Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].C([O-])(=O)C.[Na+].C(O)(=O)C>C(OCC)(=O)C.O>[C:1]1([C:7]2[C:15]([CH:16]=[C:24]3[S:18][C:19](=[S:20])[NH:21][C:22]3=[O:23])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 86.9 %

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (15.0 g), rhodanine (9.44 g), sodium acetate (16.6 g) and glacial acetic acid (90 ml) was refluxed for 10 hours. Water (200 ml) and ethyl acetate (90 ml) were added to the reaction mixture and the resulting precipitates were collected by filtration to give 5-(2-phenylpyrazolo[1,5-a]pyridine-3-yl)methylenerhodanine (cis and trans mixture) (19.8 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(N(CCCC)CCCC)CCC>O1CCOCC1>[Cl:18][C:4]1[N:3]=[C:2]([C:20]2[NH:19][CH:23]=[CH:22][N:21]=2)[C:11]2[C:6]([C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: c1c[nH]cn1
Reactant: Clc1nc(Cl)c2ccccc2c1-c1ccccc1
Solvent: C1COCCO1
Solvent: CCCCN(CCCC)CCCC
Product: Clc1nc(-c2ncc[nH]2)c2ccccc2c1-c1ccccc1

Procedure:
2.74 g (10 moles) of 1,3-dichloro-4-phenylisoquinoline, 1.02 g (15 mmoles) of imidazole and 2.7 g (15 mmoles) of tri-n-butylamine were heated for 18 hours in 5 ml of dioxane under reflux. Working was carried out as described under 1c.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5](=[O:15])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4](=[CH:19][N:20]([CH3:22])[CH3:21])[C:5](=[O:15])[CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CC(=O)C=Cc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: COC(=O)C(=CN(C)C)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
14.8 g. of 5-(4-chlorophenyl)-3-oxo-4-pentenoic acid methyl ester were dissolved in 100 ml. of benzene and treated with N,N-dimethylformamide dimethylacetal. The red-brown colored solution was stirred at 60° C. for 30 minutes, solvent and excess reagent were removed and there was obtained 5-(4-chlorophenyl)-2-(dimethylaminomethylene)-3-oxo-4-pentenoic acid methyl ester in the form of a red-brown oil which was further processed in this form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2=[N:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:22](=[O:23])[C:12]2=[CH:11]1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.CS(C)=O>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:21]1[C:22](=[O:23])[C:12]2=[CH:11][N:10]([CH2:9][C:3]3[CH:4]=[CH:5][C:6]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)=[CH:7][C:2]=3[F:1])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]2=[N:20]1
Reactant: O=c1c2cn(Cc3ccc(I)cc3F)c3ccccc3c-2nn1-c1ccccc1F
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3F)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-[(2-Fluoro-4-iodophenyl)methyl]-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazol[4,3-c]quinolin-3-one [(Example 187, Step 2), 68 mg, 0.13 mmol], pyrazole (18 mg, 0.26 mmol, 2 equiv) and copper(I) iodide (10 mg, 0.053 mmol, 0.4 equiv) were combined in a sealed tube, to which was added dimethylsulfoxide (1 mL), (±)-trans-N,N′-bismethyl-1,2-cyclohexane diamine (15 mg, 0.11 mmol, 0.8 equiv) and an aqueous (0.2 ml) solution of potassium phosphate (84 mg, 0.40 mmol, 3 equiv). The vessel was flushed with nitrogen, sealed and placed into a preheated oil bath at 100° C. for 1 hour. The mixture was cooled to ambient temperature, poured into water (15 mL) and extracted with chloroform (2×15 mL). The combined organic extracts were washed once with water (5 mL) and brine (5 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.09 (1H, s), 8.54 (1H, d, J=2.6 Hz), 8.21 (1H, dd, J=7.9, 1.5 Hz), 7.82 (1H, dd, J=11.9, 2.1 Hz), 7.73-7.73 (2H, m), 7.68-7.59 (3H, m), 7.55 (1H, t, J=7.6 Hz), 7.49-7.32 (4H, m), 6.56 (1H, dd, J=2.3, 2.0 Hz), 5.82 (2H s) ppm; high resolution mass spectrometry (ES+) m/z 454.1467 [(M+H)+; calculated for C26H18F2N5O: 454.1474].
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:10][C:5]=2[S:4][C:3]=1[C:21]([NH2:23])=[O:22].C1CCN2C(=NCCC2)CC1.C(N)(=[S:37])C>CN(C=O)C.Cl>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([SH:37])=[C:3]([C:21]([NH2:23])=[O:22])[S:4][C:5]=2[CH:10]=1
Reactant: CC(N)=S
Reactant: NC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: NC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1S
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 21.6 %

