinopropyl methanesulfonate, which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10](Cl)[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1.[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[N:18][N:17]=[N:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N=C(Cl)C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
Five grams (21.0 mmol) of N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 7, 2.46 g (37.8 mmol) of sodium azide, 1.45 g (10.5 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 15 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 5.05 g of 1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 98.3%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44]C(=O)C)/[C:8]([NH:10][C@@H:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.Cl.[OH-].[Na+].[OH-].[K+]>CO.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[OH:44])/[C:8]([NH:10][C@@H:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([O:27][CH:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
Diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (41.3 g) was suspended in methanol (420 ml) at room temperature, concentrated hydrochloric acid (24.9 ml) was added below 15° C. thereto. After the reaction mixture was stirred at room temperature for 30 minutes, concentrated hydrochloric acid (6.7 ml) was added thereto at the same temperature. After stirring at room temperature for 2 hours, poured into a mixture of ethyl acetate (1.2 l) and pH 6.86 buffer (1.5 l). The pH was adjusted to pH 5.0 with 30% aqueous sodium hydroxide, and then was adjusted to pH 6.0 with 2N-potassium hydroxide. The organic layer was separated, and herein THF (0.5 l) was added thereto with brine (1.0 l). The organic layer was washed with brine (1.0 l), dried over magnesium sulfate, and evaporated until the volume amounted to 500 ml. A mixture of IPE (500 ml) and ethyl acetate (700 ml) was added thereto. Resulting precipitate was filtered, dried under reduced pressure to afford diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (33.6 g) as powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20](=[O:22])[CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20](=[O:22])[CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:29]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(C(=O)O)c(N)c1
Product: COc1ccccc1C(=O)Nc1cc(NC(=O)c2ccccc2OC(C)=O)ccc1C(=O)O

Procedure:
By the procedure similar to that described in Example 23, 2-amino-4-(2'-acetoxybenzamido)-benzoic acid and 2-methoxybenzoylchloride were reacted and treated to obtain crude crystals. Recrystallization from water-ethanol gave 2-(2'-methoxybenzamido)-4-(2'-acetoxybenzamido)-benzoic acid which was identical to that of Example 23.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1.[CH3:19][NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH3:19])=[O:34])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)[CH:5]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(cc(C=O)cc2OC(F)F)NC1=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OC(F)F)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 403A and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J=6.82 Hz, 3H) 2.45-2.49 (m, 4H) 2.73 (d, J=4.55 Hz, 3H) 3.24 (d, J=4.80 Hz, 4H) 3.43 (s, 2H) 4.74 (q, J=6.74 Hz, 1H) 6.80 (s, 2H) 6.93 (d, J=9.09 Hz, 2H) 6.95-7.35 (m, 1H) 7.70 (d, J=8.84 Hz, 2H) 8.10-8.17 (m, 1H) 10.80 (s, 1H). ESI-MS: m/z 461.4 (M+H)+. mp 210.4-213.0° C.
Reaction SMILES: [H-].[Na+].CCO.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[C:20]([CH2:26]Br)[CH:19]=1>CCOCC>[Br:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:22][CH:23]=1)[CH2:24][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:6]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)Cc2ccc(Br)cc2C1
Reaction time: 0.08 h
Yield: 72.3 %

Procedure:
Sodium hydride (60% in mineral oil, 123 mg, 3.1 mmol) was added in small portions to EtOH (2 mL) in Et2O (6 mL) at room temperature under N2. After the addition was complete, the nearly clear and colorless solution was stirred for 5 min. To this solution, diethyl malonate (234 mg, 1.46 mmol) was added followed by the addition of 4-bromo-1,2-bis(bromomethyl)benzene (500 mg, 1.46 mmol). Immediately, a precipitate was formed, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified on silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound (360 mg, 72%). 1HNMR (400 MHz, DMSO-d6): δ 7.44 (d, 1H), 7.35 (d, 1H), 7.20-7.18 (m, 1H), 4.15 (q, 4H), 3.48 (s, 2H), 3.43 (s, 2H), 1.16 (t, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[CH3:15]S(C)=O>>[CH3:15][N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13]
Reactant: CS(C)=O
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Product: CN1C(=O)COc2ccc([N+](=O)[O-])cc21

