Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Fc1cccc(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Fc1cccc(NCc2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To 2,6-difluoro-pyridine (20, 3.80 g, 33.0 mmol) in 20.0 mL ofN-methylpyrrolidone, 4-chloro-benzylamine (21, 5.6 mL, 46.0 mmol) and N,N-diisopropylethylamine (10.0 mL, 57.4 mmol) were added. The reaction was stirred at 90° C. overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 25% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum, and the resulting material was washed with ethyl acetate/hexane to provide the desired compound as a white solid (22, 5.30 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:25](Cl)(Cl)=[O:26]>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][N:10]([C:25]([NH:10][CH2:9][CH:8]=[CH2:5])=[O:26])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Fc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCNC(=O)N1CC(c2ccc(F)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-N-(diphenylnethyl)azetidine (17) (0.67 g) in dichloromethane (5 mL) at 0° C. was added dropwise a solution of 20% phosgene in toluene (2.5 mL). The mixture was stirred for 90 minutes then concentrated in vacuo. To the concentrate was added dichloromethafe (5 mL) and to this solution at 0° C. was added, dropwise, with stirring, allylamine (0.5 mL). The mixture was stirred for 18 hrs at room temperature, diluted with dichloromethane (20 mL), washed (water. brine), dried (Na2SO4) and concentrated in vacuo. Recrystallisation from diisopropyl ether gave 3-(4-(fluorophenyl)-N-(2-propeny)azetidine-1-carboxamide (18) (0.30 g), m.p. 119-120° C. (diisopropyl ether). Found: C, 66.61; H, 6.37; N, 11.74. C13H15FN2O requires C, 66.65; H. 6.45; N, 11.95%.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([CH2:25][C:26]([CH2:29][CH2:30]I)([F:28])[F:27])([C:9]([C:12]([C:15]([C:18]([C:21]([F:24])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7]>>[C:6]([CH2:25][C:26]([CH2:29][CH2:30][OH:2])([F:28])[F:27])([C:9]([C:12]([C:15]([C:18]([C:21]([F:24])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7]
Reactant: O=S(=O)(O)O
Reactant: FC(F)(CCI)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: OCCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Ethylene (15 g) was introduced to an autoclave charged with C6F13CH2CF2I (170 g) and d-(+)-limonene (1 g), and then the reactor was heated at 240° C. for 12 h. Product was isolated by vacuum distillation to provide C6F13CH2CF2CH2CH2I. Fuming sulfuric acid (129 mL) was added slowly to C6F13CH2CF2CH2CH2I (112 g). The mixture was stirred at 60° C. for 1.5 h. Then the reaction was quenched with ice-cold 1.5 wt % aqueous Na2SO3 and heated at 95° C. for 0.5 h. The bottom layer was separated and washed with 10% sodium acetate aqueous solution and distilled to provide C6F13CH2CF2CH2CH2OH.: mp 38° C.
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9]=2[CH:22]=1>O1CCCC1>[NH2:1][C:13]1[CH2:12][N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:9]2[CH:22]=[C:5]([Cl:4])[CH:6]=[CH:7][C:8]=2[N:14]=1
Reactant: S=C1CN=C(c2ccccn2)c2cc(Cl)ccc2N1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC1=Nc2ccc(Cl)cc2C(c2ccccn2)=NC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
300 ml of 25% aqueous ammonia solution and 100 ml of methanol were added to a solution of 18.5 g of 7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione in 800 ml of tetrahydrofuran. The mixture was stirred at room temperature for 17 h., with the solution which formed being concentrated to about 200 ml in a vacuum. The crystals were filtered off, washed with water and dried, stirred in 25 ml of dioxan at 100° C., cooled and filtered off. There were obtained 16.3 g of 2-amino-7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine which was used without further purification for the next step. A sample recrystallized from dioxan melted at 213-215° C.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCCCCC#CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC#CCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Thereto, 2-octadecyn-1-ol (510 mg) was dissolved in dichloromethane (20 mL) and carbontetrabromide (960 mg) and triphenylphosphine (660 mg) were added at 0° C., followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate-99:1→95:5) to obtain the title compound (630 mg) having the following physical property values.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:36])[NH:10][N:9]=2)[CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:36])[NH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
In a vial, 1-(5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (56 mg, 0.098 mmol) was dissolved in DCM (984 μl, 0.098 mmol) and then TFA (37.9 μl, 0.492 mmol) was added. After 30 min at rt, LCMS showed product. The reaction was quenched with saturated aqueous NaHCO3 (1 mL). White solid precipitated out of the solution and was filtered off with the aid of water. The solid was washed with 3 mL of water and dried to afford 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (32 mg, 72.4% yield). m/z (ESI) 449.0 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[C:16]1([S:22][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1F
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Sc1ccccc1
Temperature: 80 °C
Yield: 71.3 %

