Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([O-])(=O)C.[K+].[N:23](Cl)=[O:24]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N:23]([N:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:7][CH:8]=1)[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[O:24]
Reactant: O=NCl
Reactant: CCCCCc1ccc(NC(=O)C(C)C)cn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCc1ccc(N(N=O)C(=O)C(C)C)cn1

Procedure:
24.8 g of N-(2-pentyl-5-pyridyl)-isobutyramide (boiling point 167°-171°/0.27 bar; obtainable by reacting 2-chloro-5-nitropyridine with Na-2-butylmalonic acid diethyl ester to give 2-(5-nitro-2-pyridyl)-2-butylmalonic acid diethyl ester, hydrolysis and decarboxylation to give 2-pentyl-5-nitropyridine, hydrogenation on 10% strength Pd-C in methanol at 40°-50° under 1 bar to give 2-pentyl-5-aminopyridine and acylation with isobutyric anhydride) are dissolved in a mixture of 110 ml of acetic acid and 50 ml of acetic anhydride, 49 g of anhydrous potassium acetate are added, and a solution of 6.9 g of nitrosyl chloride in 27 ml of acetic anhydride is then added at 0°. N-nitroso-N-(2-pentyl-5-pyridyl)-isobutyramide is formed as the intermediate and is not isolated. After the mixture has been stirred at 0° for 15 minutes, it is poured onto ice and extracted five times with 140 ml of thiophene each time. The phases are separated, the organic phase is kept at 0° and made into a slurry with 22 g of K2CO3 and 35 g of Na2SO4, and the slurry is decanted. The organic phase is warmed at 50° and, when the evolution of gas has ended, boiled for 2 hours, and evaporated and the residue is separated on silica gel using toluene. 2-(2-Pentyl-5-pyridyl)-thiophene, boiling point 180°-185°/0.013 bar, c.p. -45° is obtained; a little 3-(2-pentyl-5-pyridyl)-thiophene, boiling point 170°-180°/0.015 bar, c.p. -80°, is also formed.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:20])=[CH:8][C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.I[CH3:22]>CN(C=O)C>[CH3:22][O:3][CH2:4][C:5]1[O:6][C:7]([CH3:20])=[CH:8][C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1oc(C)cc(=O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a suspension of sodium hydride (0.48 g, 20 mmol, 2 eq.) in 30 ml dry DMF was added 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (2.46 g, 10 mmol, 1 eq.) followed by dropwise addition of iodomethane (4.26 g, 30 mmol, 3 eq.) at 0° C. under nitrogen. After stirring for 30 minutes at this temperature, the reaction mixture was poured into ice cold water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic fractions were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to yield the crude product (2.6 g,˜100%) as an orange oil which solidified on cooling. Recrystallisation from CH2Cl2/Pet. ether 40/60 afforded the pure product (2.35 g, 90%) as a white crystalline solid. m.p. 30-32° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>Br.ClCCl>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cccc(C2CCCN2CCN2CCOCC2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(C2CCCN2CCN2CCOCC2)c1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
1-[2-(4-Morpholinyl)ethyl]-2-(3-methoxyphenyl)pyrrolidine (3.6 g) in 48% hydrobromic acid (50 ml) was heated at 100° C. for 8.5 hrs. The reaction mixture was cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution and diluted with dichloromethane. The layers were separated and the aqueous phase was extracted with dichloromethane (3 times). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, ether). The appropriate fractions were collected and concentrated to give 2.0 g (59%) of 3-{1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinyl}phenol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:23]#[N:24])=[C:6]1[S:25][CH2:26][CH3:27].[CH2:28]([NH2:30])[CH3:29].[ClH:31]>O1CCOCC1>[ClH:31].[CH2:28]([NH:30][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:23]#[N:24])=[C:6]1[S:25][CH2:26][CH3:27])[CH3:29]
Reactant: CCN
Reactant: CCSC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1CCCBr
Agent: Cl
Solvent: C1COCCO1
Product: CCNCCCN1C(=O)C(c2ccccc2)(c2ccccc2)C(C#N)=C1SCC

