Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC(=O)NC
Reactant: ClSCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N(C)SCl
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a solution of 45.2 g (0.44 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to -5° C. under a nitrogen atmosphere was added a solution made up of 50.9 g (0.4 mole) of n-butyl N-methylcarbamate, 44.5 g (0.44 mole) of triethylamine and 100 ml of methylene chloride. The addition took 2 hours while the temperature was maintained at -15° C. to 0° C. After stirring for 1 hour the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. Solid was removed by extracting the product with hexanes. After filtration the hexane solution was concentrated to give 57.3 g of n-butyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[C:11]1(C)[CH:16]=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[CH3:14][C:13]1[N:1]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=2)[C:16]([CH3:15])=[CH:11][CH:12]=1
Reactant: Cc1nc(N)nc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1Br

Procedure:
To a stirred solution containing 2.00 g (9.89 mmol) of 2-amino-5-bromo-4,6-dimethylpyrimidine (3) in 16 mL of anhydrous toluene were added 1.36 mL (11.5 mmol) of 2,5-hexadienone followed by 96 mg (0.50 mmol) of p-toluene sulfonic acid. The reaction mixture was stirred at reflux overnight under argon atmosphere. The reaction mixture was poured into 150 mL of water and then extracted with a portion of 200 mL of ethyl acetate. The organic solution was washed with a portion of 150 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 5:1 gave the expected product as light yellow crystals: yield 2.23 g (81%). 1H-NMR (CDCl3) δ 5.90 (s, 2H), 2.67 (s, 6H), 2.34 (s, 6H); 13C-NMR (CDCl3) δ 166.92, 155.32, 129.56, 118.62, 108.74, 24.90, 14.50.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([OH:22])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.I[CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[N:19][C:18]([O:22][CH2:33][CH2:34][CH3:35])=[CH:17][CH:16]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:30])[F:31])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1
Reactant: Cc1nc(O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CCCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCOc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 50 °C
Reaction time: 13 h
Yield: 73.8 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-ol (65.3 mg, 0.141 mmol) in toluene (1.5 mL) was added silver carbonate (77.8 mg, 0.282 mmol) and 1-iodopropane (68.8 μL, 0.705 mmol). The reaction mixture was stirred at 50° C. for 13 hrs. After cooling the mixture was filtered through on the pad of celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (52.5 mg, 0.104 mmol, 74%).
Reaction SMILES: P(Cl)(Cl)Cl.[P:5]([OH:8])([OH:7])[OH:6].[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[NH:14][CH:15]=O>O>[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[NH:14][CH:15]([P:5]([OH:8])(=[O:6])[OH:7])[P:5]([OH:8])(=[O:7])[OH:6]
Reactant: O=CNc1nccs1
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=P(O)(O)C(Nc1nccs1)P(=O)(O)O
Reaction time: 1 h
Yield: 29.9 %

Procedure:
7 g of phosphorus trichloride are mixed with 4.0 g of phosphorous acid and the mixture is heated, while stirring, at 60° for 1 hour. 6.12 g of N-(thiazol-2-yl)formamide are added thereto and the mixture is heated for a further 6 hours at approximately 60°. The mixture is then stirred with 30 ml of water, filtered with suction, subsequently washed with aqueous methanol and dried under reduced pressure. 2.0 g of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 275° (decomposition) are obtained.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH3:9])[N:6]([CH3:8])[CH:7]=1.C[O:12][CH:13](O)[C:14]([F:17])([F:16])[F:15].C([O-])([O-])=O.[K+].[K+]>>[OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH3:9])[N:6]([CH3:8])[C:7]=1[CH:13]([OH:12])[C:14]([F:17])([F:16])[F:15]
Reactant: COC(O)C(F)(F)F
Reactant: Cc1cc(=O)c(O)cn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(=O)c(O)c(C(O)C(F)(F)F)n1C
