Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:23][NH:22][CH2:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
18 g (42 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate in 250 ml of dichloromethane are introduced into a round-bottomed flask and under a nitrogen stream, and 16 ml (208 mmol) of trifluoroacetic acid are added. The mixture is stirred at room temperature overnight and the reaction medium is hydrolysed with a saturated potassium carbonate solution. The mixture is extracted with dichloromethane, the organic phase decanted off, washed with water, dried over magnesium sulphate and evaporated off. The residue obtained is triturated in ethyl acetate and 14.4 g (78%) of the expected product are obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12.[CH3:25][S:26]SC>CCCCCC.O1CCCC1>[CH3:25][S:26][CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(C)=C21
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CSC)=C21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The starting material is prepared as follows: 36.4 ml of 2.5 M n-butyl lithium in hexane are added dropwise under nitrogen and at room temperature to the stirred suspension of 7.8 g of 1-methyl-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]-azepin-2-one in 70 ml of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 45 minutes and cooled in a dry ice-acetone bath. The solution of 5.45 ml of dimethyl disulfide in 60 ml of tetrahydrofuran is added dropwise and the mixture stirred with said cooling for 2 hours. It is quenched by the slow addition of 150 ml of water, the mixture is extracted with chloroform, the extract is dried and evaporated. The residue is crystallized from diethyl ether and recrystallized from ethyl acetate, to give the 1-methylthiomethyl-3,4,5,5a,6,7-hexahydro9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 182°-184°.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.Br[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][N:1]2[CH2:4][CH:3]([OH:5])[CH2:2]2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(CCBr)cc1OC
Reactant: OC1CNC1
Product: COc1ccc(CCN2CC(O)C2)cc1OC

Procedure:
In a manner similar to Preparation 73, react azetidin-3-ol with 1-bromo-2-(3,4-dimethoxyphenyl)ethane to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH:21]=O)[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:21][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH3:28])=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=2)[CH2:10][CH2:9]1)[CH3:16]
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: CCOc1ccc(C=O)cc1OCC
Product: CCOc1ccc(CNCCCN2CCN(CCCNCc3ccc(OCC)c(OCC)c3)CC2)cc1OCC
Yield: 80 %

Procedure:
The title compound was prepared by a similar way as in Preparation Example 1, except that 1,4-bis(3-aminopropyl)piperazine was used instead of trans-1,2-cyclohexane diamine and 3,4-diethoxybenzaldehyde was used instead of veratraldehyde.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[BH4-].[Na+].[OH-].[Na+].O1CCOCC1>C(O)C>[CH:1]1([CH:4]([OH:5])[C:6]2[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(C(=O)C2CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc(C(O)C2CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To ethyl 4-(cyclopropanecarbonyl)benzoate (400 mg, 1.83 mmol) in ethanol (10 mL) was added at room temperature NaBH4 (69 mg, 1.83 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture was then concentrated in vacuo and NaOH (1.5 g, 9.38 mmol) and dioxane (1.5 mL) were added and the reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was concentrated in vacuo to half the volume and pH was adjusted to 2 with 3 N HCl. The aqueous layer was extracted with ethyl acetate (3×10 mL), and the combined organics were washed with brine solution (5 mL), dried over MgSO4 and concentrated in vacuo to give 4-[cyclopropyl(hydroxy)methyl]benzoic acid (300 mg, 85%). ESI-MS m/z calc. 192.2. Found 193.5 (M+1)+; Retention time: 0.78 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.89 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 5.33 (d, J=4.4 Hz, 1H), 4.04 (dd, J=7.3, 4.3 Hz, 1H), 1.12-0.87 (m, 1H), 0.54-0.20 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([C:27]#[N:28])=[CH:16][N:15]=2)=[N:6]1.S(=O)(=O)(O)[OH:34]>>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([C:27]([NH2:28])=[O:34])=[CH:16][N:15]=2)=[N:6]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Product: NC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 5 °C
Reaction time: 24 h

