Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.O.OO>O>[NH2:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:4]([NH2:3])=[O:1])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: NCc1ccc(C(N)=O)cc1
Temperature: 25 °C
Yield: 809 %

Procedure:
In a reactor equipped with a motor-driven stirrer, 45 g of water, 1.38 g of sodium hydroxide (reagent, purity: 96%) and 43.56 g of p-aminomethylbenzonitrile were charged in this sequence and then stirred at room temperature. 74.8 g of 30 wt % hydrogen peroxide water was gradually added so that the reaction temperature reaches 30° C. or lower, followed by mixing with stirring. After foaming and temperature rise were terminated, the reaction solution was cooled to 5° C. The deposited crystal was collected by filtration and then dried to obtain 41.92 g of p-aminomethylbenzamide (yield based on p-aminomethylbenzonitrile: 81%). The purity of p-aminomethylbenzamide determined by analyzing using high-performance liquid chromatograph was 97%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH:14]([C:25]([O:27][CH3:28])=[O:26])[CH2:13]1.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:15][CH:14]([C:25]([O:27][CH3:28])=[O:26])[CH2:13]1
Reactant: COC(=O)C1CC(O)CN(C(=O)OC(C)(C)C)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
To a solution of dimethylsulfoxide (2.2 mL, 41.46 mmol) in dry dichloromethane (50 mL) at −78° C. was added dropwise at oxalyl chloride (1.57 mL, 18.2 mmol). After 10 min, a solution of 1-tert-butyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate (4.3 g, 16.59 mmol) in dichloromethane was added dropwise. After 15 min, triethylamine (6.92 mL, 49.7 mmol) was added dropwise and the reaction mixture was then allowed to warm to room temperature. After 3 h, the mixture was diluted with dichloromethane and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate (4.2 g) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][C@@:11]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([C:22]3[C:26]4[S:27][CH:28]=[CH:29][C:25]=4[O:24][N:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:13][O:12]1.ClC(Cl)C>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:10][C@:11]([CH3:13])([OH:12])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[C:26]4[S:27][CH:28]=[CH:29][C:25]=4[O:24][N:23]=3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: C[C@@]1(COc2cccc(-c3noc4ccsc34)c2)CO1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: C[C@](O)(CNCc1ccc(F)cc1)COc1cccc(-c2noc3ccsc23)c1

Procedure:
Add a solution of 4-fluorobenzylamine (Aldrich Chemical Company) in ethanol (3 mL, 0.2774 M, 1.77 equivalents) to a reaction tube. Add ethanol (3 mL) to the reaction tube and then add a solution of (S)-3-[3-(2-methyloxiranylmethoxy)phenyl]thieno[2,3-d]isoxazole (example 7, 1.38 mL, 0.337 M) and dichloroethane. Shake the reaction mixture under argon at reflux temperature overnight in a Bohdan apparatus. Cool and concentrate to remove the solvent. Purify the residue by flash chromatography (silica gel) eluting in step gradient fashion sequentially with 1%, 3%, 6%, and 10% methanol in dichloromethane. Combine and concentrate the desired fractions to give the title compound (0.18 g), LC/MS (APCI, condition 6) m/e 413 (MH+), retention time 2.23 min. Preparation of a larger sample and conversion to the hydrochloride salt is described as example 102.
Reaction SMILES: [CH2:1]([N:8]=[C:9]([CH:11]1[CH:16]([C:17](O)=O)[CH2:15][CH:14]([CH3:20])[CH2:13][NH:12]1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH:11]2[CH:16]([CH2:15][CH:14]([CH3:20])[CH2:13][NH:12]2)[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CNC(C(O)=NCc2ccccc2)C(C(=O)O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1CNC2CN(Cc3ccccc3)CC2C1
Reaction time: 17 h

