Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.FC(F)(F)S(O[CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCC(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
To a stirred solution of tert-butyl 2-((diphenylmethylene)amino)acetate (1 g, 3.39 mmol) in THF (20 mL) cooled to −78° C. under nitrogen atmosphere was added a 2M solution of LDA in THF (2.54 mL, 5.08 mmol) dropwise for 30 min. To this mixture was then added 3,3,3-trifluoropropyl trifluoromethanesulfonate (1.083 g, 4.40 mmol). The reaction was gradually warmed to rt and stirred for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride at 0° C. The reaction mixture was then extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water (1×10 mL) and brine (1×10 mL), dried over sodium sulfate and then concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography (2% ethyl acetate in hexane) to afford tert-butyl 2-((diphenylmethylene)amino)-5,5,5-trifluoropentanoate (800 mg, 2.02 mmol, 60% yield) as a yellow oil. LC/MS (ESI) m/e 391.9 [(M+H)+, calcd for C22H25F3NO2, 392.2]; LC/MS retention time (method E): tR=2.49 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Product: COc1ccc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of Example 1.4 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.26 g, 1 mmol) and 4-methoxy-benzoyl chloride (2 mmol) to give the title compound: Rf =0.44 (silica gel, 6% methanol in dichloromethane).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.[NH2:46][C:47]1[N:52]=[C:51](Cl)[N:50]=[C:49]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:48]=1[N+:59]([O-:61])=[O:60]>O1CCOCC1.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>[NH2:46][C:47]1[N:52]=[C:51]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[CH:2][CH:3]=3)[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[N:9]=2)[N:50]=[C:49]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:48]=1[N+:59]([O-:61])=[O:60]
Reactant: CCOC(=O)c1nc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under argon, 3.85 g (10.91 mmol) of the compound from example 24A were initially charged in dioxane (100 ml) and the reaction mixture was purged with argon. Subsequently, 8.27 ml (16.36 mmol) of hexabutylditin and 2.96 g (12.00 mmol) of ethyl 6-amino-2-chloro-5-nitropyrimidine-4-carboxylate (prepared according to J. Chem. Res. 1989, 2086-2097) were added. Thereafter, 3.83 g (5.45 mmol) of bis(triphenylphosphine)palladium(II) chloride were added and the reaction mixture was stirred at 100° C. overnight. Thereafter, the mixture was cooled to RT and filtered through Celite, and the residue was washed with methanol. The filtrate was concentrated, and the residue was extracted by stirring with ethyl acetate and filtered off. The filtrate was concentrated and the residue was purified by means of prep. HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient). This gave 1.36 g (71% purity, 14% of theory) of crude product, which was converted without further purification.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([F:24])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1>O1CCOCC1.C(Cl)Cl>[C:1]1([C@H:7]([NH:9][C:11]2[C:20]3[C:15](=[CH:16][C:17]([F:24])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Nc1ncnc2cc(F)c([N+](=O)[O-])cc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 74 ml of (R)-1-phenylethylamine in 100 ml of dioxane is dropped into 108.8 g of 4-chloro-6-nitro-7-fluoro-quinazoline in 800 ml of methylene chloride with cooling. The reaction mixture is washed with water after stirring overnight at room temperature, the organic phase is separated, dried and evaporated. The obtained residue is purified by chromatography over a silica gel column (petroleum ether/ethyl acetate=1:1). Yield: 52.9 g (35% of theory); melting point: 203° C.; mass spectrum (ESI+): m/z=313 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[O:24])[C:12]3[C:17]([O:18][C:19]=2[C:20]=1[C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH2:5].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[CH2:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[O:24])[C:12]3[C:17]([O:18][C:19]=2[C:20]=1[C:21](=[O:23])[CH:22]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc2c(=O)c3ccccc3oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(=O)c3ccccc3oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-allyloxy-4-acetylxanthen -9one (2.2 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2 g of product m.p. 150-152° C., 1H-NMR (CDCl3)δ:4.73-4.74 (m, 2H); 5.25-5.42 (m, 2H); 5.92-6.05 (m, 1H); 7.07 (d, 1H, J=8.9 Hz); 7.13 (d, 1H, J=16 Hz); 7.36-7.44 (m, 6H); 7.52-7.60(m, 2H); 8;31-8.36 (m, 1H); 8.43 (d, 1 H, J=8.9 Hz).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:14][C:13]=1[F:30])=[O:11].[CH2:31](I)[CH3:32]>>[CH2:31]([O:8][C:6]1[CH:7]=[CH:2][C:3]2[N:9]=[C:10]([C:12]3[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH3:21])=[CH:14][C:13]=3[F:30])[O:11][C:4]=2[CH:5]=1)[CH3:32]
