Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of ethyl 2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (145 mg, 0.29 mmol) in dioxane (1.5 mL) was added 1 M LiOH aqueous solution (1.16 mL, 1.161 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid. The solid precipitate was collected to give the title compound (125 mg). LCMS m/z=471.8 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.55-1.65 (m, 1H), 2.00-2.10 (m, 1H), 2.17-2.26 (m, 2H), 2.65 (dd, J=−16.1, 8.5 Hz, 1H), 3.00 (dd, J=16.1, 5.4 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.94 (m, 1H), 4.14-4.22 (m, 1H), 5.19 (s, 2H), 6.23 (s, 1H), 6.91 (dd, J=8.8, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.19 (d, J=−8.7 Hz, 1H), 7.83 (s, 1H), 7.94 (s, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:25])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]1=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:36][O:37][CH3:38]>ClCCl>[Si:1]([O:8][CH2:9][CH:10]([O:25][CH2:36][O:37][CH3:38])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]1=[O:24])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)cnc2ccc(OC)cc21
Reaction time: 2 h
Yield: 38.5 %

Procedure:
1-(3-{[Tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-7-methoxyquinoxalin-2(1H)-one (2.0 g, 5.49 mmol) was dissolved in dichloromethane (30 ml). N,N-Diisopropylethylamine (3.35 ml, 19.22 mmol) and chloromethylmethyl ether (1.04 ml, 13.73 mmol) were added to this solution under cooling on ice, and the mixture was stirred for 2 hours. N,N-Diisopropylethylamine (3.35 ml, 19.22 mmol) and chloromethylmethyl ether (1.04 ml, 13.73 mmol) were further added to the reaction solution and stirred for 14 hours, and the reaction solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 863 mg (39%) of the title compound in the form of a yellow oily product.
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][O:7][N:8]=[C:9]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH:13]([OH:18])[CH:12]([N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:22])[CH3:21])[CH:11]=[C:10]1[CH3:30].[H-].[Na+].CI>C(O)(=O)C>[CH3:6][O:7][N:8]=[C:9]1[CH2:15][C:14]([CH3:16])([CH3:17])[CH:13]([O:18][CH3:2])[CH:12]([N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:22])[CH3:21])[CH:11]=[C:10]1[CH3:30]
Reactant: CON=C1CC(C)(C)C(O)C(N(Cc2ccccc2)C(C)=O)C=C1C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)O
Product: CON=C1CC(C)(C)C(OC)C(N(Cc2ccccc2)C(C)=O)C=C1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of tetrahydrofuran (40 ml) containing the 4-(N-acetylbenzylamino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime obtained in step 2 (9.5 g, 27.6 millimoles) there was gradually added 55% sodium hydride (3.6 g) while cooling on ice. After then adding methyl iodide (7.8 g, 55.2 millimoles) and stirring for 30 minutes, the mixture was returned to room temperature and stirring was continued for one hour. The reaction solution was poured into ice water (100 ml) containing acetic acid (1 ml), and subjected to extraction with benzene. After washing the benzene solution with water, it was dried over anhydrous magnesium sulfate. The benzene was distilled off, and the resulting residue was subjected to silica gel column chromatography with benzene-ethyl acetate (9:1) as the eluent, to obtain 8.51 g (86%) of 4-(N-acetylbenzylamino)-5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14]>CO>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:14][CH2:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:9]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: NCCCc1ccc(O)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)CCNCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a methanol solution (25 mL) of 4-(3-aminopropyl)phenol (1.83 g), tert-butyl acrylate (1.7 mL) was added dropwise thereto at room temperature, followed by stirring at room temperature overnight. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=3:1) to give the title compound (1.55 g) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17](=[O:19])[NH2:18])[CH:14]=[CH:13][C:12]=2[O:20]C)=[O:9])=[C:6]([NH:22][C@H:23]([C:25]2[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29](=[O:37])[C:28]3=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]3[N:26]=2)[CH3:24])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17](=[O:19])[NH2:18])[CH:14]=[CH:13][C:12]=2[OH:20])=[O:9])=[C:6]([NH:22][C@H:23]([C:25]2[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29](=[O:37])[C:28]3=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]3[N:26]=2)[CH3:24])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(C(N)=O)cc1NC(=O)c1c(N)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3cc(C(N)=O)ccc3O)n(-c3ccccc3)c(=O)c12
Yield: 5 %