Procedure:
20.7 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidine-5-carbonitrile (31-1, 0.049 mmol, 1 eq.) were added to ice bath cooled conc. sulfuric acid (1.84 mmol, 37.5 eq.) and stirred for five minutes at 5° C. and further 24 hours at room temperature. Ice was added to the suspension. The suspension was filtered off, washed with water and the filter cake was dried under vacuo at 50° C. to yield 23.0 mg (0.05 mmol, 106%) of the analytically pure target compound.
Reaction SMILES: [ClH:1].[NH2:2]N.C[N:5](/[CH:7]=[C:8]1/[CH:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]/1=O)C>C(O)C.C(O)(=O)C>[ClH:1].[CH3:15][C:12]1([CH3:16])[C:13]2[C:8](=[CH:7][NH:5][N:2]=2)[CH:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:11]1
Reactant: Cc1cc(C#N)ccc1C1CCC(C)(C)C(=O)/C1=C\N(C)C
Reactant: NN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C#N)ccc1C1CCC(C)(C)c2n[nH]cc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Hydrazine hydrochloride (0.14 g, 2 mmol) is added to 4-[(2Z)-2-(dimethylaminomethylene)-4,4-dimethyl-3-oxo-cyclohexyl]-3-methyl-benzonitrile (0.2 g, 0.67 mmol) in ethanol (30 mL), then acetic acid (two drops) is added to the mixture. After the addition is complete, the reaction mixture is stirred at 80° C. for 3 h. The mixture is cooled to room temperature and concentrated in vacuo. The residue is diluted with ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic phase is separated and the aqueous phase extracted with ethyl acetate (3×50 mL). The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (eluted with pet ether:EtOAc=2:1 to 1:1) to give the title compound. The product is added to HCl/ethyl acetate and concentrated in vacuo to give the HCl salt of the title compound (0.12 g, 67%). ES/MS 266 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH2:13][CH2:12]1>C(OCC)C.ClCCl>[CH3:10][N:11]1[CH2:12][CH2:13][CH:14]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16]1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C1CN(C)CCC1c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (3.5 ml, 1.4 molar equivalents) was stirred at −5 to −10° C. under nitrogen, and a solution of arecoline (0.78 g) in dichloromethane (4.0 ml) added over 15 minutes at −5° C. The clear solution was stirred at −5° C. for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans 1 ethyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 965 mg (77 %).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH:25]3[CH2:27][CH2:26]3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH:25]3[CH2:27][CH2:26]3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(C#CCO)cc2c1=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(CCCO)cc2c1=O
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of N-(4-chlorobenzyl)-1-cyclopropyl-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.17 g) from Example No. 25 in THF (3 mL) and methanol (3 mL) is added platinuim oxide (0.01 g). The mixture is placed under an atmosphere of hydrogen gas. After 1 hour, the mixture is filtered through Celite with THF:methanol washes. The filtrate is concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 4% methanol in dichloromethane. The product-containing fractions are concentrated under reduced pressure to afford 0.13 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].Cl[CH2:14]I.[NH4+].[Cl-].[OH-].[Na+]>C(OCC)C.O1CCCC1>[Cl:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=2[F:12])[CH2:14][O:4]1
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: ClCI
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(C2(CCl)CO2)c(F)c1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
To a stirred and cooled (−78° C.) mixture of 2-chloro-1(2,4-difluorophenyl)-1-ethanone (30 g), chloroiodomethane (56.4 g) and tetrahydrofuran 267 ml) was added dropwise a 6% solution of methyllithium-lithiumbromide complex in diethylether (215 ml). The reaction mixture was slowly warmed to room temperature and was then hydrolysed with NH4Cl. Aqueous NaOH was added and the mixture was stirred for 1 hour. The organic layer was separated, washed, dried, filtered and the solvent evaporated. The residue was purified over silica gel (eluent: hexane/CH3COOC2H5 98/2). The solvent of the desired fraction was evaporated, yielding 11 g (16.8%) of 2-(chloromethyl)-2-(2,4-difluorophenyl)oxirane (interm. 1).
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:24]=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C(C)=CC=CC=1.[C:37]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>O>[C:37]([C:41]1[CH:42]=[CH:43][C:44]([C:45]([C:24]2[N:16]3[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]4[CH:27]=[CH:28][C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:8][CH:9]=4)[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17]3)=[CH:26][CH:25]=2)=[O:46])=[CH:48][CH:49]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)cc1
Yield: 6.8 %