Procedure:
To a mixture of 3-chloro-6-((2,4-dichlorobenzyl)oxy)-1-benzothiophene-2-carboxamide (193.6 mg) in DMF (dry) (2.5 mL) were added DBU (0.225 mL) and thioacetamide (113 mg). The mixture was stirred at 80° C. for 5.5 h. After cooling, the mixture was diluted with 1N HCl and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The precipitate was washed with hexane and THF to give the title compound (41.6 mg).
Reaction SMILES: OC1C(C(CC)(C)C)=CC(C(CC)(C)C)=CC=1N=NC1C=CC=CC=1[N+]([O-])=O.[OH:29][C:30]1[C:35]([CH:36]([CH3:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34][C:33]([CH3:44])=[CH:32][C:31]=1[N:45]=[N:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[N+:53]([O-])=O>>[OH:29][C:30]1[C:35]([CH:36]([CH3:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34][C:33]([CH3:44])=[CH:32][C:31]=1[N:45]1[N:53]=[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]2=[N:46]1
Reactant: Cc1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)c2ccccc2)c1
Agent: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Product: Cc1cc(C(C)c2ccccc2)c(O)c(-n2nc3ccccc3n2)c1

Procedure:
When in Example 1, the 2'hydroxy-3',5'-di-tert-amyl-2-nitroazobenzene is replaced by an equivalent amount of 2'-hydroxy-3'-(α-methylbenzyl)-5'-methyl-2-nitroazobenzene, the product 2-(2-hydroxy-3-(α-methylbenzyl)-5-methylphenyl)-2H-benzotriazole is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13](Cl)(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][C:3]=1[F:18].[CH3:19][NH:20][CH3:21]>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13]([N:20]([CH3:21])[CH3:19])(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][C:3]=1[F:18]
Reactant: CNC
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2cc(F)c(Cl)cc21
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cn(C)c2cc(Cl)c(F)cc2c1=O
Reaction time: 70 h

Procedure:
7-Chloro-6-fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (8.73 g) was added to a stirred solution of dimethylamine in ethanol (33%; 170 ml) at ambient temperature. The mixture was stirred for 70 hours and then evaporated to dryness. The residue was stirred with water (50 ml) for 30 minutes. The solid product was collected, dried and crystallised from industrial methylated spirit to give the novel compound 7-chloro-6-fluoro-1,N,N-trimethyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 219°-221° (dec).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[SH:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:31][CH3:32])[N:4]=[C:3]([CH2:2][S:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1)[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: CCCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
A mixture of propyl 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.3 g), 2-mercapto-1-methylimidazole (821 mg), potassium carbonate (1.08 g) and N,N-dimethylformamide (60 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (7:3, v/v), propyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2- [(1-methylimidazol-2-yl)thiomethyl]quinoline-3-carboxylate (1.77 g, 51%) was obtained and recrystallized from acetone/isopropyl ether.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:42]([N:44]=[C:45]=NCCCN(C)C)C.O1CCCC1.CNC>CN(C)C=O.CCCCCC.C(OCC)(=O)C.CO.O>[CH3:42][N:44]([CH3:45])[C:27](=[O:28])[CH2:26][CH:23]1[S:22][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:20][CH:19]=3)=[N:25][CH2:24]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)ccc3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.3 %