Procedure:
(S)-4-Amino-N-(5-carbamoyl-2-methoxyphenyl)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxamide (400 mg, 49% purity, 0.35 mmol) was treated with boron tribromide (1M in dichloromethane, 1.1 ml, 1 mmol) in dichloromethane (8 ml) according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 10 mg (5% yield) as a solid. Purity 90%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1/[CH:8]=[N:9]/[NH:10][CH3:11].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[N:10]([CH3:11])[N:9]=[CH:8][C:7]=12
Reactant: CN/N=C/c1c(Br)cncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(Br)cncc21
Yield: 44.2 %

Procedure:
In analogy to GP 2, 5.34 g of N-[1-(3,5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-N′-methyl-hydrazine (Intermediate 1.1, 18.23 mmol, 1 eq) were dissolved in 163 mL dry THF, treated at rt with 994 mg 50-60% sodium hydride (22.78 mmol, 1.2 eq) and subsequently refluxed for 90 min. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo. The precipitate was filtered and subsequently triturated with diisopropylether to yield 1.71 g of the desired product. Flash column chromatography of the mother liquor provided a second batch of the analytically pure product.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][C@@H:9]([CH3:10])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:10][C@@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: [H][H]
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@H]2[C@@H]1OC[C@@H]2O
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1 h

Procedure:
Methanol (1.25 mL) was added dropwise to a mixture of 10% palladium on charcoal (20 mg) and bicyclic alcohol (108) (49 mg, 0.177 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1 hour then filtered through celite in vacuo. The filter cake was washed with ethanol (10 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with diethyl ether (3×3 mL) to obtain the crude (3R,3aR,6R,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (107) which was used without further purification.
Reaction SMILES: CC[O:3][C:4]([C@H:6]1[CH2:11][N:10]([CH2:12][CH2:13][CH:14]=[C:15]([C:22]2[S:26][CH:25]=[CH:24][C:23]=2[CH3:27])[C:16]2[S:20][CH:19]=[CH:18][C:17]=2[CH3:21])[CH2:9][CH2:8][CH2:7]1)=[O:5].Cl>O>[CH3:27][C:23]1[CH:24]=[CH:25][S:26][C:22]=1[C:15]([C:16]1[S:20][CH:19]=[CH:18][C:17]=1[CH3:21])=[CH:14][CH2:13][CH2:12][N:10]1[CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCC=C(c2sccc2C)c2sccc2C)C1
Agent: Cl
Solvent: O
Product: Cc1ccsc1C(=CCCN1CCC[C@@H](C(=O)O)C1)c1sccc1C
Temperature: 57.5 °C
Yield: 87.1 %

Procedure:
To a 1 L flask, 50 g of tiagabine ethyl ester, 750 ml of water and 11 g of conc. hydrochloric acid were charged. The mixture was heated to reflux for 2 hours and then ethanol/water, a total of 400 ml, was distilled off over a period of 4 hours. The remaining solution was stirred under reflux overnight. It was cooled to 55-60° C. and then an additional 37.5 g of conc. hydrochloric acid was added over a period of 5 min. The solution was cooled to 50-52° C. and was stirred at this temperature for 18 hours. The resulting precipitate was collected by filtration and was washed with 20 ml of water. The product was dried under vacuum at room temperature to give 40.5 g of Tiagabine, hydrochloride.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:30]3[N:29]=[C:27](N)[NH:26][C:24](=O)[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:31])[C@@H:16]1[OH:32])(OP(OP(O)(O)=O)(O)=O)(=[O:3])[OH:2].[Na+].[Cl-].[Mg+2].[Cl-].[Cl-].C[C@@H](N)CC1NC=[N:43]C=1>C1N(CCO)CCN(CCS(O)(=O)=O)C1>[CH:27]1[N:26]=[C:24]([NH2:43])[C:23]2[N:22]=[CH:21][N:20]([C@@H:18]3[O:19][C@@H:15]4[CH2:14][O:13][P:1]([OH:2])([O:32][C@H:16]4[C@H:17]3[OH:31])=[O:3])[C:30]=2[N:29]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: C[C@@H](N)Cc1cnc[nH]1
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: [Cl-]
Agent: [Mg+2]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Reaction time: 0.25 h

