Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].C(N(CC)CC)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Under a nitrogen atmosphere a solution of 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.7 mmol) in didhloromethane (50 mL) was cooled to 0° C. Triethylamine (415 μL, 2.98 mmol) was added followed by benzenesulfonyl chloride (345 μL, 2.71 mmol). The reaction mixture was allowed to warm slowly to ambient temperature and then it was maintained overnight. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (50 g of silica gel eluting with 7.5% methanol in dichloromethane). The purified material was recrystallized from propyl acetate, triturated with hexanes, and then dried in a vacuum oven to provide 590 mg of N-{8-[4-amino-2-(2-methoxyetyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzenesulfonamide as a yellow powder, m.p. 146-149° C. Analysis: Calculated for C27H35N5O3S: %C, 63.63; %H, 6.92; %N, 13.74; Found: %C, 62.96; %H, 7.03; %N, 13.09. Karl Fisher showed 0.16% or 0.045 mole water.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]=1)([F:4])[CH3:3].[C:19](=[O:28])([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)N>>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]=1)([F:4])[CH3:3]
Reactant: COc1ccc(-n2nc(C(C)(F)F)cc2N)cc1
Reactant: NC(=O)Oc1ccccc1
Product: COc1ccc(-n2nc(C(C)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Yield: 64 %

Procedure:
3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-amine was converted to the phenyl carbamate using the procedure for Example 282A Step 2. Purification using silica gel chromatography eluting with EtOAc/hexane (5-40%) afforded phenyl 3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate in 64% yield. LC-MS (ESI) m/z 374 (M−H)−
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:12][OH:13]>CO.N1C=CC=CC=1>[C:1]1(=[N:12][OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: ON=C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
1-Indanone (4.00 g, 30.3 mmol) and hydroxylamine hydrochloride (5.26 g, 75.7 mmol) were dissolved in a mixture of methanol (40 ml) and pyridine (10 ml) and stirred for 3 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the resultant residue was diluted with 1N HCl (100 ml) and extracted three times with methylene chloride. The organic layer was dried over MgSO4 and concentrated in vacuo to provide 4.13 g (93% yield) of the desired 1-indanone oxime as white needles.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CS(C)=O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (2.54 mL, 24 mmol) and N-methylpiperazine (2.22 mL, 20 mmol) was dissolved in DMSO (25 mL) and irradiated in a microwave oven (max power 250 W, 160° C.) for 10 min, then cooled to room temperature. The solvent was removed under high vacuum, and the residue was dissolved in EtOAc and extracted with 0.5M aqueous HCl. The aqueous extracts were combined, basified to pH 8, and extracted with EtOAc. The organic layer was washed with brine, and then dried over MgSO4. Evaporation of the solvent provided the crude 1-methyl-4-(4-nitrophenyl)piperazine as an brown oil.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C>[C:23]1(=[O:24])[N:19]([O:7][CH2:6][C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])[C:20](=[O:29])[C:21]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of thymidine (24.22 g, 0.1 mol), N-hydroxyphthalimide (21.75 g, 0.13 mol), triphenylphosphine (34 g, 0.13 mol) in dry DMF (400 ml) was added diisopropylazodicarboxylate (30 ml, 0.15 mol) over a period of 3 h at 0° C. After complete addition the reaction mixture was warmed up to room temperature and stirred for 12 h. The solution was concentrated under vacuum (0.1 mm, <40° C.) to furnish an orange-red residue. The residual gum was washed several times with Et2O and washing were discarded. The semi-solid residue was suspended in EtOH (500 ml) and heated (90° C.) to dissolve the product. On cooling 30.98 g (80%) of 5′-O-phthalimidothymidine was collected in 3-crops as white crystalline material, mp 233-235° C. (decomp.); H NMR (DMSO-d6) δ 11.29 (s, 1, NH), 7.85 (m , 4, ArH), 7.58 (s, 1, C6H), 6.20 (t, 1, H1′, J1′,2′=7.8 Hz, J11′,2″=6.5 Hz), 5.48 (d, 1, OH3′), 4.36 (m, 3, H4′,5′,5″), 4.08 (m, 1, H3′), 2.09-2.13 (m, 2, H2′,2″), and 1.79 (s, 3, CH3). Anal. Calcd. for C18H17O7N3.0.7 H2O: C, 54.05; H, 4.64; N, 10.51. Found: C, 53.81; H, 4.25; N, 10.39.