Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:79][CH2:80][C:81]#[N:82]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:82][CH2:81][C:80]#[N:79])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: N#CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added aminoacetonitrile monosulfate (14 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of aminoacetonitrile monosulfate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(cyanomethyl)acetamide. (12 mg, 0.027 mmol, 19%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+]([O-])([O-])=[O:11].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CO>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(C)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A 1.22 g quantity of p-methyl anisole and 23.0 g of ammonium cerium(IV) nitrate are placed into a reactor, and 100 ml of methanol is further placed into the reactor. The mixture is stirred at room temperature for about 30 minutes. After the completion of the reaction, the methanol is distilled off from the reaction mixture. The residue is subjected to extraction with benzene three times. The extract is washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and distilled to remove the benzene. The residue is distilled in a vacuum, giving 1.32 g of anisaldehyde. Yield 96.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=[O:15].[H-].[Na+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH:8]=[CH:7][C:6]2=[O:15]
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc(=O)c3cc(OC)c(OC)cc32)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6,7-Dimethoxy-4(1H)-quinolone (0.5 g) was dissolved in dimethylformamide (10 ml). 60% Sodium hydride (130 mg) and 4-methoxybenzyl bromide (0.42 ml) were added to the solution, and the mixture was stirred at room temperature for 15 hours. Water was added to the mixture, and extraction was conducted with ethyl acetate. The extract was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 30 g). Elution with a mixed solvent of chloroform (90 parts) and methanol (10 parts) gave 6,7-dimethoxy-1-(4-methoxybenzyl)-4(1H)-quinolone (compound 17, 0.39 g).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].C[C:6]([CH3:8])=O.[OH:9][S:10](O)(=O)=[O:11].O=[Cr](=O)=O>C(O)(C)C>[S:10]1(=[O:11])(=[O:9])[CH2:6][CH2:8][CH2:4][C:2](=[O:3])[CH2:1]1
Reactant: O=S(=O)(O)O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Solvent: CC(C)O
Product: O=C1CCCS(=O)(=O)C1

Procedure:
To a solution of tetrahydrothiopyran-3-o1-1,1-dioxide (7.5 g, 0.05 moles) and acetone (150 mL) was slowly added enough Jones reagent to maintain a brown color for at least 10 minutes without need for additional reagent. The excess reagent was reduced by addition of isopropanol (5 mL). The mixture was filtered through anhydrous magnesium sulfate and the chromium salts were washed 3× with acetone. The solvent was removed in vacuo to give a solid which was triturated with ethanol. The resulting crystals were isolated by filtration and rinsed 3× with diethyl ether. After drying, 5.0 g of product was obtained. H' NMR CDCl3 4.0 (singlet, 2H) 3.3 (triplet, 2H) 2.6 (triplet, 2H) 2.3 (multiplet, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:22](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1.[H][H]>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:22]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccn1
Yield: 89.1 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)-3-pyrrolyl]propenoate (1.80 g), 5% palladium-carbon (2.32 g) and tetrahydrofuran (30 ml) was stirred overnight in a hydrogen atmosphere at room temperature. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)-3-pyrrolyl]propionate (1.61 g, yield: 89%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccc(Cl)cc1Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccc(Cl)cc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(2,4-dichlorobenzyl)-4-phenyl-5-oxohexanoic acid (5.48 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.03 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. Then the reaction solution is cooled to room temperature, diluted with water (200 ml.) and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is then acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which precipitates is filtered and air-dried, yield 5.5 g., m.p. 215°-226°C. Recrystallizations from ethanol gives material with m.p. 224.5°-227°C.
Reaction SMILES: [CH:1]([C:3]1(O)[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH2:6][CH2:5][CH2:4]1)=[CH2:2].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)(=O)C>[C:14]([S:15][CH2:2][CH:1]=[C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH2:6][CH2:5][CH2:4]1)(=[NH:13])[NH2:16]
Reactant: NC(N)=S
Reactant: C=CC1(O)CCCc2sccc21
Solvent: CC(=O)O
Product: N=C(N)SCC=C1CCCc2sccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Vinyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol (10.1 g, 56 mmol) was dissolved in acetic acid (70 mL) and thiourea (4.3 g, 56 mmol) was added in one portion. The reaction was stirred at 25° C. for 2 hours and then the majority of the acetic acid was removed in vacuo. The residue was diluted with diethyl ether to afford a white solid. This was filtered off and washed with additional ether before being dried in vacuo. The title compound was isolated as the acetate salt (13.8 g, 83%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=O)([CH3:3])[CH3:2].[N:15]1([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=2)[CH:19]=[N:18][CH:17]=[N:16]1>CO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:8]2[NH:27][C:22]3[CH:21]=[C:20]([N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)[CH:25]=[CH:24][C:23]=3[N:26]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])([CH3:3])[CH3:2]
Reactant: Nc1ccc(-n2cncn2)cc1N
Reactant: COc1ccc(C=O)cc1OC(C)C
Solvent: CO
Product: COc1ccc(-c2nc3ccc(-n4cncn4)cc3[nH]2)cc1OC(C)C
Yield: 70.5 %