Procedure:
Antagonist activity of selected compounds was tested for inhibition of [35S] GTP γ [S] binding to H3R membranes in the presence of agonists. Assays were run at room temperature in 20 mM HEPES, 100 mM NaCl, 5 mM MgCl2 and 10 uM GDP at pH 7.4 in a final volume of 200 ul in 96-well Costar plates. Membranes isolated from H3R8-expressing HEK293 cell line (20 ug/well) and GDP were added to each well in a volume of 50 μl assay buffer. Antagonist was then added to the wells in a volume of 50 μl assay buffer and incubated for 15 minutes at room temperature. Agonist R(−)alpha methylhistamine (RBI) at either a dose response from 1×10−10 to 1A1-5 M or fixed concentration of 100 nM were then added to the wells in a volume of 50 μl assay buffer and incubated for 5 minutes at room temperature. GTP γ [35S] was added to each well in a volume of 50 μl assay buffer at a final concentration of 200 pM, followed by the addition of 50 μl of 20 mg/ml WGA coated SPA beads (Amersham). Plates were counted in Wallac Trilux 1450 Microbeta scintillation counter for 1 minute. Compounds that inhibited more than 50% of the specific binding of radioactive ligand to the receptor were serially diluted to determine a K[i](nM). The results are given below for the indicated compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4]>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH:15]=[O:16])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(/C=C/C=C/CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: CC(C)Oc1ccc(/C=C/C=C/C=O)cc1
Yield: 99 %

Procedure:
According to the same manner as that described in Reference Example 20, (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienol was oxidized with activated manganese dioxide to give (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienal as an oil (yield: 99%).
Reaction SMILES: [Cl:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([S:37]([OH:40])(=[O:39])=[O:38])[C:13]([CH:16]=[CH:17][C:18]3[C:19]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27](Cl)[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1.[NH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:48]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:47][CH:46]=[CH:45][C:44]=2[C:43]=1[S:56]([OH:59])(=[O:58])=[O:57]>>[Cl:1][N:2]1[N:7]=[C:6]([NH:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[S:52]([OH:55])(=[O:54])=[O:53])[C:43]=2[S:56]([OH:59])(=[O:58])=[O:57])[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([S:37]([OH:40])(=[O:39])=[O:38])[C:13]([CH:16]=[CH:17][C:18]3[C:19]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27]([NH:41][C:42]5[CH:51]=[CH:50][C:49]6[C:44](=[CH:45][CH:46]=[CH:47][C:48]=6[S:52]([OH:55])(=[O:54])=[O:53])[C:43]=5[S:56]([OH:59])(=[O:58])=[O:57])[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1
Reactant: O=S(=O)(O)c1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1S(=O)(=O)O
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O
Product: O=S(=O)(O)c1cc(NC2=CC(Nc3ccc4c(S(=O)(=O)O)cccc4c3S(=O)(=O)O)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Nc3ccc4c(S(=O)(=O)O)cccc4c3S(=O)(=O)O)=NN(Cl)N2)cc1S(=O)(=O)O

