Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:15]([C:16]1[CH:17]=[CH:18][C:19]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:21]=1)[CH2:14][CH2:13][CH3:12]
Reactant: CCCCc1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and n-butylbenzene (0.62 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-n-butylbenzoin was obtained as crystal (362.7 mg, 67.2% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1.CO.[OH-].[Na+]>O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(OCCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(OCCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
4-Hydroxyphenylacetic acid (100 g, 0.6 mol) and cesium carbonate (250 g) were suspended in 300 mL of anhydrous acetonitrile followed by addition of 1,2-dibromoethane (300 mL). The suspension was brought to reflux for 24 hours in a 2 L 3 neck round bottom flask fitted with a mechanical stirrer and reflux condenser then cooled to room temperature. The mixture was diluted to a volume of 2 L by addition of ethyl ether and the suspension was filtered. Concentration of the filtrate in vacuo afforded a colorless oil which was purified by vacuum distillation (0.2 mm Hg, 140-145° C.) to give methyl 4-(2-bromoethoxy)-phenylacetate (93.14 g, 60% yield) as a colorless oil. The methyl 4-(2-bromoethoxy)-phenylacetate was taken into methanol (250 mL) and the resulting solution was cooled to 0° C. Sodium hydroxide (29 g) in a minimum of water was added to the methanol solution in portions and the mixture was stirred at 0° C. for an additional 30 minutes. The solution was warmed to room temperature then concentrated to a white solid. The residue was taken into water and the solution washed once with ethyl ether. The aqueous solution was then acidified to pH 1 by addition of concentrated aqueous hydrochloric acid to give a thick suspension. Filtration and drying afforded 4-(2-bromoethoxy)-phenylacetic acid (86 g, 97% yield) as a colorless solid. The 4-(2-bromoethoxy)-phenylacetic acid (50 g) was taken into thionyl chloride (70 mL) and brought to reflux under an atmosphere of nitrogen for 2 hours. Fractional vacuum distillation (0.2 mm Hg, 139-140° C.) afforded 4-(2-bromoethoxy)phenylacetyl chloride (46.0 g, 86% yield) as a colorless oil that quickly crystallized on cooling. 1H NMR (CDCl3) 6.95, 6.76, 6.60 (m, 11H, Ar—H), 4.68 (m, 1H), 4.24 (m, 2H), 3.80 (m, 1H), 3.41-3.63 (m, 3H), 3.07 (m, 1H), 2.87 (m, 2H), 2.61 (m, 1H); ES-MS (m/z) 458 [M+H]+.
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([SH:11])[N:6]=1.I[CH3:13]>O>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11][CH3:13])[N:6]=1
Reactant: CI
Reactant: Cc1ccnc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nccc(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of NaOH (7.46 g, 186.4 mmol) in water (120 mL), 4-methylpyrimidine-2-thiol hydrochloride (13.78 g, 84.7 mmol) was added and subsequently iodomethane (13.23 g, 93.2 mmol) was added dropwise under argon atmosphere. It was stirred at room temperature for 2 h. It was extracted with CH2Cl2 (×2). The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 10.26 g of the desired compound (yield: 86%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:40]1[N:41]=[C:42]([NH:45][C:46]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[S:43][CH:44]=1)[C:10]([NH:12][CH:13]1[C:38](=[O:39])[N:15]2[C:16]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:17]([CH2:20][Cl:21])[CH2:18][S:19][C@H:14]12)=[O:11].ClC1C=CC=C(C(OO)=[O:73])C=1.O>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:40]1[N:41]=[C:42]([NH:45][C:46]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[S:43][CH:44]=1)[C:10]([NH:12][CH:13]1[C:38](=[O:39])[N:15]2[C:16]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:17]([CH2:20][Cl:21])[CH2:18][S:19](=[O:73])[C@H:14]12)=[O:11]
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 104.3 %

Procedure:
To a solution of benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (6.5 g) in ethyl acetate (40 ml) was added dropwise a solution of m-chloroperbenzoic acid (1.54 g) in ethyl acetate (10 ml) at 0° C. The mixture was stirred for two hours under ice-cooling and then poured into a mixture of ethyl acetate (50 ml) and water (100 ml). The organic layer was washed with brine and then dried. The solvent was evaporated in vacuo and the residue was pulverized with diisopropyl ether to give benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (6.90 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccc(F)cc3)C2=O)cn1
Yield: 33 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-4-fluorobenzene. Yield 33%. MS M+H calculated 384.1. Found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an I IC50 of 0.05 uM.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCCCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)OCCCCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.5 %