Procedure:
13.0 g of crude 5-methyl-hexahydropyridine-2,3-dicarboxylic acid N-benzylimide are added in the form of a solution in 50 ml of absolute tetrahydrofuran to 4.6 g (0.12 mol) of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran, already present in the vessel. Then the mixture is boiled for 17 hours under reflux. 4.6 g of water in 14 ml of tetrahydrofuran, 4.6 g of 10 % strength sodium hydroxide solution and 13.8 g of water are added dropwise one after the other. The salts are filtered off, the filtrate is concentrated by evaporation and the residue is distilled.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:27][CH:26]=3)[N:18]=2)=[CH:13][C:12]=1[F:44])([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].[NH:45]1[CH:49]=[CH:48][N:47]=[CH:46]1>>[CH2:1]([O:4][C:5]([NH:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)=[CH:29][CH:30]=3)[N:18]=2)=[CH:13][C:12]=1[F:44])([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(CCOS(=O)(=O)c4ccc(C)cc4)cc3)ncc2Cl)cc1F
Reactant: c1c[nH]cn1
Product: C=CCOC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(CCn4ccnc4)cc3)ncc2Cl)cc1F
Yield: 78.1 %

Procedure:
The title compound was prepared from 4-[4-(1-allyloxycarbonylamino-1-methylethyl)-3-fluorophenyl]-5-chloro-N-[4-(2-p-toluenesulphonyloxyethyl)-phenyl]pyrimidine-2-amine (504 mg, 0.79 mmol) and imidazole (337 mg, 4.95 mmol) following the method described for Example 5. The crude product was purified by column chromatography (silica; 5% methanol in CH2Cl2) to give the title compound as a yellow solid (330 mg) m.p. 88° forms gum. δH (CDCl3) 8.43 (1H, s), 7.69 (1H, dd, J 8.2, 1.8 Hz), 7.61 (1H, dd, J 13.3, 1.8 Hz), 7.54 (2H, d, with fine splitting, J 8.6 Hz), 7.50 (1H, t, J 8.5 Hz), 7.34 (1H, s), 7.18 (1H, s), 7.04 (3H, m), 5.89 (1H, bs), 5.30-5.12 (3H, m), 4.50 (2H, dt, J 5.6, 1.4 Hz), 4.16 (2H, t, J 7.1 Hz), 3.03 (2H, t, J 7.0 Hz), 1.78 (6H, s); MS (ESI) 535 (MH+, 100%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[C:6](C2C=CC=CC=2)[CH:5]=1)=O.[NH2:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([N+:29]([O-:31])=[O:30])=[CH:22][C:21]=1[NH2:32]>C1C(Cl)=CC=C(Cl)C=1>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:2]2[NH:19][C:20]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([N+:29]([O-:31])=[O:30])=[CH:22][C:21]=3[N:32]=2)=[CH:12][CH:11]=1)([O:10][C:4]1[CH:12]=[CH:11][CH:7]=[CH:6][CH:5]=1)=[O:9]
Reactant: O=C(Cl)c1ccc(C(=O)[O-])c(-c2ccccc2)c1
Reactant: Nc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1N
Solvent: Clc1ccc(Cl)cc1
Product: O=C(Oc1ccccc1)c1ccc(-c2nc3cc([N+](=O)[O-])c([N+](=O)[O-])cc3[nH]2)cc1
Yield: 58 %

Procedure:
To a solution containing 10 g (38.4 mmole) of p-chlorocarbonylphenylbenzoate dissolved in 100 ml of dichlorobenzene was added 2.53 g (12.8 mmole) of 1,2-diamino-4,5-dinitrobenzene. After heating the resulting mixture under nitrogen to reflux (frothing), it was maintained at that temperature for 2 hours. The solution was then allowed to cool in ice for one hour, and the precipitate that formed was filtered by suction, washed with benzene, and air-dried. The crude product was chromatographed on a 2× 18 inch dry column of silica gel. Elution with methylene chloride removed traces of impurities, while further elution of the column with 20/1 methylene chloride-THF slowly removed a broad band of the desired product, leaving a third band of side-product on the column. After all of the second band had been removed from the column, the solvent was removed in vacuo leaving a pale yellow residue. Recrystallization from THF-n-propanol yielded 3.0 g (58%) of 2-[p-carbophenoxyphenyl]-5,6-dinitrobenzimidazole as pale yellow needles, m.p. 239°-240°.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[S:9][C:10]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[ClH:1].[C:2]1([C:8]2[S:9][C:10]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1nc(-c2ccccc2)sc1CN1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccccc2)sc1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
Concentrated HCl (2.8 ml, 33.9 mmol) was added to a solution of tert-butyl 2-phenyl-5-(pyrrolidin-1-ylmethyl)thiazole-4-carboxylate (2.1 g, 6.1 mmol) in THF (30 ml). The mixture was stirred at rt overnight, and concentrated in vacuo to give 2-phenyl-5-(pyrrolidin-1-ylmethyl)thiazole-4-carboxylate hydrochloride (1.5 g, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([Br:13])[C:3]=1N.OS(O)(=O)=O.N([O-])=O.[Na+].CCOC(C)=O>CCO.O>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([CH3:11])([CH3:10])[CH3:12])[CH:6]=[C:5]([Br:13])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)c(N)c(Br)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Br)cc(Br)c1
Reaction time: 37 h