Procedure:
Under reflux, 20 ml of methanol solution containing 4.27 g of 3-isopropoxy-4 -methoxybenzaldehyde and 10.81 g of ferric chloride hexahydrate was added dropwise to 35 ml of methanol solution containing 3.50 g of 4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained in Reference Example 2. The resulting mixture was refluxed for 1 hour and then cooled, and the insoluble matter was collected by filtration. This was suspended in ethyl acetate/water and alkalified with liquid ammonia, and then the insoluble matter was removed by Celite filtration. The ethyl acetate layer was collected and dried over magnesium sulfate, and then the solvent was evaporated. By crystallizing the resulting residue with ethyl acetate/hexane, 4.92 g (70%) of the title compound was obtained. Its physical property values coincided with the data obtained in the above step (1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:31])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[N:13]([C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.B(O)O.C(=O)(O)[O-].[Na+]>CC1CCCO1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:31])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:24]4[CH:23]=[CH:22][C:27]([Cl:28])=[CH:26][CH:25]=4)[CH:18]=3)[N:13]([C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(Br)cc23)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: OBO
Solvent: CC1CCCO1
Product: Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Under a nitrogen atmosphere, a 50-liter flask is charged with compound 5 (1.735 kg, 3.304 mol) prepared from Example 3 in 2-methyl-THF, boronic acid 6 (0.877 kg, 5.617 mol), PdCl2(PPh3)2 (0.116 kg, 0.165 mol) and an aqueous sodium bicarbonate (0.833 kg, 9.912 mol) solution (8.7 L). The reaction mixture is degassed and heated to reflux for 7 hrs and stirred at room temperature overnight. Compound 6 (129.0 g) and PdCl2(PPh3)2 (6.6 g) are added again and the reaction mixture is heated to reflux for another 5 hrs. Celite (1.735 kg) is added and the mixture is stirred for 30 minutes and then filtered through a pad of celite. The residue is washed with 2-methyl-THF. The organic layer is separated, washed with a 10% NaCl aqueous solution (4 L) for three times, further washed with a 20% NaCl aqueous solution, filtered, and dried over Na2SO4. The filtrate is concentrated by removing about 80-85% of solvent, added ethyl acetate (3.5 L) and stirred overnight. The mixture is filtered and washed with ethyl acetate (2×3.5 L) twice. Compound 7, is isolated after removing the solvents and drying at 45° C. for 48 hrs (2.765 kg, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15]C.ClC1C=C(Cl)C=CC=1C1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:30])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH3:15]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C)c(-c2ccc(Cl)cc2Cl)nc1C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ); 7.50–7.48, 7.32–7.28, 5.81, 5.48, 4.38, 3.70, 3.52, 3.14, 2.41, 2.26, 1.20; HRMS (FAB) calcd for C23H23Cl2N3O+H 428.1296, found 428.1288.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl[CH2:46][C:47]1[O:48][C:49]([CH3:52])=[N:50][N:51]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:46][C:47]3[O:48][C:49]([CH3:52])=[N:50][N:51]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nnc(CCl)o1
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC(F)(F)C(F)(F)C4)c3n2)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as white solid. MS (m/e): 415.3 (MH+).
Reaction SMILES: [I-].[CH2:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:21][CH2:22][C:23]([CH3:27])([CH3:26])[N+:24]=1C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:28](C1C=CC=CC=1C=O)[CH2:29]CCCCCCCCCC.C1(CCCCCCCC[Mg]Br)C=CC=CC=1.COC1C=CC=CC=1C1OCC(C)(C)N=1>O1CCCC1>[C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[O:21][CH2:22][C:23]([CH3:26])([CH3:27])[N:24]=2)[CH:11]=[CH:12][CH:13]=[CH:29][CH:28]=1
Reactant: CCCCCCCCCCCCc1ccccc1C1=[N+](C)C(C)(C)CO1
Reactant: CCCCCCCCCCCCc1ccccc1C=O
Agent: Br[Mg]CCCCCCCCc1ccccc1
Agent: COc1ccccc1C1=NC(C)(C)CO1
Agent: [I-]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCc2ccccc2)=N1
Reaction time: 24 h