Procedure:
2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and thiophenol (17.1 mmol) were dissolved in 10.0 mL DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 80° C. for 24 hrs. After cooling, the mixture was added to 50 mL of saturated potassium carbonate solution and extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 9:1 petroleum ether 60-80 and dichloromethane as eluent to give a yellow oil (2.46 g, 71%). 1H NMR (200 MHz, CDCl3): δ 7.07 (dd, J1=7.8, J2=1.2, 1H), 7.27-7.45 (m, 7H), 7.87 (dd, J1=7.3, J2=2.0, 1H), 10.37 (s, 1H) ppm.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9](N)[CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:5]([OH:7])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: Nc1cc(N)cc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Diaminobenzoic acid (4.3 mg, 0.028 mmol, 0.40 equiv.) was dissolved in 10 mL of anhydrous DMF. To the solution was added H-PEOZ-p-NPC 10K (1.00 gm, 0.0692 mmol, 1.0 equiv.; an active NHS ester can also be used), followed by addition of N,N-Diisopropylethyl amine (DIPEA, 36.2 μL, 0.208 mmol, 3.0 equiv.). Following overnight stirring at room temperature, the solution was evaporated to dryness by rotary evaporation under vacuum at 50° C. The residue was dissolved in dichloromethane, and then precipitated by addition into diethyl ether with stirring. The precipitate was filtered and dried under vacuum. The molecular weight of H-PEOZ2-benzoic acid was verified by GPC.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([N:27]2[CH2:32][CH2:31][NH:30][C@@H:29]([CH3:33])[CH2:28]2)=[N:19][N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([N:27]2[CH2:32][CH2:31][N:30]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)[C@@H:29]([CH3:33])[CH2:28]2)=[N:19][N:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Product: C[C@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1c1ccc(C#N)cn1
Yield: 23 %

Procedure:
Following the above procedure, 6-chloro-nicotinonitrile (50 mg, 0.36 mmol, 1.2 eq) and 1-benzyl-4-((S)-3-methyl-piperazin-1-yl)-phthalazine (100 mg, 0.31 mmol, 1.0 eq) afford the title compound as a white solid (30 mg, 23% yield).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([N:7]([CH2:14][CH2:15][OH:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].Cl.[OH-].[Na+]>O.C1C=CC=CC=1>[CH2:5]([N:7]([CH2:14][CH2:15][OH:16])[C:8]1[CH:9]=[CH:10][C:11]([N:1]=[O:3])=[CH:12][CH:13]=1)[CH3:6]
Reactant: CCN(CCO)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCN(CCO)c1ccc(N=O)cc1
Yield: 59.6 %

Procedure:
A solution was prepared by dissolving 18.5 g (0.26 mol) of sodium nitrite, of a purity of 97%, in 30 ml of water. This solution was added dropwise to a solution composed of 41.3 g (0.25 mol) of N-ethyl-N-2-hydroxyethylaniline, 200 g of water and 105 ml of conc HCl with stirring at a temperature between 5° and 10° C. for one-half hour. After stirring the solution obtained at a temperature between 10° and 20° C. for one hour, the solution was neutralized to pH 8 with a 15% aqueous solution of sodium hydroxide. 100 ml of benzene was added to the neutralized solution with stirring. After standing, the organic phase of the solution was separated. The benzene of the organic phase obtained was removed under reduced pressure. 28.9 g of N-ethyl-N-2-hydroxyethyl-p-nitrosoaniline which is a dark brown colored viscous liquid was obtained. The yield was 59.6%.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:43])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:35]([S:43][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CCCCCCCCS
Product: CCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1

