Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[H][H]>CO.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:2]2([CH3:1])[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:3]2)=[CH:15][CH:16]=1
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)C=Cc2ccccc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(COc2ccc(N)cc2)CCc2ccccc2O1
Yield: 70.8 %

Procedure:
780 mg of 2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 3) were dissolved in 20 ml of methanol, and 160 mg of 10% w/w palladium-on-carbon were added to the solution. The solution was then hydrogenated at room temperature at a hydrogen pressure of about one atmosphere for about 10 hours. At the end of this time, the catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 2:1 by volume mixture of hexane and ethyl acetate, to afford 500 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: P(=O)([O-])O[C:3]([CH2:13][C:14](F)(F)F)(CC(F)(F)F)[C:4]([O:6][CH3:7])=[O:5].C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:48]([C:50]1[CH:51]=C([CH:55]=[CH:56][CH:57]=1)C=O)#[N:49]>C1COCC1.CCOC(C)=O.CCCCCC>[C:48]([C:50]1[CH:51]=[C:14]([CH:55]=[CH:56][CH:57]=1)[CH:13]=[CH:3][C:4]([O:6][CH3:7])=[O:5])#[N:49]
Reactant: N#Cc1cccc(C=O)c1
Reactant: COC(=O)C(CC(F)(F)F)(CC(F)(F)F)O[PH](=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl) phosphonate (1.00 g, 3.14 mmol) and 18-crown-6 (4.14 g, 15.7 mmol) in THF (50 mL) at −78 C, potassium bis(trimethylsilyl)amide (6.3 mL, 0.5 M in toluene, 3.15 mmol) was added dropwise. After the addition was completed, 3-cyanobenzaldehyde (0.412 g, 3.14 mmol) in THF (8 mL) was added. The mixture was stirred at −78 C for 30 min before it was quenched with aq. NH4Cl. Water and ether were added. Aqueous phase was separated, extracted with ether once more. The combined organic solutions were dried over Na2SO4, concentrated in vacuo to give a solid, which was purified by a silica gel column, first eluted with EtOAc/hexane (5/95), then with EtOAc/hexane (10/90) to give the titled compound (0.40 g) (yield: 68%). 1H NMR (CDCl3) 7.85 (s, 1H), 7.77 (d, 1H, J=8 Hz), 7.60 (d, 1H, J=8 Hz), 7.45 (t, 1H, J=8 Hz), 6.91 (d, 1H, J=12 Hz), 6.06 (d, 1H, J=12 Hz).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([N:11]1[C:19]2[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[CH2:9][CH3:10])(=O)=O.[CH3:32]O[Na]>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:8]([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)([CH2:9][CH3:10])[CH2:7][CH2:6][O:5][CH3:32])=[CH:26][CH:27]=1
Reactant: CCC(CCOS(C)(=O)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CO[Na]
Solvent: CO
Product: CCC(CCOC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 40 °C

Procedure:
To a mixture of 3-(4-chlorophenyl)-3-(4-(methylsulfonamido)-1H-indol-1-yl)pentyl methanesulfonate (10 mg, 0.02 mmol), as described in Example 40 Step I, in methanol (2 mL) was added CH3ONa (21 mg, 0.4 mmol) at room temperature. Then the mixture was heated to 40° C. for 2 h. The solution was quenched with saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by Prep-HPLC (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title compound as a white solid. LC/MS m/z=421.1[M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][Mg]Br>C1COCC1.CN1C(=O)CCC1>[Cl:16][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[C:2]([CH3:17])[N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cc(NC(=O)OC(C)(C)C)cc(Cl)n1
Reaction time: 0.25 h

Procedure:
tert-butyl (2,6-dichloropyridin-4-yl)carbamate (460 mg, 1.75 mmol) from Step 1 of this example, ferric acetylacetonate (309 mg, 0.87 mmol) was added in THF:NMP (1:1, 17.4 mL), methyl magnesium bromide (3 mL [3M], 8.9 mmol) was added drop-wise and stirred for 15 min. The reaction was quenched with ice-cold ammonia chloride saturated solution (100 mL), extracted with ethyl acetate (100 mL), second wash with brine (50 mL). The organic phase was dried by magnesium sulfate and filtered through silica gel (1 inch deep), concentrated and purified by column chromatography through a 50 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 10% ethyl acetate/hexanes to give the title compounds as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:17][C:18]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: N#Cc1ccc(CC(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)Cc1ccc(C#N)cc1