Reactant: CCI
Reactant: C[C@@H](COc1cnc(C(=O)Nc2ccc(O)cc2O)c(F)c1)NC(=O)OC(C)(C)C
Product: CCOc1ccc2nc(-c3ncc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3F)oc2c1

Procedure:
Using tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate and ethyl iodide, and in the same manner as in Example 2, steps D-E, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12](O)=O>>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: O=CO
Reactant: Cc1ccc(C(N)=O)c(N)c1
Product: Cc1ccc2c(=O)[nH]cnc2c1
Temperature: 100 °C
Yield: 84.5 %

Procedure:
A mixture of 2-amino-4-methylbenzamide (20 g, 133 mmol) and formic acid (120 ml, 3129 mmol) was heated to 100° C. for 6 h. The reaction was cooled to RT and the volatiles were removed under reduced pressure. The residue was then washed carefully with aqueous saturated sodium bicarbonate and then with water. The tan solid was then dried in a vacuum oven at 45° C. overnight to give 7-methylquinazolin-4(3H)-one (18.00 g, 84% yield). MS (ESI, pos. ion) m/z: 161 [M+H]+
Reaction SMILES: S(O[CH2:12][C:13]12[CH2:27][CH:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=31)[C:19]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=1)(C1C=CC(C)=CC=1)(=O)=O.[O-][C:29]#[N:30].[K+]>CN(C)C=O.O>[CH:15]1[C:14]2[C:13]3([CH2:12][C:29]#[N:30])[CH2:27][CH:20]([C:21]4[C:26]3=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: N#C[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC23CC(c4ccccc42)c2ccccc23)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC12CC(c3ccccc31)c1ccccc12
Temperature: 150 °C

Procedure:
A mixture of 9-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene (188 mg) and potassium cyanate (40 mg) in dimethylformamide (2 ml) was heated at 150° C. for 7 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give crude crystals of (9,10-dihydro-9,10-methano-9-anthryl)acetonitrile, which was recrystallized from isopropanol to give pure crystals. M.P. 130°-131° C.
Reaction SMILES: [CH2:1]([C:4](=[CH2:8])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](I)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](/[CH:8]=[C:4](\[CH2:1][CH2:2][CH3:3])/[C:5]([OH:7])=[O:6])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)I)cc1
Reactant: C=C(CCC)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC/C(=C\S(=O)(=O)c1ccc(C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2-Propylacrylic acid (5.0 g, 43.80 mmol) was added to a solution of toluene-4-sulfonyl iodide (14.32 g, 65.70 mmol) in dichloromethane (100 ml). The solution was stirred overnight at room temperature and then cooled to 0° C. Triethylamine (12.2 ml, 87.6 mmol) was added and the solution was stirred for 1 hour then allowed to warm to room temperature over 2 hours. The organic solution was washed with water (100 ml), 1N hydrochloric acid ((100 ml) 10% aqueous sodium bisulfite (50 ml), then extracted with sodium hydroxide (5 g) in water (100 ml). The aqueous layer was washed with ethyl acetate (20 ml) and then acidifed with conc. sulfuric acid (3 ml). The product was extracted into ethyl acetate (2×50 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporated to give the title compound in 85% yield. This yellow solid was dissolved in methanol (100 ml ) and stirred with activated charcoal (1 g). Filtration and evaporation gave a pale yellow solid which was slurried in dichloromethane:heptane 20:80. Filtration gave the title compound as white crystals (8.3 g, 70%).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.Cl.[OH:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[NH:37][OH:38].C(N(CC)CC)C.Cl>C1COCC1.CCCCCC.C(OCC)(=O)C.O.C(Cl)Cl>[OH:38][N:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[OH:26])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([C:1]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: ONc1ccc2ccccc2c1O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)N(O)c2ccc3ccccc3c2O)c1