Procedure:
A mixture of 1.22 g (10 mmol) of 3-hydroxybenzaldehyde, 2.3 g (11 mmol) of 5-bromopentyl acetate, 3.82 g (27.7 mmol) of anhydrous, granular potassium carbonate, and 25 mL of dimethyl sulfoxide was stirred at room temperature for 20 hr. The resulting brown slurry was diluted with ether and washed with water and saturated brine. Completion of the usual work-up gave 2.59 g (100%) of 3-[[5-(acetyloxy)pentyl]oxy]benzaldehyde as a yellow oil which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.[C:20]([N:27]1C=CN=C1)(N1C=CN=C1)=[O:21].[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[NH:33]N>O1CCCC1>[NH:27]([C:20]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1)=[O:21])[NH:33][C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(COC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
To a suspension of N-(4-{2-[4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (161.5 mg, 0.584 mmol) in anhydrous tetrahydrofuran (2.4 ml) was added 1,1′-carbonyldiimidazole (142.1 mg, 0.876 mmol), and the mixture was stirred at room temperature for 1.5 hr. tert-Butyl carbazate (115.9 mg, 0.877 mmol) was added, and the mixture was stirred for 16 hr. tert-Butyl carbazate (77.3 mg, 0.584 mmol) was added, and the mixture was stirred for 4 hr. tert-Butyl carbazate (77.3 mg, 0.584 mmol) was added again, and the mixture was stirred for 2 hr. tert-Butyl carbazate (115.9 mg, 0.877 mmol) was added again, and the mixture was stirred for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 10 g, ethyl acetate:hexane=5:5→6:4→7:3). The residue was further purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. DM2035 5 g, ethyl acetate:hexane=5:5→1:0) to give 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl tert-butyl hydrazine-1,2-dicarboxylate (207.0 mg, 0.476 mmol, yield 81.6%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=[CH:6][CH:5]=2.[Li:17]CCCC>>[CH3:1][C:2]1[CH-:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=[CH:6][CH:5]=2.[Li+:17]
Reactant: [Li]CCCC
Reactant: CC1=Cc2c(cccc2-c2ccccc2)C1
Product: Cc1cc2c(-c3ccccc3)cccc2[cH-]1
Product: [Li+]
Reaction time: 17 h
Yield: 89 %

Procedure:
To a solution of 2-methyl-4-phenylindene (10.03 g, 49.3 mmol) in 200 mL of hexanes was added dropwise over 10 minutes 32 mL of 1.6M n-BuLi. The resulting yellow suspension was stirred for 17 hours. The suspension was filtered and the solid washed twice with 5 mL of hexane. The light yellow solid was dried in vacuo for 2 hours to leave 9.21 g (89 percent yield) of lithium 2-methyl-4-phenylindenide. A second crop (0.61 g) was obtained by concentrating the filtrate to about 80 mL and filtering after 4 hours at room temperature. Overall yield was 9.82 g, 95 percent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[C:32]([F:33])=[CH:31][C:30](B(O)O)=[C:29]([O:37][CH3:38])[CH:28]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:30]3[CH:31]=[C:32]([F:33])[C:27]([F:26])=[CH:28][C:29]=3[O:37][CH3:38])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: COc1cc(F)c(F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Yield: 95.5 %

Procedure:
Bis(tricyclohexylphosphine)palladium (236 mg, 0.35 mmol) was added to a stirred solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (6.5 g, 17.73 mmol), potassium carbonate (3.67 g, 26.6 mmol) and 4,5-difluoro-2-methoxyphenylboronic acid (5 g, 26.6 mmol) in 156 ml, dioxane were reacted as above and purified by flash chromatography with a gradient of 0-5% ethyl acetate in hexanes to give 6.51 g (95.6%) of 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=[C:11]([C:21]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=3)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(CN)on1
Reactant: Cc1ccc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)cc1C
Product: COc1cc(CNC(=O)c2cc(-c3ccc(C)c(C)c3)c(OCC(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(3,4-dimethylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BO) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 100%, 436.1476 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH2:11])=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH3:11])=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: C=Cc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(N)cn1

Procedure:
10% Palladium-carbon (50% wet, 90 mg) was added to 5-nitro-2-vinylpyridine (450 mg) in ethanol (30 mL), followed by stirring in a hydrogen atmosphere at room temperature for 15 hours. The catalyst was removed from the reaction mixture by filtration. Subsequently, the solvent was evaporated under reduced pressure, to thereby give the title compound as an oily substance (359 mg, 98%).