Procedure:
4.8 g (3 mmol) of (4-cyano-phenyl)-acetic acid are suspended in 25 ml of methylene chloride and refluxed for 15 minutes after the addition of 5 ml thionyl chloride. The solvent is distilled off, the residue dissolved in 100 ml chlorobenzene and after the addition of 4.9 g (2.5 mmol) of methyl 2-amino-5-nitro-benzoate refluxed for 2 hours. Three-quarters of the volume of chlorobenzene is distilled off and the residue is combined with ether/petroleum ether. The crystalline product is suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:6][N:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:19][C:18](F)([F:20])[C:17](F)([F:22])[CH2:16]3)=[CH:13][CH:14]=2)[CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.O>C(OCC)(=O)C>[F:20][C:18]1[C:17]([F:22])=[CH:16][N:15]([C:12]2[N:11]=[CH:10][C:9]([N:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:35])[C:5]([C:24]4[N:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:27]=[CH:26][CH:25]=4)=[N:6]3)=[CH:14][CH:13]=2)[CH:19]=1
Reactant: COc1cn(-c2ccc(N3CC(F)(F)C(F)(F)C3)nc2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)nc2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
A mixture of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-3-yl]pyridazin-4(1H)-one (367 mg), cesium carbonate (1.23 g) and DMF (4 ml) was stirred at 100° C. for 4 hr. To the reaction mixture were added water and ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized from DMSO-ethanol to give the title compound (146 mg) as whitish yellow crystals.
Reaction SMILES: [CH3:1][S:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=O.[CH2:14]([Cl:16])Cl>C(N(CC)CC)C>[C:7]([CH:6]1[CH:9]([C:10]2[CH:11]=[CH:12][CH:5]=[CH:4][C:14]=2[Cl:16])[N:3]([S:2][CH3:1])[C:7]1=[O:8])(=[O:8])[CH:6]=[CH2:5]
Reactant: ClCCl
Reactant: CSN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Product: C=CC(=O)C1C(=O)N(SC)C1c1ccccc1Cl
Yield: 88 %

Procedure:
To a solution of 25 (4.00 g, 11.2 mmol) in 40 ml of CH3CN in an ice-water bath was added ceric ammonium nitrate (18.39 g, 33.54 mmol) in 40 ml of water. The resultant mixture was stirred for 5 min, and 20 ml of water was added. The solution was extracted (3×5 ml) with EtOAc. The combined organic layers were washed with 5% NaHSO3, 5% NaHCO3, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to yield 2.14 g (76%) of 26 as a crude brown oil. Without further purification, compound 26 (2.00 g, 8.0 mmol) was dissolved in 30 ml of dry CH2Cl2 and N-(methylthio)phthalimide (2.30 g, 11.9 mmol) and 3-5 drops of triethylamine were added. The resultant mixture was refluxed for overnight. The solvent was removed under reduced pressure to yield a brown solid. The brown solid was redissolved in CH2Cl2, and washed with 1% NaOH. The organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure to yield a brown semi-solid, which was purified by column chromatography on silica gel with gradient elution (1:9 then 1:4 EtOAc:hexanes) to yield 2.00 g (88%) of 27 as a white solid. 1H NMR (250 MHz) δ 7.35-7.26 (m, 4H), 6.20 (d, J=5.1 Hz, 1H), 6.06 (dd, J=16.7, 1.9 Hz, 1H), 5.78 (dd, J=16.7, 10.4 Hz, 1H), 5.68 (dd, J=10.4, 1.9 Hz, 1H), 5.54 (d, J=10.4 Hz, 1H), 2.51 (s, 3H). 13C NMR (63 MHz) δ 168.3, 163.4, 156.6, 134.3, 132.6, 129.8, 128.6, 126.6, 126.3, 62.1, 21.9.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][CH2:32][CH:31](NC)[CH2:30]4)=[CH:25][CH:24]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.C[CH2:37][N:38](C(C)C)C(C)C>ClCCl>[CH:7]1([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][CH2:32][CH:31]([CH2:37][NH:38][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH2:30]4)=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CNC1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)cc3)cc2)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)NCC1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)cc3)cc2)C1
Reaction time: 12 h

Procedure:
Ethyl chloroformate (8 μl) was added dropwise to a solution of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea (20 mg) and Hünig's base (10 mg) in dichloromethane (3 ml). After 12 hours, the reaction mixture was concentrated and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 466.59 (C26H34N4O4); MS (ESI): 467 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]C=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:20](O)(=O)[CH3:21].[ClH:24].P(=O)(O)(O)O>O>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:20]=1[CH2:21][Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccc3ccccc23)cc1
Reactant: CC(=O)O
Reactant: Cl
Agent: C=O
Agent: O=P(O)(O)O
Solvent: O
Product: ClCc1ccc2ccccc2c1Cc1ccccc1
Temperature: 90 °C
Yield: 32 %