Procedure:
8.8 g 1-(3-bromopropyl)-2-ethylthio-5-oxo-4,4-diphenyl-2-pyrroline-3-carbonitrile and 3.0 g ethylamine are stirred for two days at room temperature in 300 ml dioxan. The solvent is removed on a Rotavapor and the residue partitioned between chloroform and dil. sodium bicarbonate solution. The organic phase is evaporated and the residue chromatographed on silica gel with toluene/ethanol 10+1 as elution agent. The base so obtained is converted in ethanolic solution into the corresponding hydrochloride by mixing with ethereal hydrochloric acid solution. One obtains 1.0 g of colorless crystals of mp 173°-174° C., decomp.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1.CCCCCC>C1COCC1>[F:37][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.5 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1.50 g, 5.81 mmol) in THF (25.0 mL) was cooled to −78° C. followed by drop wise addition of LDA (1.80 M in THF, 6.50 mL, 11.62 mmol) and the mixture stirred at the same temperature for 45 min followed by addition of N-fluorobenzenesulphonimide (3.60 g, 11.62 mmol) at −78° C. The temperature of the reaction was slowly raised to rt and left to stir for 5-6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 2% EtOAc:hexane to obtain the product as an orange viscous liquid (1.0 g, 63% yield). MS: 276.27 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[NH:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)(O)[O-].[Na+].Br[CH2:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[CH2:29][C:30]([OH:35])([C:31]([F:34])([F:33])[F:32])[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1Cl

Procedure:
To a mixture of 3-chloro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (10 mmol) and sodium bicarbonate (20 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is added. After heating the reaction mixture at 70°-75° C. for 20 hours, the solvent is removed. The residue is redissolved in methylene chloride and washed with water. The organic fractions are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture is chromatographed (silica gel, toluene/ethyl acetate, 7/3) to give 2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>>[S:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: C1CSCCN1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(N2CCSCC2)cc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and thiomorpholine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15]([NH2:17])=[S:16])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15]2[S:16][C:27]3[CH2:28][CH2:29][CH2:30][CH:25]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=4)[C:26]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: COc1cc(NC(N)=S)ccc1-c1cnco1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1cnco1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A suspension of (3-methoxy-4-oxazol-5-yl-phenyl)-thiourea (74.8 mg, 0.3 mmol) and of 2-bromo-6-phenyl-cyclohexanone (75.9 mg, 0.3 mmol, preparation: WO9404487) in ethanol (4 mL) was heated over night to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (101 mg, 83%) as an off-white foam. MS ISP (m/e): 404.5 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.29 (s, 1H), 8.31 (s, 1H), 7.66 (s, 1H), 7.50 (d, 1H), 7.46-7.51 (m, 3H), 7.09-7.31 (m, 3H), 6.83 (s, 1H), 4.00 (m, 1H), 3.46 (s, 3H), 2.73 (m, 2H), 2.12 (m, 1H), 1.70-1.94 (m, 3H).
Reaction SMILES: [O:1]=[C:2]([C:10]([F:13])([F:12])[F:11])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([C:10]([F:11])([F:12])[F:13])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)C(O)C(F)(F)F