Procedure:
To a stirring solution of 2,6-dibromo-4-tert-butylaniline in 115 mL of EtOH was added 11.5 mL of concentrated H2SO4. To the stirring solution at 90° C. was added 8.8 g of NaNO2 in several portions. After 37 h, EtOAc and 120 mL of H2O were added, and the layers separated. The organic layer was washed with 40 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (hexanes) provided 8.15 g of 1,3-dibromo-5-tert-butylbenzene as a yellow-brown oil with some impurity.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(C)c(C)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 67.5 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate (35 mg, 0.13 mmol) and 1-(3-methoxy phenyl)piperazine (50 mg, 0.26 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (40 mg, 0.26 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 37 mg of the titled compound (yield, 68%). 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.39 (s, 3H), 3.22-3.30 (m, 4H), 3.75 (m, 4H), 3.80 (s, 3H), 4.13 (s, 3H), 6.46-6.49 (m, 2H), 6.55-6.58 (m, 1H), 7.20-7.23 (m, 1H), 7.52 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: [Mg].BrC(Br)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][C:15]1([CH3:28])[CH2:19][O:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2OC)=[N:16]1.[Cl-].[NH4+]>O1CCCC1>[CH3:14][C:15]1([CH3:28])[CH2:19][O:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:16]1
Reactant: Cc1ccc(Br)cc1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Yield: 85.1 %

Procedure:
Tetrahydrofuran (200 ml) was added to 2.5 g (103 mmol) of flaky magnesium, followed by the addition of a small amount of dibromoethane under stirring. After the confirmation of bubbling, 13 ml (106 mmol) of 4-bromotoluene was dropwise added thereto. After the confirmation of the dissolution of the magnesium, the mixture was further stirred at room temperature for one hour. This reaction liquid was dropwise added to a solution of 10.0 g (48.7 mmol) of 4,4-dimethyl-2-(2'-methoxyphenyl)oxazoline in tetrahydrofuran (100 ml), followed by stirring for 12 hours. The reaction liquid was poured into a saturated aqueous solution of ammonium chloride, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 11.0 g of the title compound as a crystal (yield 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([O:9]CCCCC)=[O:8])=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCOC(=O)c1ccc(OC)c(OCCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCOc1cc(C(=O)O)ccc1OC
Temperature: 25 °C
Yield: 80.2 %