Reaction time: 1 h
Yield: 54.7 %

Procedure:
Into a 25 ml dry methylene chloride solution of 500 mg (2.78 mmol) of monomethyl isophthalate and 215 μl (2.78 mmol) of DMF was added under N2 atmosphere 546 μl (6.26 mmol) of oxalyl chloride at 0° C., and subsequently, the mixture was returned to room temperature and stirred for one hour. The mixture was added dropwise under an N2 atmosphere to a solution of 1.76 g (8.34 mmol) of 1-hydroxy-2-naphthylhydroxylamine hydrochloride, 2.9 ml (21 mmol) of triethylamine in THF (25 ml), and water (5 ml), followed by stirring as such at room temperature for one hour. The reaction was completed by an addition of 4N hydrochloric acid, and the mixture extracted with methylene chloride. The organic layer was washed with 4N hydrochloric acid, water, and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the crude product obtained was subjected to silica gel column chromatography (hexane:ethyl acetate 6:1→4:1) to give 513 mg (55%) hydroxyamic acid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]([CH2:29][C:30]1[CH:31]=[C:32]([CH:36]([CH2:39]/[CH:40]=[C:41](/[C:43]2[CH:52]=[CH:51][C:50]3[C:49]([CH3:54])([CH3:53])[CH2:48][CH2:47][C:46]([CH3:56])([CH3:55])[C:45]=3[CH:44]=2)\[CH3:42])[C:37]#N)[CH:33]=[CH:34][CH:35]=1)[Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O:59]CC)C>>[O:11]([CH2:29][C:30]1[CH:31]=[C:32]([CH:36]([CH2:39]/[CH:40]=[C:41](/[C:43]2[CH:52]=[CH:51][C:50]3[C:49]([CH3:54])([CH3:53])[CH2:48][CH2:47][C:46]([CH3:56])([CH3:55])[C:45]=3[CH:44]=2)\[CH3:42])[CH:37]=[O:59])[CH:33]=[CH:34][CH:35]=1)[Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C/C(=C\CC(C#N)c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C/C(=C\CC(C=O)c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
Diisobutylaluminum hydride (1.0M in hexanes, 1.54 mL, 1.54 mmol) was added dropwise to a solution of 26 (0.74 g, 1.18 mmol) in anhydrous diethyl ether (22 mL) at 0° C. under argon. The reaction mixture was allowed to warm to room temperature over 2.5 h. The reaction was quenched with ethyl acetate (2.5 mL) and 1N H2SO4 solution (5 mL) and stirring was continued for 10 min. The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted again with diethyl ether. The organic layers were combined, washed sequentially with 1N NaOH solution and saturated sodium chloride solution, and concentrated in vacuo to give 0.72 g (97%) of 27 as a dark yellow oil. 1H NMR showed the presence of trace impurities, but the compound decomposed on silica gel. The material was used without purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ9.73 (s, 1H, CHO), 7.61-7.77 (m, 4H, ArH), 7.03-7.42 (m, 13H, ArH), 5.62 (t, J=9 Hz, 1H, CH=C), 4.78 (s, 2H, CH2OSi), 3.66 (t, J=6 Hz, 1H, CHCHO), 2.92-3.01 (m, 1H, 1×CH2CH), 2.55-2.67 (m, 1H, 1×CH2CH), 1.95 (s, 3H, C=CCH3), 1.66 (s, 4H, CH2CH2), 1.28 (s, 12H, 4×CH3), and 1.07 (s, 9H, SiC(CH3)3).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]3[C:22](=[O:25])[CH2:23][CH2:24][C:17]=3[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2.[Al+3].[Cl-].[Cl-].[Cl-].[C:30](Cl)([CH3:32])=O.C([O-])(O)=O.[Na+]>C1([N+]([O-])=O)C=CC=CC=1.O>[CH2:22]([CH:24]1[C:17]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:8][CH2:7][CH:3]4[CH2:4][CH2:5][CH2:6][N:2]4[CH3:1])[C:21]=3[CH:20]=[CH:19][C:18]=2[C:22](=[O:25])[CH2:23]1)[CH2:23][CH2:24][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:16][CH2:15][CH2:10][CH2:11][CH2:12][CH2:13][CH2:30][CH3:32]
Reactant: CN1CCCC1CCn1c2ccccc2c2c3c(ccc21)C(=O)CC3
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCCCCCCCCCCCC1CC(=O)c2ccc3c(c21)c1ccccc1n3CCC1CCCN1C
Reaction time: 0.67 h

Procedure:
Compound 65 (0.336 g, 1.00 mmol) was dissolved in PhNO2 (7 mL). The solution was cooled down in an ice bath. Then, AlCl3 (0.67 g, 5.02 mmol) and after that, AcCl (0.36 mL, 5.04 mmol) were added. The resulting mixture was kept for 40 min (LC/MS monitoring), diluted with water, neutralized with aqueous NaHCO3 solution, extracted with CHCl3, and evaporated. The product was purified on a short thick column, eluent: 100:0→90:10. Yield of product: 0.307 g (82%) (R); S-isomer was obtained similarly (77%).