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19](=[O:21])[CH3:20])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([CH2:7][C:6]([OH:22])=[O:5])[CH:9]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc2c(c1)c(C(C)=O)cn2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)c(C(C)=O)cn2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3-acetyl-5-methoxy-indol-1-yl)-acetic acid tert-butyl ester (520 mg, 1.71 mmol) in CH2Cl2 (15 mL) was added TFA (1.32 mL, 17.1 mmol). The reaction mixture was stirred at RT overnight. Volatiles were evaporated, then the crude material was taken up in 5 mL of 1M aqueous NaOH solution and washed with CH2Cl2 which was discarded. The water phase was acidified to pH=1 by adding a 6M aqueous HCl solution, and then was extracted twice with AcOEt. The combined organic phases were dried (Phase separator) and evaporated to give the title compound. MS (LC/MS): 248.1 [M+H]+, 246.1 [M−H]−; tR (HPLC conditions c): 3.47 min.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](F)=[N:8][CH:9]=1.[OH:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>O1CCCC1.CN1CCCN(C)C1=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[N:8][CH:9]=1
Reactant: Fc1ccc(Br)cn1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Sodium hydride (60% disp. in oil, 908.0 mg, 22.72 mmol) was added portionwise at room temperature to a solution of 5-bromo-2-fluoropyridine A-5 (1.16 mL, 11.36 mmol) and methyl 3-hydroxy-2,2-dimethylpropanoate (1.88 mL, 14.77 mmol) in anhydrous tetrahydrofuran (32.9 mL) and anhydrous 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5.0 mL) under an atmosphere of argon and in the presence of 4 Å molecular sieves. After 2 h of stirring at room temperature, the reaction mixture was heated at 50° C. for 10 h and then at 70° C. for 3 h. The suspension was cooled to room temperature, filtered over a thin celite pad, and the pad was rinsed with diethyl ether (150 mL). The filtrate was concentrated to a volume of ca. 5 mL, then diluted with diethyl ether (150 mL), quenched with water (90 mL) and decanted. The aqueous layer was extracted with diethyl ether (2×100 mL); the combined extracts were successively washed with water (3×70 mL), brine (70 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (100:0 to 80:20 hexanes:ethyl acetate gradient) to give methyl 3-(5-bromopyridin-2-yloxy)-2,2-dimethylpropanoate A-6 (1.796 g, Yield=55%). MS (ESI), [M+1]+ 288, 290.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1([CH:18]2SCCCS2)[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[OH2:24].B(F)(F)F>O1CCCC1.CCOCC>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1([CH:18]=[O:24])[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: CN1CCC(OCc2ccccc2F)(C2SCCCS2)CC1
Reactant: O
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCC(C=O)(OCc2ccccc2F)CC1
Yield: 36.9 %

Procedure:
The compound 4-(2-fluorophenylmethoxy)-1-methyl-4-(1,3-dithian-2-yl)piperidine hydrochloride (5 g, 13.1 mmole) was suspended in tetrahydrofuran (50 ml), and water (5 ml) was added to completely dissolve the compound. Red mercuric oxide (8.6 g, 39.7 mmole) was added to the solution. After a complex was formed, BF3 etherate (32.3 ml, 39.7 mmole) was added dropwise to the stirred suspension under nitrogen and reaction was taken to completion as indicated by TLC. The reaction mixture was diluted with an equal volume of ether and filtered. The filtrate was treated with saturated potassium carbonate to form a precipitate. The mixture was extracted with ethyl acetate, and the ethyl acetate extracts were washed with saturated brine. The washed extract was dried over anhydrous potassium carbonate, filtered and taken to dryness. The residue was dissolved in ether from which the hydrochloride was precipitated. The resulting material was recrystallized from ethyl acetate/ethanol. After filtration, washing with ethyl acetate and ether, the product was air-dried to yield 1.3 g (4.5 mmole, 36.9%) of 4-(2-fluorophenylmethoxy)-1-methyl-4-oxomethyl piperidine hydrochloride. MS (MH+ =252), NMR (CDCl3) and IR (CHCl3) were consistent with the structure, mp=164°-167° C.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:24]=[CH:25][C:18]=12>C1COCC1.C(OCC)(=O)C>[Cl:32][C:31]1[C:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6])=[C:18]3[CH:25]=[N:24]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)OC
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
Sodium hydride (62.4 mg, 1.56 mmol) was to (S)-methyl 2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y6) (200 mg, 1.04 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and then 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (360 mg, 1.35 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (245 mg, 55.8%). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, 3H), 3.33-3.48 (m, 5H), 3.74-3.82 (m, 4H), 4.13-4.18 (m, 2H), 5.81-5.86 (m, 1H), 7.43-7.48 (m, 1H), 7.98-8.02 (m, 1H), 8.39-8.41 (m, 1H), 8.58 (s, 1H), 8.60-8.63 (m, 1H); m/z (ESI+) (M+H)+=422.36; HPLC tR=1.93 min.