Procedure:
4,4′-Bis-(2,4-dichlorotriazin-6-ylamino)-stilbene-2,2′-disulfonic acid was reacted with 2-aminonaphthalene-1,5-disulfonic acid in a similar manner to Example 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:14][N:13]=[C:12]([CH2:15][NH:16][CH3:17])[N:11]=1)=[O:8].CO.[CH3:23][C:24]1[C:28]([CH:29]=O)=[C:27]([CH3:31])[O:26][N:25]=1.C([BH3-])#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:23][C:24]1[C:28]([CH2:29][N:16]([CH2:15][C:12]2[N:11]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)=[O:8])[S:14][N:13]=2)[CH3:17])=[C:27]([CH3:31])[O:26][N:25]=1
Reactant: CNCc1nsc(NC(=O)NCc2cccc(F)c2)n1
Reactant: Cc1noc(C)c1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1noc(C)c1CN(C)Cc1nsc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 25 °C

Procedure:
1-(3-Fluoro-benzyl)-3-(3-methylaminomethyl-[1,2,4]thiadiazol-5-yl)-urea (Intermediate XXVII) was taken up in DCM and methanol with 3,5-Dimethyl-isoxazole-4-carbaldehyde (2 eq.) and acetic acid (several drops). Reaction was stirred for several hours at ambient temperature. Sodium cyanoborohydride (2 eq.) was added at once and the reaction was stirred overnight at ambient temperature. An additional equivalent of 3,5-Dimethyl-isoxazole-4-carbaldehyde and sodium cyanoborohydride (2 eq.) was added and stirred 4 more hours. Crude r×n mixture was loaded directly onto a silica plug and eluted with 10% saturated NH3/MeOH in DCM. Purified by column chromatography (silica, DCM, 0-10% MeOH saturated with NH3) to give the title compound. 1H NMR (400 MHz, DMSO): 11.45 (br s, 1H), 7.43-7.35 (m, 2H), 7.17-7.05 (m, 3H), 4.38 (d, 2H), 3.58 (s, 2H), 3.33 (s, 2H), 2.31 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: Br[C:2](Br)([F:4])[F:3].C(N(P(N(CC)CC)N(CC)CC)CC)C.[F:22][C:23]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][CH:32]([CH:35]3[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:24]=1[CH:46]1[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]1>C1COCC1>[F:22][C:23]1[CH:28]=[C:27]([CH:29]2[CH2:30][CH2:31][CH:32]([CH:35]3[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:37][CH2:36]3)[CH2:33][CH2:34]2)[CH:26]=[CH:25][C:24]=1[CH:46]1[CH2:47][CH2:48][C:49](=[C:2]([F:4])[F:3])[CH2:50][CH2:51]1
Reactant: FC(F)(Br)Br
Reactant: CCCCCC1CCC(C2CCC(c3ccc(C4CCC(=O)CC4)c(F)c3)CC2)CC1
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(c3ccc(C4CCC(=C(F)F)CC4)c(F)c3)CC2)CC1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Dibromodifluoromethane (16.2 g) and THF (30 ml) were put into a vessel under a nitrogen atmosphere and cooled to 10° C. Trisdiethylaminophosphine (38.2 g) in THF (50.0 ml) solution was added dropwise thereto and the stirring was continued for another 60 minutes. The compound (T-8) (16.5 g) in THF (400 ml) solution was then added dropwise in the temperature range of 20° C. to 35° C., and allowed to react overnight while the reaction mixture was coming to room temperature. The reaction mixture obtained was poured into ice-water (400 ml) and mixed. Organic and aqueous layers were separated by adding toluene (300 ml) and the aqueous layer was extracted with toluene. The organic layers combined were washed sequentially with water, 3N-hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and purified by means of column chromatography (silica gel; heptane/ethyl acetate), giving 4-[2-fluoro-4-(4′-pentyl-1,1′-bicyclohexane-4-yl)phenyl]difluoromethylenecyclohexane (T-9) (15.1 g). The yield based on the compound (T-8) was 85%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]3)=[O:16])[NH:12][C:9]2=[N:10][CH:11]=1.Cl.[CH3:26][C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:23][C:20]1([F:24])[CH2:21][CH2:22][N:17]([C:15]([C:13]2[NH:12][C:9]3=[N:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]4[CH2:29][CH2:30][CH2:31][C@@H:27]4[CH3:26])[CH:7]=[C:8]3[CH:14]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: O=C(c1cc2cc(OCCCCl)cnc2[nH]1)N1CCC(F)(F)CC1
Reactant: C[C@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1CCCOc1cnc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Yield: 57 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from [5-(3-chloro-propoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, (S)-2-methyl-pyrrolidine hydrochloride (commercially available) and potassium carbonate in acetonitrile to give the desired product as a colorless solid (57%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([NH2:19])[C:7]([NH2:18])=[CH:8][C:9]=1[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:20](=S)=[S:21].CC(O)=O>CCO.O>[Cl:3][C:4]1[C:9]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]2[NH:18][C:20](=[S:21])[NH:19][C:6]=2[CH:5]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(C#Cc2ccccc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: S=c1[nH]c2cc(Cl)c(C#Cc3ccccc3)cc2[nH]1
Temperature: 110 °C