Procedure:
1-Benzylnaphthalene (3.0 g; 13.7 mMol), as prepared above, formaldehyde (1.0 g; 35.7 mMol), glacial acetic acid (4.3 g; 71.7 mMol), concentrated hydrochloric acid (6.5 mL) and 85% phosphoric acid (4.3 mL) were combined and heated in an oil bath maintained at 90° C. for 4.5 hr. The reaction mixture was cooled, a small amount of water was added, and extraction was carried out with diethyl ether. The combined organic extractions were washed with sodium carbonate (10% aqueous), and brine; then dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue subjected to medium pressure chromatography on silica gel eluting with hexane. The product (1.18 g; 32% yield) was isolated as a colorless oil which subsequently crystallized.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23].OS(O)(=O)=O.[N:30]([O-])=O.[Na+]>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:13]=[N:30][CH:11]=[C:10]2[OH:12])=[O:24]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(C(C)=O)c(N)c(F)c1Nc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(O)cnnc2c(F)c1Nc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 5-acetyl-4-amino-2-(4-bromo-2-fluorophenylamino)-3-fluorobenzoic acid methyl ester (1.00 equiv.) in THF and conc H2SO4 (4.00 equiv.) is added a solution of NaNO2 (1.50 equiv.) in water at 0° C. The reaction mixture is warmed to 60° C. and stirred for 3 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer is washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[CH2:9][N:8]([CH:16]([CH3:19])[CH2:17][CH3:18])[CH2:7][CH2:6]2.[H][H]>C(OCC)(=O)C.[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[NH2:13])[CH2:9][N:8]([CH:16]([CH3:19])[CH2:17][CH3:18])[CH2:7][CH2:6]2
Reactant: CCC(C)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C)N1CCc2cc(OC)c(N)cc2C1
Yield: 96.1 %

Procedure:
6-(methyloxy)-2-(1-methylpropyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.23 g, 0.87 mmol) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 6-(methyloxy)-2-(1-methylpropyl)-1,2,3,4-tetrahydro-7-isoquinolinamine (196 mg, 96%). 1H NMR (400 MHz, CDCl3) δ ppm 0.90 (t, J=7.4 Hz, 3 H), 1.02 (d, J=6.6 Hz, 3 H), 1.28-1.40 (m, 1 H), 1.59-1.69 (m, 1 H), 2.56-2.75 (m, 5 H), 3.48-3.67 (m, 4 H), 3.77 (s, 3 H), 6.35 (s, 1 H), 6.47 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=3)[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C=O.[C:32]([O-])([O-])=[O:33].[K+].[K+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)([CH2:32][OH:33])[CH2:10][OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(C2(c3cccc(Br)c3)CO2)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCC(CO)(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
A mixture of the crude 2,2-bis(3-bromophenyl)oxirane (7.4 g, 20.90 mmol) and p-toluenesulfonic acid monohydrate (360 mg, 2.1 mmol) in toluene (25 mL) was stirred at 95° C. for 1 h. The solution was washed with aq NaHCO3 (10 mL) and water (20 mL). The organic layer was dried and concentrated. The residue was dissolved in EtOH (20 mL). To the solution was added formaldehyde (15.56 mL, 209 mmol, 37% aqueous solution) and K2CO3 (1.44 g, 10.45 mmol). The mixture was stirred at 85° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (60 mL×4). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether˜Petroleum ether: EtOAc=2:1) to afford 4.6 g of 2,2-bis(3-bromophenyl)propane-1,3-diol (11.9 mmol, 57% after two steps). LC/MS: [M−18+1]=368. 1HNMR (CDCl3), 400 MHz: δ 2.53 (brs, 2H), 2.41 (s, 4H), 7.09-7.20 (m, 4H), 7.36-7.40 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.C1C[O:31]CC1>C(OCC)(=O)C>[OH:31][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(Cl)nccc12
Reactant: C1CCOC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(O)nccc12
Temperature: 90 °C

Procedure:
N-(1-chloroisoquinolin-5-yl)-N′-[4-(trifluoromethyl)benzyl]urea (Example 69; 47 mg, 0.12 mmol) was added to a mixture of 3N HCl (aq. 5 ml) and THF (1 ml). The mixture was heated at 90° C. for 20 hours, then 5N HCl (aq. 2 ml) was added and the reaction heated at 90° C. for a further 20 hours. After cooling to room temperature, ethyl acetate (20 ml) was added and the layers separated (some solid was suspended in the organic layer). The organic phase was washed with saturated aqueous NaHCO3 (20 ml), then evaporated. The residue was triturated in refluxing isopropyl alcohol (5 ml), then cooled to room temperature. The white solid was collected by filtration and washed with isopropyl alcohol (2×1 ml) to give the title compound (22 mg). m/z (ES+) 362 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:17]1[CH:18]=[N:19][CH:20]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=C(O)c1ccncc1NCc1ccc(Cl)c(Cl)c1
Yield: 37 %