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=3)[N:10]=[C:9](C(O)=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[N:27](CC)CC.[CH3:32][CH2:33][O:34][C:35](C)=[O:36].O>CCO.O1CCOCC1>[CH2:33]([O:34][C:35](=[O:36])[NH:27][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]([C:12]2[CH:13]=[CH:14][C:15]([S:18](=[O:20])(=[O:21])[NH2:19])=[CH:16][CH:17]=2)[N:10]=1)[CH3:32]
Reactant: CCOC(C)=O
Reactant: CCN(CC)CC
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)cc1
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Nc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of acid 4 (0.74 g, 2 mmol) in 10 mL of EtOH and 10 mL of 1,4-dioxane was added diphenylphosphonylazide (0.52 mL, 2.4 mmol) followed by Et3N (0.34 mL, 2.4 mmol). The reaction mixture was refluxed overnight. After cooling the reaction mixture to room temperature, EtOAc and water were added. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to give the titled compound (0.48 g, 62%) as a white solid. mp 120.9-127.5° C. 1H NMR (300 MHz, DMSO-d6): δ 10.30 (s, 1H), 7.79 (d, J=8 Hz, 2H), 7.50-7.34 (m, 7H), 7.33-7.25 (m, 2H), 6.74 (s, 1H), 4.14 (q, J=7 Hz, 2H), 1.24 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:17])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C:10]([C:18]([O:20]C)=O)=[N:9]2)=[CH:4][CH:3]=1.C[Al](C)C.[I:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:17])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C:10]([C:18]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([I:26])=[CH:28][CH:29]=3)=[O:20])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=NN(c2ccc(F)cc2)C(C)(C(=O)OC)C1
Reactant: Nc1ccc(I)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COC(=O)C1(C)CC(C(=O)Nc2ccc(I)cc2)=NN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
The compound of Example 11 (0.5 g) was dissolved in dichloromethane (5 ml) and added to a mixture of trimethylaluminum (2M in toluene, 1.68 ml) and 4-iodoaniline (0.7 g) in dichloromethane (10 ml). The mixture was stirred at room temperature for 16 hours and partitioned between 1N HCl (100 ml) and dichloromethane (100 ml). The organic layer was dried and evaporated to leave a solid. Recrystallization from ether/hexanes gave the title compound (0.73 g): m.p.: 84°-85° C. NMR (CDCl3) 8.4 (br, NH), 7.7-6.9 (m, ArH, 12H), 3.8 (s, OMe, 3H), 3.8 (d, CH, 1H), 3.3 (d, CH, 1H), 1.7 (s, Me, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6]N[CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>O>[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N:19]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)O
Reactant: CN1CCNCC1
Solvent: O
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
1-Methylpiperazine (0.962 mL, 8.67 mmol) was added to a suspension of 2-methoxy-4,5-dinitrobenzoic acid (2.0 g, 8.26 mmol) in water (5 mL). The mixture was heated at 50° C. for 1.5 h then 75° C. for 3 h. A further 0.5 equivalents of 1-methylpiperazine was added and the mixture was heated overnight. The mixture was then allowed to cool and stand. A crystalline solid formed which was collected by filtration, washed with water and then dried on the filter to give the title compound (1.87 g, 77%) as a yellow crystalline solid; 1H NMR: 2.25 (3H, s), 2.45-2.49 (4H, m), 3.13-3.21 (4H, m), 3.93 (3H, s), 6.63 (1H, s), 8.32 (1H, s); m/z: ES+ MH+ 296.5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH2:12][CH2:11][NH:10][C:9](=[O:15])[C:8]=2[C:7]=1[C:16]([F:19])([F:18])[F:17])=[O:5])[CH3:2].[H-].[Na+].Br.Br[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH2:12][CH2:11][N:10]([CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:9](=[O:15])[C:8]=2[C:7]=1[C:16]([F:18])([F:19])[F:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(c1C(F)(F)F)C(=O)NCC2
Reactant: CCN(CC)CCBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2c(c1C(F)(F)F)C(=O)N(CCN(CC)CC)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