Temperature: 130 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A mixture of 5-hydroxy-1,2-dimethyl-1H-pyridin-4-one (9.40 g, 67.6 mmol), trifluoroacetaldehyde methyl hemiacetal (28 mL) and K2CO3 (1.40 g, 10.0 mmol) was sealed in a parallel reactor and stirred overnight at 130° C. The reaction mixture was evaporated to dryness, and the residue was purified by flash column chromatography using a mixture of i-PrOH and a 28-30% conc. NH4OH solution (70/30, v/v) as eluant. Fractions containing pure product were pooled together, and evaporated to give the title compound as a light orange powder (6.3 g, 39% yield). HPLC purity (peak area percent) of this compound is 99.8% at λ=254 nm using HPLC Method 2 as described above. 1H NMR (400 MHz, DMSO-D6) δ: 6.83 (br s, 2H, 20H), 6.21 (s, 1H), 5.88 (q, J=8.7 Hz, 1H), 3.73 (s, 3H, NCH3), 2.31 (s, 3H, CH3); MS m/z 238.1 [M+1]+, 220.2, 192.3, 172.3 (100%). A second less pure fraction of the title compound (7.0 g) was also obtained, and was used without further purification in step 1 of Example 14 below.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][N:31]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:36][C:33]4[CH:34]=[N:35][N:31]([CH3:30])[CH:32]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: Cn1cc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (388 mg) and 1-methylpyrazole-4-carboxyaldehyde (540 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (519 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 1 day. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:3) to give methyl 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (321 mg) as yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH:12]([C:19]2[N:20]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[N:21]=[C:22]3[CH2:26][CH2:25][CH2:24][C:23]=23)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:11][S:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=3)=[C:23]3[CH2:24][CH2:25][CH2:26][C:22]3=[N:21]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(SCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(SCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 2, 4-{2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethylsulfanyl}-benzoic acid methyl ester was hydrolysed using aqueous sodium hydroxide solution in MeOH to give the title compound as off-white solid. MS: m/e=481.4 [M+H+].
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:20]4[CH2:23][CH:22]([OH:24])[CH2:21]4)[C:17]=3[F:19])[C:12](=[O:26])[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]2)[CH2:8][CH2:7]1.O>N1C=CC=CC=1>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:20]4[CH2:21][CH:22]([O:24][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:23]4)[C:17]=3[F:19])[C:12](=[O:26])[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(OS(C)(=O)=O)C3)c(F)cc2c1=O
Temperature: 0 °C
Yield: 74 %

Procedure:
6.3 g (55.0 mmoles) of mesyl chloride are slowly added to a solution of 1.0 g (2.75 mmoles) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 50 ml of pyridine cooled to 0° C., and the reaction is maintained at 0° C. for 3 hours. The solution is added to a mixture of ice and water giving a precipitate which is filtered and washed with water. The solid is dried under vacuum yielding 0.9 g (73%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-mesyloxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate melting at 191°-193° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][NH:13][C:14]([C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][N:17]2[C:18](=[O:29])[N:19]3[O:24][S:25]([O-:28])(=[O:27])=[O:26])=[O:15])[CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([O:12][NH:13][C:14]([C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][N:17]2[C:18](=[O:29])[N:19]3[O:24][S:25]([OH:28])(=[O:26])=[O:27])=[O:15])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOC1CNC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium ({[(2S,5R)-2-({[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 40 (0.1 g, 0.15 mmol) in DCM (8.8 mL) was added trifluoroacetic acid (0.44 mL, 5.7 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)—N-(azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 8 (Table 1) (0.01 g, 20%) as a white solid.