Procedure:
Using the procedure of Example 6 with 5-chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole and octyl mercaptan, the title compound is prepared.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[F:1][C:2]1[C:3]([NH:17][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(COc2ncc(F)c(N)n2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(COc2ncc(F)c(NS(=O)(=O)c3ccc(C)cc3)n2)cc1
Reaction time: 0.08 h
Yield: 45.2 %

Procedure:
To a magnetically stirred solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-amine (200 mg, 0.857 mmol) in sure seal THF (4 mL) was added 1M lithium bis(trimethylsilyl)amide (LiHMDS) solution in THF (1.28 mL, 1.28 mmol) causing a slight exotherm. After stirring for 5 min, p-toluenesulfonyl chloride (196.65 mg, 1.028 mmol) was added and after 10 min the orange solution turned light yellow and turbid. The mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo and the resulting viscous gold oil was diluted in EtOAc (50 mL), poured into a separatory funnel containing EtOAc (75 mL) and washed with 1N HCl aqueous solution (4×75 mL) followed by brine solution (1×100 mL). The organic extract was dried over Na2SO4, filtered, and evaporated. To the crude oil material was added distilled water (150 mL) and the resulting mixture was vigorously stirred at room temperature over 72 h forming an off-white solid. The solid was collected by vacuum filtration and air dried for 1 hour followed by drying under vacuum for 24 hours. The white solid was then suspended in Et2O (2 mL) for 1 h, then collected by vacuum filtration washed with Et2O (1×1 mL), and air dried for 1 h to yield N-(5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-yl)-4-methylbenzenesulfonamide (150 mg, 45.2% yield) as a white solid: mp 120-122° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, J=2.9 Hz, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.23 Hz, 2H), 7.16 (d, J=7.92 Hz, 2H), 5.08 (s, 2H), 2.33 (s, 3H), 2.29 (s, 3H) MS (ESI) m/z 386.3 (M−H)−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1>CN(C=O)C>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:9]([CH:7]=[O:8])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])[N:23]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C=O)cccc1Oc1nc(OC)cc(OC)n1
Temperature: 0 °C
Yield: 56.1 %