Procedure:
Pentyl 4-methoxy-3-pentyloxybenzoate (17.4 g, 0.056 mol) was dissolved in methanol (85 ml). A 1N aqueous sodium hydroxide solution (85 ml, 0.085 mol, 1.5 eq) was added, and the mixture was refluxed under heating for 1.5 hours. This reaction mixture was cooled to room temperature, and washed with n-hexane (100 ml). A 10% aqueous hydrochloric acid solution (ca. 120 ml) was added to the aqueous layer under ice-cooling to make the same acidic. This was extracted twice with ethyl acetate (220 ml). The organic layers were combined, washed with saturated brine (400 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by recryst azation from ethyl acetate to give 4-methoxy-3-pentyloxybenzoic acid (10.7 g, 79.6%) as colorless crystals.
Reaction SMILES: C1C=CC=CC=1.[NH2:7][C:8]1[C:16]([O:17][CH3:18])=[C:15]([Br:19])[C:14]([I:20])=[C:13]([CH3:21])[C:9]=1[C:10]([OH:12])=[O:11].[C:22](Cl)(=O)[C:23]([CH3:26])([CH3:25])[CH3:24].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:19][C:15]1[C:14]([I:20])=[C:13]([CH3:21])[C:9]2[C:10](=[O:12])[O:11][C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:7][C:8]=2[C:16]=1[O:17][CH3:18]
Reactant: COc1c(N)c(C(=O)O)c(C)c(I)c1Br
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1c(Br)c(I)c(C)c2c(=O)oc(C(C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A benzene (1.0 ml) suspension of 2-amino-4-bromo-5-iodo-3-methoxy-6-methylbenzoic acid (I-4) (77 mg, 199 μmol) was cooled at 0° C., pivaloyl chloride (61.4 μl, 499 μmol), pyridine (40.3 μl, 499 μmol) were put thereinto, followed by stirring at room temperature for 1 hour. Ethyl acetate (30 ml) was added to the reaction liquid, the organic layer was washed with 1 N hydrochloric acid (30 ml×2), saturated brine (30 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure. To the residue, added were toluene (2.0 ml), 4-dimethylaminopyridine (25.6 mg, 209 μmol), followed by stirring at room temperature for 15 minutes and then stirring at 50° C. for 1.15 hours, further followed by refluxing for 30 minutes. After cooling, ethyl acetate (30 ml) was added, the organic layer was washed with 1 N hydrochloric acid (30 ml×2), saturated brine (30 ml×2), then dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 7-bromo-2-tert-butyl-6-iodo-8-methoxy-5-methylbenzo[d][1,3]oxazin-4-one (87.5 mg, 97%) as a yellow ocher solid. A tetrahydrofuran (1.0 ml) solution of a part of it (65 mg, 144 μmol) was cooled at 0° C., followed by adding aqueous 28% ammonia (97.1 μl, 1.44 mmol) and stirring overnight with gradually heating up to room temperature. On the next day, this was further cooled at 0° C., followed by adding aqueous 28% ammonia (97.1 μl, 1.44 mmol) and stirring for 2 hours with gradually heating up to room temperature. Aqueous saturated ammonium chloride solution (30 ml) was added to the reaction liquid, the product was extracted with ethyl acetate (30 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=4:1→chloroform:methanol=20:1) to obtain the entitled compound (35.8 mg, 53%) as a colorless solid.
Reaction SMILES: N1C2C(=NC3C=CC=CC=3N=2)C(=O)NC=1[C:16]([OH:18])=[O:17].[CH2:19]([O:21][C:22]([C:24]1[NH:41][C:40](=[O:42])[C:27]2=[N:28][C:29]3[C:30](C)=[C:31](C)[C:32](C)=[C:33](C)[C:34]=3[N:35]=[C:26]2[N:25]=1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[NH:41][C:40](=[O:42])[C:27]2=[N:28][C:29]3[CH:30]=[C:31]4[O:18][CH2:16][O:17][C:32]4=[CH:33][C:34]=3[N:35]=[C:26]2[N:25]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1nc2nc3c(C)c(C)c(C)c(C)c3nc2c(=O)[nH]1
Reactant: O=C(O)c1nc2nc3ccccc3nc2c(=O)[nH]1
Product: CCOC(=O)c1nc2nc3cc4c(cc3nc2c(=O)[nH]1)OCO4

Procedure:
pyrimido[5,6-b]quinoxaline-4(3H)-one-2-carboxylic acid, and ethyl-6,7,8,9-tetramethyl-pyrimido[5,6-b]quinoxaline-4(3H)-one-2-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:3]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30](O)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OC(C)(C)C)=O)=[N-])=O)(C)(C)C.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:30]([C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]=3)[CH3:31])=[CH:15][CH:14]=2)=[N:3]1
Reactant: CC(O)c1ccc2ccccc2n1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Agent: CC(C)(C)OC(=O)[N+](=[N-])C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Oc1ccc(-c2nn(C)cc2-c2ccncc2)cc1)c1ccc2ccccc2n1
Temperature: 60 °C