Procedure:
The title compound was prepared from 6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine using the method described in Example 19. Yield: 3.01 g (56%) of product as a yellow solid. mp 185-187; 'H NMR (300 MHz, DMSO) and 7.968 (dd, J=8.9 Hz, 2H), 7.78 (d, J=2.5H 1H), 7.363 (d, J=8.9 2H), 4.799 (s, 2H), 3.32 (s, 3H); 13C NMR (75 MHz, DMSO) and 164.430, 144.77, 135.913, 118.824, 115.808, 111.5142, 66.944, 20.82; Mass Spectrum M+ m/z 208.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(=O)([O-])[O-].[NH4+:16].[NH4+]>S(Cl)(Cl)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:16])=[O:11]
Reactant: O=C(O)Cc1ccccc1I
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: O=S(Cl)Cl
Product: NC(=O)Cc1ccccc1I
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 2-iodophenylacetic acid (20.5 g, 78.2 mmol) in thionyl chloride (70 mL) was stirred at 75° C. for 3 hours. The thionyl chloride was removed in vacuo and the resulting residue was dissolved in DCM (100 mL). Ammonium carbonate (15.03 g, 156.5 mmol) was added and the resulting mixture was stirred at 60° C. for 20 hours. The volatiles were evaporated in vacuo, water (100 mL) was added and the resulting suspension was sonicated for 1 minute, before filtering and washing the filter cake with water then Et2O. After air drying, the title compound I6 was obtained as a light cream coloured solid (12.9 g, 63%); 1H NMR (300 MHz, d6-DMSO) δ 7.82 (d, J=8.3 Hz, 1H), 7.41 (brs s, 1H), 7.30-7.37 (m, 2H), 6.95-7.01 (m, 2H), 3.55 (s, 2H). LCMS-B: rt 5.108 min; m/z 262 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:18][CH:19]1[O:23][CH2:22][CH2:21][O:20]1.Cl>C(OCC)(=O)C.CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:18][CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[C:6](=[O:14])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrCC1OCCO1
Reactant: CC(=O)N1CC(=O)Nc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CC(=O)N(CC2OCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 15 mL of an N,N-dimethylformamide solution containing 957 mg of 4-acetyl-3,4-dihydro-2-oxo-1H-quinoxaline, 668 mg of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 2.6 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90° C. for 6 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; chloroform] to obtain 1.30 g of a brown oily substance, 4-acetyl-1-(1,3-dioxolan-2-ylmethyl)-2-oxo-3,4-dihydro-1H-quinoxaline.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([F:34])[C:27]=2[F:35])=[CH:18][C:16]=1[NH2:17].C(N(CC)C(C)C)(C)C.O>C(#N)C>[Cl:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([F:34])[C:27]=2[F:35])=[CH:18][C:16]=1[NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1c(C)ncnc1Cl
Reactant: COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1c(C)ncnc1Nc1cc(OCc2c(OC)ccc(F)c2F)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96.7 %

Procedure:
A solution of ethyl 4-chloro-6-methylpyrimidine-5-carboxylate (0.3 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.49 g) and N,N-diisopropylethylamine (0.26 mL) in acetonitrile (4.5 mL) was stirred at 130° C. in a reaction vessel equipped with a reflux condenser for 1 day. To the reaction mixture was added water (3 mL), and the resulting mixture was stirred at room temperature for 40 minutes. The insoluble material was collected by filtration. The collected material was washed with water and diethyl ether, and dried under reduced pressure to give ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.71 g). The obtained ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.2 g) was dissolved in tetrahydrofuran (1.6 mL)−methanol (1.2 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (1.2 mL), and the mixture was stirred at 60° C. for 30 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid (3 mL), and the precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylic acid (0.1 g). To this material were added 1,4-dioxane (4.5 mL), triethylamine (0.12 mL) and diphenylphosphoryl azide (0.071 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give the title compound (0.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH:7]([OH:14])[C:6]=2[CH:15]=1.ClC1C=CC2OC(C(O)=O)CC(=O)C=2C=1.[BH4-].[Na+].[CH2:33]([NH2:36])[CH:34]=[CH2:35]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:36][CH2:33][CH:34]=[CH2:35])=[O:13])[CH:8]=[C:7]([OH:14])[C:6]=2[CH:15]=1
Reactant: C=CCN
Reactant: O=C(O)C1CC(O)c2cc(Cl)ccc2O1
Agent: O=C1CC(C(=O)O)Oc2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCNC(=O)C1C=C(O)c2cc(Cl)ccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 512 mg of the ethyl ester of 6-chloro-3,4-dihydro-4-hydroxy-2H-1-benzopyran-2-carboxylic acid, (prepared by treating the ethyl ester of 6-chloro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid (Witiak et al., supra) with sodium borohydride), 570 mg of 2-propenamine and 20 ml of ethanol was stirred at room temperature for 72 hours, then stirred for 3 hours while heated by a steam bath. The solvent was stripped off and the residue was crystallized from methylene chloride/hexane to give 7, as white crystals, mp: 129°-130.5° C.