Procedure:
The title compound was prepared in 37% yield from 3,4-dichlorobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.48 (br s, 1H), 8.10 (s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.57-7.65 (m, 3H), 7.35 (dd, 1H, J=8.3, 1.9 Hz), 4.59 (s, 2H). [M+H] calc'd for C13H10Cl2N2O2, 297, 299. found 297, 299.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([N+:19]([O-])=O)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][N:14]=1.C(O)(=O)C>C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([NH2:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: Cc1nc2c(-c3ccc(Cl)cc3Cl)nccn2c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2c(-c3ccc(Cl)cc3Cl)nccn2c1N
Reaction time: 1 h
Yield: 35.4 %

Procedure:
8-(2,4-Dichlorophenyl)-2-methyl-3-nitroimidazo[1,2-a]pyrazine (25 mg, 0.077 mmol) was dissolved in ethanol (0.36 mL), then acetic acid (0.5 mL) and iron powders (22 mg) were added thereto, and the mixture was stirred for 1 hour by heating under reflux. After the reaction mixture was allowed to cool, the solvent was evaporated and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=4:1) to give 8-(2,4-dichlorophenyl)-2-methylimidazo[1,2-a]pyrazin-3-amine (8 mg) as yellow crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:33])=[CH:30][C:29]=1[C:37]([F:38])([F:39])[F:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OCc2ccccc2)c(C(F)(F)F)c1)N1CSc2ccccc21
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (282 mg) and 37% formalin (0.19 mL) in the same manner as in Example 1 was dissolved in chloroform (6 mL), and triethylamine (0.62 mL) and 4-benzyloxy-3-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at mom temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (356 mg) as a pale yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.C(N(CC)CC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CN(C=O)C>[F:10][C:4]1[CH:3]=[C:2](/[CH:20]=[CH:19]/[C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(F)c(O)c(F)c1
Temperature: 110 °C
Reaction time: 21 h
Yield: 68.1 %

Procedure:
In a 350-mL pressure-tube was added 4-bromo-2,6-difluorophenol (23.82 g, 0.11 mol), triethylamine (55 mL, 0.39 mol), ethyl acrylate (34.27 g, 0.34 mol), DMF (50 mL), palladium (II) acetate (1.29 g, 5.75 mmol), and tri-o-tolyphosphine (2.34 g, 7.6 mmol) under N2. The mixture was sealed in the glass tube and was stirred at 110° C. overnight (21 hours). The reaction was cooled to room temperature and EtOAc (150 mL) was added. The mixture was stirred for 30 minutes, filtered through celite and rinsed with EtOAc (100 mL×3). The filtrate was acidified with 2N HCl to pH ˜2. The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL×2). The organic layers were combined and washed with water ((100 mL×2), brine (100 mL) and dried over sodium sulfate. After filtration, heptane (200 mL) was added and the solution was concentrated in vacuo. The resulting precipitate was filtered, washed with heptane (50 mL×2) and dried to afford the desired product (10) (17.09 g) as a light-yellow solid. The mother liquor was concentrated to obtain additional desired product (4.29 g) as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.50 (d, J=15.9 Hz, 1H), 7.09 (d, J=8.3 Hz, 2H), 6.29 (d, J=15.9 Hz, 1H), 5.54 (br, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:15][O:14][C:13]([CH:16]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])=[CH:25][CH:24]=2)[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[N:12]=[C:13]([CH:16]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:32])[CH3:33])=[CH:27][CH:28]=2)[CH2:17][C:18]([O:20][CH3:21])=[O:19])[O:14][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)C1=NC(C(=O)OCc2ccccc2)CO1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Product: COC(=O)CC(Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)c1nc(C(=O)OCc2ccccc2)co1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of methyl (±)-3-[4-(benzyloxycarbonyl)-1,3-oxazolin-2-yl]-4-[4-(triisopropylsilyloxy)phenyl]butanoate (4.45 g, 8.03 mmole) in CH2Cl2 (40 mL) at 0° C. was added DBU (1.4 mL, 9.64 mmole), followed by bromotrichloromethane (0.95 mL, 9.64 mmole). The mixture was allowed to warm to RT as the bath warmed. After 18 hr the mixture was concentrated. The residue was chromatographed on silica gel (20% EtOAc/hexanes) to give the title compound (2.23 g, 50%) as a clear oil: MS (ES) m/e 552 (M+H)+.