Reaction SMILES: [NH2:1][C:2](=[O:33])[CH2:3][N:4]([CH3:32])[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([S:30][CH3:31])=[CH:12][N:13]2[C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][N:23]=3)=[CH:18][N:17]=2)=[CH:9][CH:8]=1)=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:39]>>[NH2:1][C:2](=[O:33])[CH2:3][N:4]([CH3:32])[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([S:30]([CH3:31])=[O:39])=[CH:12][N:13]2[C:16]2[N:17]=[CH:18][C:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][N:23]=3)=[CH:20][N:21]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: COc1ccnc(-c2cnc(-n3cc(SC)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1ccnc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1

Procedure:
Oxidation of 283a) with m-chloroperoxybenzoic acid (0.18 g, 0.39 mmol). White solid. Yield: 0.065 g (35% of theory)
Reaction SMILES: [O:1]([CH2:9][CH3:10])S(C(F)(F)F)(=O)=O.[C:11]1([C:17](C2C=CC=CC=2)(C2C=CC=CC=2)[N:18]2[CH:22]=[C:21](C(=O)C)[N:20]=[C:19]2[CH3:26])C=CC=CC=1>C(Cl)Cl>[CH2:17]([N:18]1[C:22]([C:9](=[O:1])[CH3:10])=[CH:21][N:20]=[C:19]1[CH3:26])[CH3:11]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Solvent: ClCCl
Product: CCn1c(C(C)=O)cnc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
Ethyl triflate (11 ml, 83.2 mmol) was added dropwise over 15 minutes to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 23.4 g, 64 mmol) in DCM (300 ml) and the mixture stirred for 5 hours at ambient temperature. The solution was diluted with DCM (100 ml) and extracted with 1M aqueous citric acid solution (5×75 ml). The aqueous extracts were combined, basified with solid sodium hydrogen carbonate and the extracted with DCM (5×75 ml). The organic extracts were combined, dried and evaporated to give the title compound (8.59 g, 88%) as a pale yellow oil. NMR 1.32 (t, 3H), 2.41 (s, 6H), 4.29 (q, 2H), 7.68 (s, 1H); m/z 153.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>C1COCC1>[Cl:7][CH2:8][CH2:9][NH:10][C:11]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: O=C=NCCCl
Reactant: NC1CCCC1
Solvent: C1CCOC1
Product: O=C(NCCCl)NC1CCCC1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A 0° C. solution of cyclopentylamine (4.63 mL, 47.0 mmol) in THF (235 mL) was treated drop-wise with 2-chloroethyl isocyanate (4.41 mL, 51.7 mmol) which was allowed to warm to RT, then concentrated to dryness. The solid was suspended in toluene and concentrated again to dryness to afford 1-(2-chloroethyl)-3-cyclopentylurea (8.95 g, 100%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.01 (d, J=7.3 Hz, 1 H), 5.91 (t, J=5.8 Hz, 1 H), 3.85-3.76 (m, 1 H), 3.54 (t, J=6.2 Hz, 2 H), 3.27 (q, J=6.1 Hz, 2 H), 1.78-1.69 (m, 2 H), 1.62-1.53 (m, 2 H), 1.51-1.42 (m, 2 H), 1.30-1.20 (m, 2 H); MS (ESI) m/z: 191.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=O.N1CCCCC1>C(Cl)(Cl)Cl>[OH:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:20][C:19]1[CH:22]=[CH:23][C:24]([O:25][C:26]([F:27])([F:28])[F:29])=[C:17]([Cl:16])[CH:18]=1
Reactant: CC(=O)c1c(O)c2ccccc2oc1=O
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: O=C(C=Cc1ccc(OC(F)(F)F)c(Cl)c1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A mixture of 2.25 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 2.25 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 20 ml of chloroform and 0.7 ml of piperidine was heated under refluxing for 2 hours and 30 minutes. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography. Resulting crystals were washed with 40 ml of t-butyl methyl ether to obtain 1.49 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (1c-6)] was obtained as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[O:31][CH:32]=[CH:33][CH:34]=1)(=[O:29])=[O:28].[OH-].[NH4+:36]>>[NH2:36][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:29])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccco1