Procedure:
13.8 g of potassium carbonate and 50 ml of DMF were placed in a 200 ml eggplant type flask, and 11.1 g of methyl 2-formyl-6-hydroxybenzoate and 14.6 g of 4,6-dimethoxy-2-methanesulfonylpyrimidine were added thereto with stirring. The mixture was stirred at 80° C. for 1 hour, and the resultant liquor was poured into an ice water after cooling. An oily product thus precipitated was extracted with ethyl acetate, and was dried with magnesium sulfate anhydride. Ethyl acetate was distilled off under reduced pressure, and the residue thus obtained was purified by column chromatography to obtain 11.0 g of the aimed compound (melting point=91° to 93° C.) at a yield of 52%.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1Cl
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1Cl
Yield: 91.8 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11(v), ethyl 2-chloro-3-(2-chlorophenyl)-3-oxopropanoate (1.0 g, 3.9 mmol) produced in the above and 2-propanol (20 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (475 mg, 91%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[CH3:33][N:34]=[C:35]=[S:36]>C1COCC1>[CH3:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)[C:2]=1[NH:1][C:35]([NH:34][CH3:33])=[S:36]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)Nc1c(C)cc(C)nc1Nc1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (300 mg, 0.66 mmol), methylisothiocyanate (56 μl, 0.86 mmol), and THF (6 ml) was stirred at room temperature for 3 days. The solvent was removed to give N-{[(2-{4-[(4,6-dimethyl-{[(methylamino)carbonothioyl]amino}-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide [MS (ESI) m/z: 527 ([M+H]+), 525 ([M−H]−)]. This was dissolved with MeCN (4 ml) and treated with MeI (54 μl) at 0° C. for 20 hours. After concentration under reduced pressure, the residue was purified by preparative TLC (EtOAc/EtOH=20/1) to afford 170 mg (52%) of the title compounds.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH:22][CH3:23])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:22]([CH3:23])[C:32](=[O:34])[CH3:33])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(NC)nc3C)c(C)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)C(C)=O)nc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
60 mg of N-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methylamine (0.17 mmol) and 86 mg of triethylamine (0.85 mmol) are dissolved in 3.0 ml of CH2Cl2 and 16 mg of acetylchloride (0.2 mmol) is added. The vial is capped with a Teflon® lined cap and shaken at room temperature for 2 h. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1 and Hexane:AcOEt=2:1) to give 33.8 mg of the title compound. Yield 50%: mass spectrum (m/e): 386 (M+1); 1H-NMR (CDCl3): 7.03 (s, 1H), 3.79 (s, 3H), 3.47 (m, 1H), 2.54 (s, 3H), 2.47 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 1.86 (m, 4H), 0.91 (t, 6H, J=7.4 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Mg].O(CC)CC.[CH3:15][N:16]1[C:20]2[C:21]([CH:25]=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1>O>[F:8][C:4]1[CH:3]=[C:2]([CH:25]([C:21]2[C:20]3[N:16]([CH3:15])[N:17]=[N:18][C:19]=3[CH:24]=[CH:23][CH:22]=2)[OH:26])[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)c1
Reactant: Cn1nnc2cccc(C=O)c21
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: Cn1nnc2cccc(C(O)c3cccc(F)c3)c21
Yield: 95.2 %

Procedure:
To a stirred and refluxed Grignard complex, previously prepared starting from 8.15 parts of 1-bromo-3-fluorobenzene, 1.2 parts of magnesium and a small amount of 1,1'-oxybisethane was added a solution of 5 parts of 1-methyl-1H-benzotriazole-7-carboxaldehyde in 80 parts of 1,1'-oxybisethane. After stirring for 2 hours at room temperature, the reaction mixture was poured into 300 parts of water. The product was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was stirred for 15 minutes in 100 parts of water and 13 parts of petroleum ether at room temperature. The product was filtered off and dried, yielding 7.6 parts (95.2%) of α-(3-fluorophenyl)-1-methyl-1H-benzotriazole-7-methanol; mp. 152° C. (int. 19).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[S:18][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: NC(N)=Nc1nc(-c2cccc(CCl)n2)cs1
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(N)=Nc1nc(-c2cccc(CSc3nc4ccccc4[nH]3)n2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
A mixture of 4-(6-chloromethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.1 g), 2-mercaptobenzimidazole (0.74 g) and potassium carbonate (0.68 g) in N,N-dimethylformamide (20 ml) was stirred for 15 hours at ambient temperature. The reaction mixture was added water and extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated to give 4-[6-(benzimidazol-2-yl)thiomethylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (1.22 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:14][C:15]1[C:16](F)=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>CCO>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=1[NH:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Solvent: CCO
Product: CCOC(=O)c1cc(CC)sc1Nc1c(Cl)cccc1[N+](=O)[O-]

Procedure:
Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate and 3-chloro-2-fluoronitrobenzene, m.p. 67°-70° C. (EtOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[CH3:36][O:37][CH2:38][C:39](O)=O>>[CH3:36][O:37][CH2:38][C:39]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: COCC(=O)O
Product: COCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following the procedures for 178, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and methoxyacetic acid were reacted to give 161. LCMS: M+H+=535.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.13 (d, 1H), 7.71 (d, 1H), 7.32 (m, 2H), 5.08 (s, 2H), 4.26 (s, br, 4H), 4.02 (s, 1H), 3.83 (s, 3H), 3.78 (m, 4H), 3.73 (s, 2H), 3.27 (s, 3H), 2.90 (m, 2H), 2.00 (m, 2H), 1.65 (m, 2H), 1.22 (m, 3H), 1.02 (s, 6H)