Reaction SMILES: CC(N(C)C)=O.Cl.Cl.[NH2:9][C:10]1[CH:18]=[CH:17][C:13]2[NH:14][N:15]=[N:16][C:12]=2[CH:11]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:34])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.N1C=CC=CC=1>[O:27]([C:26]([NH:9][C:10]1[CH:18]=[CH:17][C:13]2[NH:14][N:15]=[N:16][C:12]=2[CH:11]=1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc2[nH]nnc2c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nnc2c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
500 ml of dimethylacetamide was added to 62.1 g of 5-aminobenzotriazole dihydrochloride, and 83.7 ml of triethylamine was dropwise added thereto with cooling in an ice bath. Further, 21.0 ml of pyridine was dropwise added, followed by dropwise addition of 42.3 g of phenyl chlorocarbonate at 5° C. or lower, and then, the whole was stirred for 2 hours at room temperature. After the reaction, the reaction solution was poured into 2 liters of water for crystallization, and the crystal formed was taken out by filtration to obtain 60.8 g of 5-phenoxycarbonylaminobenzotriazole. To 5.1 g of 5-phenoxycarbonylaminobenzotriazole thus-obtained was added 40 ml of acetonitrile, and 2.6 g of N,N-diethylethylenediamine was dropwise added thereto with stirring at 45° C., and then the whole was stirred for 2 hours as such. After the reaction, the reaction solution was cooled in an ice bath, and the crystal precipitate was taken out by filtration and recrystallized from 60 ml of a mixed solvent of methyl alcohol/acetonitrile (1/5) to obtain 3.8 g of the desired product. M.P.: 149°-150° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[CH2:18]Br>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[CH2:18][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:11])[CH2:3]1
Reactant: COc1cc(Br)cc(CBr)c1
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(CC2CC(=O)Nc3ccccc32)c1
Reaction time: 1 h

Procedure:
3,4-Dihydro-2(1H)-quinolinone was purchased from Aldrich Chemical Co. (Cat. No. 41,593-6) and used without purification in this step. 0.45 grams of 3,4-dihydro-2(1H)-quinolinone (3.0 mmole) was dissolved in 15 ml dimethylformamide and cooled in an ice bath. 0.2 grams (4.5 mmole) of sodium hydride (60% wt. in oil ) was added to this solution, and after 5 minutes 0.84 grams 3-bromo-5-methoxy-benzylbromide (3 mmol) was added thereto all at once. The mixture was stirred at ice bath temperature for 1 hour and then quenched by addition of 1% hydrochloric acid. The reaction mix was extracted with ethyl acetate, which was evaporated under reduced pressure to give an oil, which was chromatographed with medium pressure eluting using 10% ethyl acetate in hexanes to yield 0.8 grams of solid 4-(3-bromo-5-methoxy-benzyl)-3,4-dihydro-1H-quinoline-2-one.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[CH3:24][C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:31]4[CH:32]=[CH:33][C:28]([C:25]([CH3:27])([CH3:26])[CH3:24])=[CH:29][CH:30]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3ccc(C(C)(C)C)cc3)c(C)sc2n1
Temperature: 150 °C
Yield: 45.3 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in toluene (2 mL) and [4-(1,1-dimethylethyl)phenyl]boronic acid (61.9 mg, 0.347 mmol), PdCl2(dppf).DCM (18.91 mg, 0.023 mmol) and Cs2CO3 (226 mg, 0.695 mmol) were added. The mixture was then heated in a microwave at 150° C. for 30 min. Water (10 mL) was added and the mixture extracted with ethyl acetate (3×10 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-20% ethyl acetate in cyclohexane, to give the title compound (51 mg). LCMS (A) m/z: 485 [M+1]+, Rt 1.70 min (basic).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[N:26]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(Cc2cccnc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2cccnc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a mixture of 4-{[4-(chloromethyl)-2-methoxyphenoxy]methyl}-2-(2-furyl)-5-methyl-1,3-oxazole (0.94 g), ethyl 3-hydroxy-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate (0.55 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature. After stirring the reaction mixture at room temperature for 1 hr, the mixture was further stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate as colorless crystals (0.81 g, yield 68%) from a fraction eluted with ethyl acetate-methanol (20:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 131-132° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([F:15])=[C:10]([Cl:16])[N:9]=1>C(O)C>[Cl:7][C:8]1[N:13]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:11]([F:15])=[C:10]([Cl:16])[N:9]=1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Reactant: C1COCCN1
Solvent: CCO
Product: Fc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A solution of morpholine (1.5 mL, 17.05 mmol) in ethanol (25 mL) was added to a cooled (−20° C.) solution of 2,4,6-trichloro-5-fluoropyrimidine (3.00 g, 14.93 mmol) in ethanol (150 mL) and the resulting mixture was stirred at −20° C. for 30 minutes and at ambient temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water and methylene chloride. The organic layer was separated, dried and the solvent evaporated under reduced pressure. The resulting white solid was triturated with ethanol, then filtered and dried to give the title compound (2.0 g, 53%).