Procedure:
A mixture of 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 4 (1.85 g), dry xylene (25 mL) and 4-tert-butylbenzoylchloride (1.97 g) was refluxed overnight. The reaction mixture was poured into water, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and filtered through a short column of Magnesol®. After eluting with several additional volumes of dichloromethane, the combined eluate was refluxed with the gradual addition of hexane until crystallization was noted. Cooling and trituration provided the desired title product (0.18 g) as off-white crystals, m.p. 143–145° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2)[CH3:2].Cl.C([OH:24])C>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]=[CH:6][C:7]1[C:8](=[O:24])[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2)[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C=Cc1cc2cc(OC)ccc2nc1Cl
Agent: Cl
Product: CCOC(=O)C=Cc1cc2cc(OC)ccc2[nH]c1=O
Temperature: 0 °C
Reaction time: 21 h
Yield: 95 %

Procedure:
A suspension of 3-(2-chloro-6-methoxy-quinolin-3-yl)-acrylic acid ethyl ester (20.2 g, 69.2 mmol) in ethanol (175 mL) was treated with 12 N aqueous HCl and heated to reflux to form a solution. After 21 h, the resulting precipitate was cooled to 0° C. for 1 h. Vacuum filtration gave the title compound (18.0 g, 95% yield) as a yellow crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[S:16].[CH3:21]I>ClCCl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[S:16][CH3:21]
Reactant: CI
Reactant: COc1ccccc1CN1Cc2ccccc2NC1=S
Solvent: ClCCl
Product: COc1ccccc1CN1Cc2ccccc2N=C1SC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.0 g (10.55 mmol) 3-(2-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-thione was dissolved in 40 mL dichloromethane, 1.31 mL CH3I was added and stirred for approx. 12 hours at room temperature. The reaction mixture was evaporated until dry and the resulting residue was stirred with a mixture of n-pentane/diethyl ether; 3.1 g white solids.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].Br[CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>C(O)CO.[I-].[Na+]>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]2[O:6][CH2:11][CH2:12][O:9][C:4]=2[CH:3]=1
Reactant: BrCCBr
Reactant: Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: OCCO
Product: Cc1ccc2c(c1)OCCO2
Temperature: 130 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 4-methylcatechol (33.04 g, 266.1 mmol), 1,2-dibromoethane (100 g, 532.3 mmol), K2CO3 (75.4 g, 545.5 mmol) and sodium iodide (0.2 g, 1.33 mmol) in ethylene glycol (500 mL) was heated to 130° C. under nitrogen for five hours. The solution was allowed to cool to ambient temperature and stirred overnight. After the mixture was filtered through celite, the solution was diluted with brine (800 mL) and extracted with organic solvents (CH2Cl2/hexane/EtOAc: 1:3:1,3×500 mL). The organic layer was dried over Na2SO4, filtered and concentrated to provide a crude oil. Flash silica gel chromatography eluting with hexane (100%) gradient to ether/hexane (8:2) afforded the title intermediate as a colorless oil 20.0 g (50%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)[CH:10]=1)=[O:5])[CH3:2].[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:20][C:21]([F:29])([F:30])[C:22]1[CH:23]=[C:24]([NH:25][C:17]([C:15]2[N:16]=[C:12]([CH2:11][N:9]3[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]3)[S:13][CH:14]=2)=[O:19])[CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(C(=O)O)cs2)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1cnn(Cc2nc(C(=O)Nc3cccc(C(F)(F)F)c3)cs2)c1
Yield: 86.7 %

Procedure:
By a reaction in the same manner as in Reference Example 19 and using the compound (281 mg, 1.00 mmol) obtained in Example 4a and 3-(trifluoromethyl)aniline (0.149 mL, 1.20 mmol), the title compound (368 mg, 86%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:24]([CH3:25])[C:15]2=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]2[N:13]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:24]([CH3:25])[C:15]2=[N:16][CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=[C:14]2[N:13]=1)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(-c2ccccc2SC(C)(C)C)nc2cc(C(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2S(=O)C(C)(C)C)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a mixture of 2-(2-tert-butylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.87 g) and chloroform (12 ml), 3-chloroperbenzoic acid (purity: not less than 65%) (0.95 g) was added under ice-cooling, heated to room temperature, and stirred for 2 hours. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of 2-(2-tert-butylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as present Compound 16) and 0.52 g of 2-(2-tert-butylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 17).
Reaction SMILES: Cl.Br[C:3]1[C:4]([F:10])=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>O1CCOCC1.CCOC(C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:10][C:4]1[C:3]([CH:11]=[CH2:12])=[CH:8][N:7]=[C:6]([NH2:9])[CH:5]=1
Reactant: Nc1cc(F)c(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1cnc(N)cc1F
Temperature: 120 °C