Procedure:
To a solution of ethyl 3-keto-2-methyl-4,4,4-trifluorobutanoate (20.1 g, 0.10 moles) in 250 ml of absolute ethanol, cooled in an ice bath, was added sodium borohydride (1.0 g, 0.25 moles) in portions with stirring. The cooling bath was removed and the reaction stirred at room temperature for 30 minutes. Acetone (5 ml) was added to quench any remaining sodium borohydride and the solvents removed by distillation at atmospheric pressure using a Vigreaux column. The residue was diluted with 200 ml of methylene chloride and poured into a separatory funnel containing 75 ml of a 1:1:1 mixture of saturated ammonium chloride:brine:water. The layers were separated and the aqueous phase extracted with methylene chloride (3×25 ml). The combined organic phase and methylene chloride extracts were dried over magnesium sulfate, filtered and distilled at atmospheric pressure to remove the solvents. The residue was then distilled at reduced pressure (20 mmHg) using a Vigreaux column to give ethyl 3-hydroxy-2-methyl-4,4,4-trifluorobutanoate, bp 78-84° C., 20 mmHg.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:31]3[C:27](=[O:37])[C:28]4=[CH:36][CH:35]=[CH:34][CH:33]=[C:29]4[C:30]3=[O:32])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(CN3C(=O)c4ccccc4C3=O)c(=O)n(CC3CC3)n2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (220 mg, 0.57 mmol) in N,N-dimethylformamide (5 mL) was added potassium phthalimide (160 mg, 0.87 mmol), and the mixture was stirred at 80° C. for 2 hours. Water (30 mL) was added to the reaction mixture. After stirring under cooling over ice water, precipitated crystals were collected by filtration, dried in air, and recrystallized from chloroform-hexane to yield the title compound as colorless needles (202 mg, 81.0%).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[CH:26])=[N:23][CH:24]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:2]2[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:4][CH:3]=2)=[N:23][CH:24]=1
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1ccc(Br)cn1
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(Br)cn3)cc2)CC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-ethyl]-4-methyl-piperidine (345 mg, 1.00 mmol) and 5-bromo-2-ethynyl-pyridine (83 mg, 0.39 mmol).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:8]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=12.C(O)(=O)C.[O-:18][C:19]#[N:20].[K+].[OH-].[NH4+]>O>[N:1]1[CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[C:10]([NH:13][C:19]([NH2:20])=[O:18])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=12
Reactant: Nc1ccc2sc3nccn3c2c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc2c(c1)N1CCN=C1S2
Reaction time: 8 h

Procedure:
To a stirred mixture of 3 parts of imidazo[2,1-b]benzothiazol-6-amine, 16 parts of acetic acid and 32 parts of water is added dropwise a solution of 1.54 parts of potassium cyanate in 32 parts of water (slightly exothermic reaction). Upon completion, stirring is continued overnight at room temperature. The reaction mixture is alkalized with ammonium hydroxide. Upon stirring, the product is precipitated. It is filtered off and dried, yielding 3 parts of N-(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)urea; mp. +300° C. Example XXXVII
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH:22]=1)[C:19](O)=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH:22]=1
Reactant: Fc1cccc(-c2cccs2)c1
Reactant: Cc1ccc(Br)cc1C(=O)O
Product: Cc1ccc(Br)cc1Cc1ccc(-c2cccc(F)c2)s1

Procedure:
2-(3-Fluorophenyl)thiophene obtained in Reference Example 75-(1) and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were treated in a manner similar to Reference Example 5 to give the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8](=[N:10][OH:11])[NH2:9])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH:18](OCC)(OCC)OCC>B(F)(F)F.CCOCC>[Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]2[N:9]=[CH:18][O:11][N:10]=2)=[CH:4][C:3]=1[C:14]([F:15])([F:16])[F:17]
Reactant: NC(/C=C/c1ccc(Cl)c(C(F)(F)F)c1)=NO
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Product: FC(F)(F)c1cc(/C=C/c2ncon2)ccc1Cl
Reaction time: 2 h
Yield: 71 %