Procedure:
A mixture of 4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenol (75 mg, 0.30 mmol) and 1-(quinolin-2-yl)ethanol (78 mg, 0.45 mmol) in p-dioxane (2 mL) was treated sequentially at RT with triphenylphosphine (126 mg, 0.48 mmol) and di-t-butyldiazodicarboxylate (110 mg, 0.48 mmol) and the mixture was heated at 60° C. for 4 h. Aqueous 2N NaOH was added and the mixture extracted with dichloromethane. The organic layers were dried, concentrated, and the residue purified on silica gel eluted with a gradient of ethyl acetate-hexanes giving a yellow solid. Yield 36 mg, 29%. 1H NMR (CDCl3, 400 mHz) δ 8.40 (m, 2H), 8.10 (d, 1H, J=8.7 Hz), 8.06 (d, 1H, J=7.5 Hz), 7.77 (d, 1H, J=8.3 Hz), 7.71 (ddd, 1H), 7.55 (d, 1H, J=8.3 Hz), 7.53-7.49 (m, 2H), 7.25 (m, 2H), 7.10 (m, 2H), 6.88 (m, 2H), 5.59 (q, 1H, J=6.6 Hz), 3.91 (s, 3H), 1.75 (d, 3H, J=6.6 Hz). HPLC-MS (system 1) 4.73 min, m/e 407 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([N:13]=[N+]=[N-])=[CH:5][C:6]1[S:7][C:8]([CH3:12])=[C:9]([Br:11])[CH:10]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[NH:13][C:10]2[C:9]([Br:11])=[C:8]([CH3:12])[S:7][C:6]=2[CH:5]=1)=[O:16]
Reactant: COC(=O)C(=Cc1cc(Br)c(C)s1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2sc(C)c(Br)c2[nH]1
Yield: 76.5 %

Procedure:
To a refluxing xylene (100 ml) was added the crude product of Step 2 (18 g) in 250 ml of xylene over a period of 20 min. After refluxing for 10 min, the reaction mixture was cooled and concentrated to volume of about 100 ml. The solid was collected by filtration to give 12.5 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16]O)[C:9]=2[F:18])[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:45])C(=O)C1>ClCCl>[Br:45][CH2:16][C:10]1[C:9]([F:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(CO)c(F)c1-c1cccc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CBr)c(F)c1-c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Into a 250 mL round bottom flask was added (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol synthesized above (1.21 g, 4.54 mmol), dichloromethane (20 mL), PPh3 (1.19 g, 4.54 mmol), and the solution was cooled to 0° C. NBS (0.81 g, 4.54 mmol) was added and the reaction stirred for 2 hours at 0° C. The organics were washed with H2O and concentrated. The residue was purified by flash column chromatography eluting with 8% ethyl acetate/hexanes to give 3-bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (I-33, 956 mg, 64%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:29]=[C:30]=O)(=O)=O.CN(C=O)C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH2:10][C:9]1([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([CH3:24])[CH3:23])[C:30]#[N:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)C(=O)N2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C=CCC1(C#N)c1ccc2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a solution 2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylic acid tert-butyl ester (0.39 g, 1.2 mmol) in THF (anhydrous, 9 mL) at −78° C. was added chlorosulfonyl isocyanate (1.15 eq, 0.12 mL, 1.4 mmol). After 120 min, DMF (20 eq, 1.8 mL, 23 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash column chromatography on silica gel (1:3 ethyl acetate/hexane) gave 2-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (0.21 g, 50%) as a white solid: mp 158.6. 1H NMR (DMSO-d6; 300 MHz) δ 1.27 (s, 6H), 1.33 (s, 9H), 6.40 (d, 1H, J=3.8 Hz), 6.90 (d, 1H, J=8.0 Hz), 7.19 (dd, 1H, J=1.8, 8.0 Hz), 7.30 (d, 1H, J=1.5 Hz), 10.50 (s, 1H). MS m/z 350 (M−H)−. Calcd for C19H22N2O3: C, 68.36; H, 6.02; N, 11.96. Found: C, 66.79; H, 6.03; N, 11.02.