Procedure:
To a solution of [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (80 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg), and 2M dimethylamine tetrahydrofuran solution (0.35 mL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio) and crystallized from acetonitrile to give the title compound (112 mg, yield 70%) as white crystals.
Reaction SMILES: Br.Br.Br[CH2:4][C:5]1[C:6]([NH2:14])=[N:7][C:8]([CH2:11][CH2:12][CH3:13])=[N:9][CH:10]=1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:28][CH2:27][N:26]([CH2:4][C:5]3[C:6]([NH2:14])=[N:7][C:8]([CH2:11][CH2:12][CH3:13])=[N:9][CH:10]=3)[CH2:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: CCCc1ncc(CBr)c(N)n1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCc1ncc(CN2CC=C(c3ccc(F)cc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
A suspension of 7.0 g (0.020 mol) of 5-bromomethyl-2-propyl-pyrimidin-4-ylamine dihydrobromide, 4.2 g (0.020 mol) of 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 8.0 g (0.060 mol) of dry potassium carbonate in 60 ml of dimethylformamide was stirred at room temperature for 18 hours. The mixture was suction filtered, the filter cake was washed with dichloromethane, the filtrate was completely freed from the solvents and the residue was recrystallized twice from ethyl acetate/cyclohexane and then from hot ethanol. 1.4 g (21%) of 5-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-2-propyl-pyrimidin-4-ylamine were obtained as white crystals; m.p. 142°-145°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:27])[C:16]=2[N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cccn2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)c(Cl)c2-n2cccn2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A 25 mL scintillation vial was charged with 4-tert-butyl-N-(4-chloro-2-pyrazol-1-yl-phenyl)-benzenesulfonamide (synthesized according to general procedure D, 78 mg, 0.2 mmol), N-chlorosuccinimide (67 mg, 0.5 mmol), benzoyl peroxide (2.4 mg, 0.01 mmol), and carbon tetrachloride (4 mL). The vial was sealed and stirred for 18 hours at 80° C. The resultant solution was partitioned between ethyl acetate and water and the combined organics were washed with 1 N HCl, saturated sodium bicarbonate, and brine; dried over magnesium sulfate; filtered; and concentrated in vacuo. The crude product was subsequently purified by flash column chromatography (10-100% ethyl acetate in hexanes) followed by preparative HPLC (10-90% gradient of MeCN:water) to afford the title compound as a white solid: MS (ES) M+H expected 424.1, found 424.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1.[O-:12][C:13]#[N:14].[Na+]>O>[NH:2]([CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1)[C:13]([NH2:14])=[O:12]
Reactant: NCc1csc2cncn12
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1csc2cncn12
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 14.8 %

Procedure:
A 1 ml portion of ice-cooled water and 0.5 ml of 5N hydrochloric acid were added to a mixture of 200 mg of 3-aminomethylimidazo[5,1-b]thiazole and 0.5 g of ice, and the mixture was then stirred at 80° C. for 5 minutes. To this solution, 254 mg of sodium cyanate was added, followed by stirring at the same temperature for 1 hour. After cooled to room temperature, the reaction solution was washed once with diethyl ether. Further, potassium carbonate was added to the separated aqueous layer to alkalify the same, and methanol was further added thereto. The solution was sufficiently stirred, and then filtered to remove impurities therefrom. The resulting filtrate was concentrated under reduced pressure, and then allowed to stand at 0° C. overnight. Afterward, the precipitated crystal was collected by filtration to obtain 38 mg of 3-ureidomethylimidazo[5,1-b]thiazole. Furthermore, the mother liquor from which the crystal was collected by the filtration was purified by a column chromatograph of Diaion HP-20 Resin to obtain 49 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[CH3:19][CH:20]([N:22]1[C:26]([NH2:27])=[CH:25][CH:24]=[N:23]1)[CH3:21]>C1C=CC=CC=1>[CH3:19][CH:20]([N:22]1[C:26]2[N:27]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:25]=2[CH:24]=[N:23]1)[CH3:21]
Reactant: CC(C)n1nccc1N
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc2c1cnn2C(C)C
Temperature: 62 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate (600 mg, 2.397 mmol) in benzene (5 mL) was added 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and the reaction mixture was stirred at 62° C. overnight. The mixture was concentrated in vacuo and the residue was dissolved into acetic acid (3 mL). The solution was stirred at reflux for 1 h and concentrated in vacuo. The residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give 530 mg (65%) of product. LCMS E-S (M+H)=340.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.57 (m, 3H), 1.61-1.71 (m, 6H), 3.88-3.96 (s, 3H), 4.55 (q, J=7.2 Hz, 2H), 5.46 (m, 1H), 7.03-7.12 (m, 2H), 8.13-8.25 (m, 3H), 8.36-8.43 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)=[O:3].Br[CH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31]>>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([S:24][CH2:26][C:27]5[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=5)[C:30]#[N:31])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CS(=O)c1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Reactant: N#Cc1cccc(CBr)c1
Product: CS(=O)c1ccc(-n2cnc3ccc(-c4nnc(SCc5cccc(C#N)c5)o4)cc32)cc1
Yield: 67 %