Procedure:
Following the procedures of Example 1(a), (b) and (c), to 8-phenyloctylmagnesium bromide (from 24.25 mmoles of 8-phenyloctyl bromide and 21.27 mmoles of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmoles) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmoles) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmoles) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmoles). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: O=Cc1ccccn1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1ccccn1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 2-pyridinecarboxaldehyde (0.5 g, 4.7 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.071 g, 58%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[CH3:1][C:2]1[C:7]2[C:8](=[O:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])ccc2[nH]c(=O)oc(=O)c12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-methyl-4H-3,1-benzoxazin-2,4-dione (20 g, 113 mmol) in 150 mL of concentrated H2SO4, cooled to -15° C., was added 7.83 g of 90% w/w HNO3 (in 30 mL of conc. H2SO4) dropwise at such a rate to keep the internal temperature below 5° C. After the addition was complete, the reaction was stirred at 0° C. for an additional 20 minutes then quenched by pouring the reaction mixture over crushed ice. Following further dilution with water, the resulting precipitate was filtered, washed with water, resuspended in water then filtered and washed again with water affording 15.1 g (60%) of 5-methyl-6-nitro-4H-3,1-benzoxazin-2,4-dione, after drying: Anal. Calc'd. for C9H6N2O5 : C, 48.66; H, 2.72; N, 12.61. Found: C, 48.19; H, 2.54; N, 12.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:26]O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[O:14][C:15]=1[CH3:16].S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:30][CH2:26][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Solvent: Cc1ccccc1
Product: COc1cc(CCl)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Yield: 100 %

Procedure:
To a mixture of (3-methoxy-4-{[5-methyl-2-(3-nitrophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)methanol (5.92 g) and toluene (250 ml) was added thionyl chloride (2.19 mL), and the mixture was heated under reflux for 1.5 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-2-(3-nitrophenyl)-1,3-oxazole (6.31 g, yield 100%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 166-168° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N+:15]([O-])=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(-n2cnc3c[n+]([O-])ccc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-n2cnc3c(Cl)nccc32)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
In 5 mL of phosphorus oxychloride, 42 mg (0.164 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine 5-oxide was dissolved and the solution was stirred at 80° C. for 14 hours. Excess reagent was distilled under reduced pressure, and the residue was partitioned between ethyl acetate (10 mL×2) and a sodium hydrogencarbonate aqueous solution (10 mL). The combined organic layers were washed with a saturated sodium chloride solution, dried on anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was separated by a silica gel column (Si-10, a product of Kusano Co., Ltd., column 30 cm, dichloromethane:methanol=19:1) to obtain 45 mg (quantitative) of 4-chloro-1-(4-nitrophenyl)-1H-imidazo-[4,5-c]pyridine as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][CH2:11][OH:12].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([S:22](Cl)(=[O:24])=[O:23])=[C:17]([CH3:26])[CH:16]=1>>[OH:12][CH2:11][CH2:10][N:9]([CH3:8])[S:22]([C:18]1[C:19]([CH3:21])=[CH:20][C:15]([O:14][CH3:13])=[CH:16][C:17]=1[CH3:26])(=[O:24])=[O:23]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CNCCO
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N(C)CCO)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (213 ml, 1,512.5 mmol) was added to a solution of 2-(methylamino)ethanol (53.5 ml, 665.5 mmol) in MC (1,250 ml) and the mixture was cooled to 0° C. A solution of 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (142 g, 605 mmol) [see AC5, Stage 1] in MC (750 ml) was then slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was then washed with aqueous 0.5 M HCl (800 ml) and water (2×1,000 ml). The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. Purification was carried out by chromatography on silica gel (heptane/ethyl acetate 1:1). The yield was 116.3 g (70%).
Reaction SMILES: [N+:1]([CH:4]([C:27]([O:29][CH3:30])=[O:28])[CH:5]([C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=1[O:25][CH3:26])[CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:7](OC)=[O:8])([O-])=O.[OH-].[Na+]>C(OCC)(=O)C>[O:8]=[C:7]1[NH:1][CH:4]([C:27]([O:29][CH3:30])=[O:28])[CH:5]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[O:25][CH3:26])[CH:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C(=O)OC)C(c1c(OC)cc(OC)cc1OC)C(C(=O)OC)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)C1NC(=O)C(C(=O)OC)C1c1c(OC)cc(OC)cc1OC
Temperature: 55 °C

Procedure:
(+)-Trimethyl 3-nitro-2-(2,4,6-trimethoxyphenyl)propane-1,1,3-tricarboxylate (7.8 g, 0.018 mol) was dissolved in ethyl acetate (100 mL). To this solution, stannous chloride dihydrate (25 g, 0.118 mol) was added in portions over a period of 10 mins under stirring. The reaction mixture was heated to 55° C. for 2 hours. The mixture was cooled to 10° C., basified with 10% sodium hydroxide solution to pH 9, filtered through a celite pad and the pad washed with ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the title compound as a white solid.