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (0.100 g, 0.186 mmol) and ammonium hydroxide (1.21 mL, 9.29 mmol) heated to 120° C. for 20 min in a microwave reactor the title compound was obtained as a white solid (54 mg, 0.104 mmol, 56.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.47 (s, 1H), 7.90 (d, J=5.5 Hz, 2H), 7.43 (d, J=3.8 Hz, 2H), 7.30 (d, J=3.3 Hz, 1H), 7.03 (d, J=3.3 Hz, 1H), 6.43-6.62 (m, 3H), 5.47 (d, J=5.3 Hz, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.45 (t, J=4.7 Hz, 4H). MS (ESI): 519.00 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 4-methyl-3-nitrobenzoic acid (5.52 g, 30.5 mmol) in MeOH (100 mL) was added 98% sulfuric acid (2 mL) and the resultant mixture was refluxed overnight, then cooled to room temperature. The mixture was concentrated and the residue was dissolved in CH2Cl2 (50 mL) and water (20 mL). Solid Na2CO3 was added until the aqueous phase was basic to litmus paper. The phases were separated and the aqueous phase was extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 5.79 g (97%) of 4-methyl-3-nitrobenzoic acid methyl ester as a white solid. To a solution of 4-methyl-3-nitrobenzoic acid methyl ester (5.01 g, 25.7 mmol) in CCl4 (65 mL) was added N-bromosuccinimide (5.04 g, 28.3 mmol) followed by 1,1′-azobis(cyclohexanecarbonitrile) (1.21 g, 4.96 mmol). The resultant mixture was refluxed for 24 hours then cooled to room temperature, filtered through filter paper, and concentrated. Purification of the crude material by column chromatography on silica gel (9:1 :hexanes-EtOAc) provided 4.30 g (61%) of 4-bromomethyl-3-nitrobenzoic acid methyl ester as a yellow oil. 1H NMR (CDCl3) δ 3.98 (s, 3H), 4.85 (s, 2H), 7.67 (d, 1H, J=7.8 Hz), 8.25 (d, 1H, J=7.8, 1.5 Hz), 8.66 (d, 1H, J=1.5 Hz).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]([CH2:34][CH3:35])[C@@H:22]([CH2:32][CH3:33])[CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]([CH2:34][CH3:35])[C@@H:22]([CH2:32][CH3:33])[CH2:23][NH2:24])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCC(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)[C@@H](CC)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)[C@@H](CC)CN
Temperature: 0 °C
Yield: 29 %

Procedure:
tert-Butyl (2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentylcarbamate was dissolved in 5 mL DCM and cooled to 0° C. TFA (5 mL) was added and the mixture was allowed to warm to ambient temperature over 1 hour. The reaction mixture was evaporated to dryness, and the residue was dissolved in 30 mL DCM and washed with 1N NaOH. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography followed by preparative TLC to give the desired product (42.5 mg, 29%). MS ESI (+) m/z 376.1 (M+1) detected.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (8.00 g), N-hydroxyphthalimide (4.13 g), potassium carbonate (7.05 g) and N,N-dimethylformamide (80 ml) was stirred at room temperature for 20 hours and water (800 ml) was added. The resultant crystals were filtered and washed with water to obtain N-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (10.1 g, yield 90%) as pale-brown crystals. m.p. 146-147° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-4-fluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1 H), 7.80 (d, J=8.7 Hz, 1 H), 7.54 (d, J=8.5 Hz, 1 H), −7.11-6.97 (m, 2 H), 6.83-6.71 (m, 2 H), 4.64 (t, 2 H), 4.20 (t, 2 H), 2.88 (t, 2 H), 1.70-1.58 (m, 2 H), 0.94 (t, J=7.3 Hz, 3 H); MS (ES) m/z 357 (M+1).