A stirred mixture of 3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (2.6 g, 9.4 mmol) in 40 ml of N,N-dimethylformamide was cooled down to 0° C. in an ice-water bath, added with sodium hydride slowly. Upon the completion of the addition, the reaction mixture was cooled down to −30˜40° C. and added with (2-bromo-ethyl)-diethyl-amine hydrobromide (2.95 g, 11.3 mmol) in 15 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature overnight and extracted with saturated sodium chloride (100 ml) and dichloromethane (100 ml). The combined organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol:ammonia (16:1:0.1) as eluents to give 5-(2-diethylamino-ethyl)-3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (1 g, 28.4) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1>[O-2].[O-2].[Mn+4].ClCCl>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1
Reactant: COCc1ccc(CO)c(N)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCc1ccc(C=O)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a mixture of (2-amino-6-methoxymethyl-pyridin-3-yl)methanol (260 mg) described in Manufacturing Example 19-1 and dichloromethane (15 mL) was added manganese dioxide (1.3 g), which was stirred overnight at room temperature. The reaction mixture was filtered through Celite, and the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=3:2) to obtain the titled compound (210 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(O)CCCBr
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a mixture of 4-bromobutyric acid (1 g), benzyl alcohol (0.65 g) and triphenyl phosphine (1.57 g) in tetrahydrofuran (12 mL) was added diethyl azodicarboxylate (40% toluene solution, 2.88 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (0.69 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:22][CH2:23][CH2:24][CH2:25][Cl:26])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C1COCC1>[Cl:26][CH2:25][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:27][CH3:28])[N:15]=[CH:14][N:13]=[C:12]2[S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Reactant: Nc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OCCCCl
Reaction time: 0.5 h

Procedure:
In a round bottomed flask, sodium hydride (121 mg, 3.14 mmol), a 60% dispersion in mineral oil, was suspended in 20 mL of dry THF. To this suspension 3-aminothiophenol (394 mg, 3.14 mmol) was added and the reaction stirred for 30 minutes. To this solution 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline (900 mg, 3.14 mmol) and the reaction stirred overnight. The reaction was quenched with water, concentrated, and partitioned between water and ethyl acetate. After extracting twice, the extracts were combined, dried over magnesium sulfate, filtered and concentrated to give 3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)aniline as a yellow solid and used without further purification. 1H (DMSO-d6) 8.70 (s, 1H), 7.34 (s, 1H), 7.15 (m, 1H), 6.80 (s, 1H), 6.75 (m, 2H), 4.28 (m, 2H), 3.99 (s, 3H), 3.84 (m, 2H), 2.38 (m, 2H); LCMS (ESI) m/z 376 (M+H).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[CH3:10]>C(Cl)(Cl)Cl>[Br:1][CH2:12][C:11]([C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([Br:3])[CH:5]=1)=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C)c(Br)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)CBr)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
A solution of bromine (0.68 mL, 13.3 mmol) in chloroform (13 mL) was added dropwise over a 35 minute period to a stirred solution of 1-(3-bromo-4-methylphenyl)ethanone (2.96 g, 13.9 mmol) in chloroform (40 mL) at 0° C. After the addition, the ice-bath was removed and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give an oil which crystallized to give the title compound (4.11 g, 95%) as an orange solid.