Procedure:
5-Bromo-4-fluoro-pyridin-2-ylamine mono HCl salt (xvii) (368 mg, 1.62 mmol), tributyl(vinyl)stannane (0.52 mL, 1.78 mmol) and palladium tetrakis(triphenylphosphine) (19 mg, 0.016 mmol) in dioxane (6 mL) under argon were heated under microwave irradiation at 120° C. for 45 min. Were then added tributyl(vinyl)stannane (0.2 mL, 0.685 mmol) and palladium tetrakis(triphenylphosphine) (7 mg, 0.006 mmol) and the RM was placed under argon and heated once more under microwave irradiation at 120° C. for 45 min. The RM was diluted with EtOAc and washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by chromatography with hexane and EtOAc to yield the title product as a yellow solid (tR 1.76 min (conditions 8), MH+=139).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2([OH:26])[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[C:14]3[C:13](=[O:25])[O:12]2)[N:4]=1.[H-].[Na+:28]>C1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([C:11]([C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:14]=2[C:13]([O-:25])=[O:12])=[O:26])[N:6]=1.[Na+:28]
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4cccs4)ccnc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1cc(OC)nc(C(=O)c2nccc(-c3cccs3)c2C(=O)[O-])n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.4 %

Procedure:
0.4 g of 7-(4,6-dimethoxypyrimidin-2-yl)-4-(2-thienyl)-7-hydroxyfuro[3,4-b]pyridin-5(7H)one was dissolved in 100 ml of benzene, and 0.05 g of 60% sodium hydride was added thereto under cooling with ice. Then the resulting mixture was stirred at room temperature for one day, and the precipitated crystals were sufficiently washed with benzene to obtain 0.4 g (yield 97%) of the desired compound. m.p.: >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:33]=[CH:32][C:17]4[O:18][CH2:19][C:20]5[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=5[CH:22]([O:23][CH2:24][CH2:25][C:26]#[N:27])[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:33]=[CH:32][C:17]4[O:18][CH2:19][C:20]5[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=5[CH:22]([O:23][CH2:24][CH2:25][C:26]5[NH:40][N:39]=[N:38][N:27]=5)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CCCOC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: Clc1ccc2ccc(COc3ccc4c(c3)C(OCCc3nnn[nH]3)c3ccccc3CO4)nc2c1

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-(2-cyanoethoxy)-6,11-dihydrodibenz[b,e]oxepine and trimethyltin azide were used and reacted in the same manner as in Example 30 to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)([O-:3])=[O:2].Br[C:26]1[CH:31]=[C:30]([C:32](=[O:41])[CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:29]=[CH:28][N:27]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C([O-])([O-])=O.[Na+].[Na+].C(COC)OC.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][C:5]=1[C:28]1[CH:29]=[C:30]([C:32](=[O:41])[CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:31]=[CH:26][N:27]=1)([O-:3])=[O:2]
Reactant: O=C(CCc1ccccc1)c1ccnc(Br)c1
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2[N+](=O)[O-])OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Yield: 81.5 %

Procedure:
A solution of 200 mg of 1-(4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine 1.1e, 168 mg of 1-(2-bromopyridin-4-yl)-3-phenylpropan-1-one 5.1a, 12 mg of Pd(OAc)2, 58 mg of PPh3 in 1.25 mL of 2 N aqueous Na2CO3 solution and 3 mL of dimethoxyethane was refluxed for 4 h. The mixture was diluted with ethyl acetate and washed with water twice. The combined organic layer was dried over Na2SO4 and the solvent was evaporated. The residue was chromatographed on silica gel eluting with a gradient of 0% to 7% ethyl acetate in dichloromethane to give 196 mg of product.