Procedure:
5.2 g (0.02 mol) of (E)-4-chloro-3-trifluoromethyl-cinnamamide oxime are introduced into 50 ml of triethyl orthoformate and 2 drops of boron trifluoride etherate are added at room temperature. The mixture is then stirred for 2 hours at reflux temperature and the entire batch is concentrated in vacuo. The residue is taken up in 100 ml of methylene chloride and washed in succession with 100 ml of 2N hydrochloric acid, saturated sodium carbonate solution and water. The organic phase is dried over sodium sulphate and the solvent is subsequently distilled off. 3.9 g (71.0 % of theory) of (E)-3-(4-chloro-3-trifluoromethyl-styryl)-1,2,4-oxadiazole are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.F[B-](F)(F)F.O=[N+:18]=O>ClCCl>[CH3:8][C:6]1[C:7]([NH2:18])=[C:2]([CH3:1])[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]=1[CH3:9]
Reactant: O=[N+]=O
Reactant: Cc1cc(C)c(C)c(C)c1C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1c(C)c(C)c(N)c(C)c1C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of pentamethylbenzene (5 g, 33.8 mmol) in dichloromethane (250 mL) at 0° C. was quickly added nitronium tetrafluoroborate (5 g). The mixture was stirred for 4 h before it was quenched with cold water. The organic layer was concentrated and the residue was reduced (Example 14, procedure C) to give pentamethylaniline in 52% yield.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][C:41]1[CH:42]=[C:43]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([S:47]([NH2:50])(=[O:48])=[O:49])[CH:42]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccc1C1CCCCC1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-cyclohexyl benzoic acid (20 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) in DMF (1 mL) was stirred at room temperature 3 min. To this solution was added 3-amino-benzenesulfonamide (17 mg, 0.10 mmol) and triethylamine (14 μL, 0.10 mmol). The reaction was stirred at room temperature for 16 h and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-cyclohexyl-N-(3-(aminosulfonyl)phenyl)benzamide. LC/MS: m/z 359.1 (M+H)+ at 3.85 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Si:21]([CH3:25])([CH3:24])(Cl)[Cl:22]>CCOCC>[Cl:22][Si:21]([CH3:25])([CH3:24])[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(c2ccccc2)Cc2ccccc21
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(Cl)C1C(c2ccccc2)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of 0.96 g (5.0 mmol) of 2-phenylindene in 30 mL of Et2O was treated at −70° C. with 3.13 mL (5.0 mmol) of a 1.6 M solution of n-BuLi. After the addition, the mixture was allowed to warm to room temperature and stirred for 50 min. Then it was cooled again to −70° C. and treated with a solution of 0.65 g (5.0 mmol) of Me2SiCl2 in 10 mL of ether. When the addition was completed, the mixture was allowed to reach room temperature and stirred overnight. The resulting reaction mixture was filtered to remove LiCl and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:5]2[O:4][C:3]([CH2:2][N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:2][C:3]4[O:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=1
Reactant: COc1cc2nc(CCl)oc2c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2nc(CN3CCCN(Cc4nc5cc(OC)c(OC)c(OC)c5o4)CC3)oc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxybenzoxazole (152 mg) and homopiperazine (28 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[N:15]=[CH:16][C:11]([CH2:9][CH3:10])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CCc1cnc(Cl)nc1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cnc(Oc2ccc(I)cc2)nc1

Procedure:
In the same manner as in Reference Example 6, 4-iodophenol (220 mg) and 5-ethyl-2-chloropyrimidine (0.121 ml) were reacted in the presence of potassium carbonate (415 mg) to obtain 2-(4-iodophenoxy)-5-ethylpyrimidine (256 mg).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C:10]3=[C:9]([C:23]([O:25]C)=[O:24])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].C(O)C>C1COCC1>[C:19]([O:18][C:16]([N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]([C:23]([OH:25])=[O:24])=[C:10]2[CH2:15]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 7-tert-butyl 1-methyl 3-phenyl-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (3A) (1.6 g, 4.47 mmol) in THF (50 mL) was added aqueous LiOH (0.7 g in 18.5 mL water) and ethanol (13 mL). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified to pH 4 with 1N aqueous HCl solution. The aqueous suspension was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give Intermediate 3B as a white solid in quantitative yield. The material was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 1.52 (s, 9H), 3.81 (m, 2H), 4:14 (m, 2H), 5.02 (s, 2H), 7.46-7.51 (m, 3H), 7.62-7.68 (m, 2H). LCMS (+ESI) m/z 344.23 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:26][CH3:27])=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:24]=[C:25]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:20]=[CH:21][C:22]=1[O:28][CH3:29]
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: COc1ccc(Br)cc1OC
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3[nH]ccc23)cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (10 g, 41.1 mmol), and 4-bromoveratrole (8.93 g, 41.1 mmol) in THF (140 mL) were added Palladium catalyst Pd(PPh3)4 (1.43 g, 1.23 mmol) and the freshly prepared sodium hydroxide solution (5.08 g in 58 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 80° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 7.47 g (72%) of 4-(3,4-dimethoxy-phenyl)-1H-indole.