Procedure:
A 2 mL Biotage™ microwave vial was charged with solid KOH (19.4 mg, 0.345 mmol), water (0.2 mL), a solution of compound 1-2 (55.8 mg, 0.230 mmol) in EtOH (1.2 mL) and carbon disulfide (69 uL, 1.2 mmol). The vial was capped and stirred at rt until KOH dissolved, and then heated in a microwave synthesizer (Biotage Initiator™) at 110° C. for 10 min. Contents of the vial were transferred to a 20 mL scintillation vial, diluted with water (8 mL) and acidified by the dropwise addition of 10% aqueous AcOH. The resulting suspension was centrifuged, the supernatant was decanted and the resulting brownish precipitate was washed with 10% aqueous AcOH (3 mL) and water (three times 3 mL). The precipitate was dissolved in EtOAc and passed through a short plug of neutral alumina. The EtOAc solution was evaporated to dryness in vacuo to give the crude product as brownish solid. LR-MS (API-ES): calculated for C15H9ClN2S 284.0, observed m/e 285.0 (M+H)+. (Rt 2.94 min). The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH:25]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])([CH3:27])[CH3:26].NC1C=CC(N2C3C(=C4C(=CC=3)C=NC=C4)NC(=O)CC2=O)=CC=1>>[CH:25]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:31])([CH3:27])[CH3:26]
Reactant: CC(C)c1ccccc1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2cnccc32)cc1
Product: CC(C)c1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 34.5 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.10 mmol) obtained in Example 1, (3), and 2-isopropylbenzoyl chloride (0.20 mmol), the title compound (16 mg, yield 35%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[CH3:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([N:38]=[C:39]=[O:40])[CH:37]=1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:39]([NH:38][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:31])[CH:37]=2)=[O:40])[CH:25]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: Cc1cccc(N=C=O)c1
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)Nc3cccc(C)c3)c2)c1

Procedure:
In a manner similar to that describe in Example 37, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 5-methylphenyl isocyanate were coupled. Purification of the crude reaction product gave the title compound as a white foam (78.8 mg).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:42]>C(#N)C>[Br:42][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)NCCc1c[nH]c2ccc(OCCCCO)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=O)NCCc1c[nH]c2ccc(OCCCCBr)cc12

Procedure:
3.92 g of the compound obtained in Step B are dissolved in 50 ml of acetonitrile, and then 5.31 g of triphenylphosphine and 6.71 g of carbon tetrabromide are added with stirring. After leaving at room temperature overnight, the acetonitrile is removed by evaporation in vacuo and the resulting residue is purified by chromatography over a column of silica gel (eluant: dichloromethane/methanol 96/4). Oil.