Procedure:
In the same manner as in Example 7 and using 5-[1-[4-(methylsulfinyl)phenyl]-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 67%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2](=[S:16])[C:3]([N:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:7]1)([CH3:5])[CH3:4].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)=O>>[Cl:28][C:23]1[CH:22]=[C:21]([C:19]2[N:1]=[C:2]([C:3]([N:6]3[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:7]3)([CH3:5])[CH3:4])[S:16][CH:18]=2)[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CCOC(=O)c1cnn(C(C)(C)C(N)=S)c1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1cnn(C(C)(C)c2nc(-c3ccc(Cl)c(Cl)c3)cs2)c1
Yield: 98 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (241 mg, 1.00 mmol) obtained in Example 16b and 2-bromo-1-(3,4-dichlorophenyl)ethanone (268 mg, 1.00 mmol), the title compound (402 mg, 98%) was obtained as a colorless oil.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:25]4[C:24]5[C@@H:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21][C:20]=5[S:19][C:18]=4[N:17]=[CH:16][N:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([O:13][C:14]3[C:25]4[C:24]5[C@@H:23]([CH2:26][CH:27]=[O:28])[CH2:22][CH2:21][C:20]=5[S:19][C:18]=4[N:17]=[CH:16][N:15]=3)[CH2:11][CH2:12]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A 50-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a dichloromethane (15 mL) solution of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (200 mg, 0.50 mmol, 1.00 equiv). Dess-Martin periodinane (318 mg, 0.75 mmol, 1.51 equiv) was added and the resulting mixture was stirred for 2 hr at 0° C. in a water/ice bath. After completion, the reaction was quenched with sodium bicarbonate (sat.) and extracted with 3×60 mL of EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:1) to afford the corresponding 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetaldehyde (150 mg, 75%) as a colorless oil. MS (ES): m/z 402 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>O1CCCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: C1CCOC1
Product: Cc1nc(NCc2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A mixture of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.20 g, 0.81 mmol), benzaldehyde (0.086 g, 0.81 mmol) and titanium(IV) isopropoxide (0.29 g, 1.01 mmol) in anhydrous tetrahydrofuran (2 mL) was stirred at ambient temperature for 18 h. Sodium cyanoborohydride (0.036 g, 0.57 mmol) was added to the mixture and stirring was continued at ambient temperature for another 6 h. The reaction was quenched with the addition of water (2 mL). The precipitate obtained was filtered and washed with ethanol. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to obtain the title compound as a white solid in 58% yield (0.16 g); m.p. 169-172° C.; 1H NMR (CDCl3, 300 MHz) δ 7.37-7.23 (m, 10H), 6.02 (s, 1H), 5.69 (s, 1H), 4.54 (d, J=5.6 Hz, 2H), 4.43 (s, 2H), 2.49 (s, 3H); MS (ES+) m/z 338.3 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.O.[C:11](Cl)(Cl)=[S:12]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:11]=[S:12])=[C:4]([CH3:9])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(I)ccc1N
Solvent: O
Solvent: ClCCl
Product: Cc1cc(I)ccc1N=C=S
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a stirring solution of 4-iodo-2-methylaniline (1.0 g, 4.2 mmol) in DCM (50 mL) was added water (20 mL) followed by thiophosgene (490 mg, 4.2 mmol). The reaction mixture was stirred overnight before the layers were separated and the organic layer dried (Na2SO4) and evaporated in vacuo to give the desired product as a brown solid (1.05 g, 89%). δH (CDCl3) 7.75 (1H, d, J 1.2 Hz), 7.62 (1H, dd, J 1.2, 8.3 Hz), 7.15 (1H, d, J 8.3 Hz), 2.20 (3H, s).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.[I:22][Si](C)(C)C.II>C(Cl)Cl>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([I:22])[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2c(F)cccc2N1
Reactant: C[Si](C)(C)I
Agent: CN(C)CCN(C)C
Agent: II
Solvent: ClCCl
Product: O=C1Nc2cccc(F)c2CCC1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.5 %

Procedure:
6-Fluoro-1,3,4,5-tetrahydro-1-benzazepin-2-one (25 g, 140 mmol) was charged to a 100-mL three neck flask with a dropping funnel and an overhead stirrer. DCM (250 ml) is added and the reaction is cooled to 0° C. TMEDA (29.5 ml, 195 mmol) is added, followed by drop wise addition of iodotrimethylsilane (26.6 ml, 195 mmol). The mixture was stirred for 45 minutes. Iodine (49.6 g, 195 mmol) is added in 5 portions and the mixture is stirred for another 1.5 h. The reaction was quenched with 250 mL Na2SO3 (aqueous solution). The solids were dissolved in dichloromethane and the layers separated. The organic layer is washed with water, dried over Na2SO4, and concentrated to give 6-fluoro-3-iodo-1,3,4,5-tetrahydro-1-benzazepin-2-one (42.5 g) as a brown solid.