Reaction SMILES: Cl.[C:2]([C:5]1[S:34][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][C@H:21]4[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:35])(=[O:4])[NH2:3]>O1CCOCC1.CO>[CH3:35][C:6]1[C:7]2[C:12]([NH:13][C:14]3[C:15]([O:20][C@H:21]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:11][CH:10]=[N:9][C:8]=2[S:34][C:5]=1[C:2]([NH2:3])=[O:4]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CCCNC3)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
HCl in Dioxane (4M; 4 ml) was added into a solution of (S)-tert-butyl 3-(3-(6-carbamoyl-5-methylthieno[2,3-d]pyrimidin-4-ylamino)pyridin-2-yloxy)piperidine-1-carboxylate (250 mg) in Methanol (8 ml). The reaction was stirred at room temperature for 1.5 h. The solution was purified by chromatography.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19]([C:26]([F:29])([F:28])[F:27])=[N:18]2)=[CH:13][CH:12]=1>CN(C=O)C>[CH3:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19]([C:26]([F:29])([F:27])[F:28])=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=1
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnn(Cc2ccc(-n3nc(C(F)(F)F)c4c3CCCC4)cc2)c1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
Sodium hydride (60% in mineral oil, 10.0 mg; 0.25 mmol) was added in one portion to a room temperature stirring solution of 4-methyl-1H-pyrazole (15.0 mg; 0.18 mmol) in anhydrous DMF (1 mL). After stirring at this temperature for 15 minutes, a solution of 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (52.0 mg; 0.16 mmol) in anhydrous DMF (1 mL) was added and the resulting mixture stirred at room temperature for a further 23 hours. The reaction was quenched with aqueous hydrochloric acid (2M; 1 mL), concentrated in vacuo and purified by MDAP, giving the title compound (35.6 mg; 60%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:27][CH2:28][CH2:29][CH3:30])[C:4]#[C:5][C:6]1[C:14]2[S:13][CH:12]=[CH:11][C:10]=2[C:9]([C:15]#[C:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[S:24][CH:25]=[CH:26][C:7]=12)[CH3:2]>[Pd].C1COCC1>[CH2:22]([CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH2:15][C:9]1[C:8]2[S:24][CH:25]=[CH:26][C:7]=2[C:6]([CH2:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:27][CH2:28][CH2:29][CH3:30])=[C:14]2[S:13][CH:12]=[CH:11][C:10]=12)[CH3:23]
Reactant: CCCCC(C#Cc1c2ccsc2c(C#CC(CC)CCCC)c2ccsc12)CC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC(CC)CCc1c2ccsc2c(CCC(CC)CCCC)c2ccsc12

Procedure:
A dry 250 mL 1-neck flask was flushed with N2 and was charged with 4,8-bis(3-ethylhept-1-ynyl)thieno[2,3-f]benzothiophene (3.04 g, 0.007 mol), Pd/C wet support (0.82 g, 10%) and THF (15 mL, 0.5 M). The flask was evacuated and backfilled with hydrogen. The flask was kept under a hydrogen atmosphere and was monitored by TLC. After the reaction was completed, the mixture was filtered through Celite and solvent was removed by rotary evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:16][C:17]=2[N+:22]([O-:24])=[O:23])=[O:7])=[CH:9][CH:10]=1
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinic chloride and 4-(t-butyl)-2-nitroaniline as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.30 (s, 1H), 9.03 (d, J=2.1, 1H), 8.83 (d, J=9.0, 1H), 8.29 (d, J=2.7, 1H), 8.25-8.21 (m, 1H), 7.80-7.76 (m, 1H), 7.52 (d, J=8.4, 1H), 1.38 (s, 9H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:20]=1)(C)(C)C>C(Cl)(Cl)Cl>[N:21]1([C:19]2[CH:20]=[C:15]([NH2:14])[CH:16]=[N:17][CH:18]=2)[CH:22]=[CH:23][CH:24]=[CH:25]1
Reactant: CC(C)(C)OC(=O)Nc1cncc(-n2cccc2)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cncc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
TFA (1 ml) was added to a chloroform (1 ml) solution containing tert-butyl(5-(1H-pyrrol-1-yl)pyridin-3-yl)carbamate (36 mg) obtained in the 1st step, followed by stirring at room temperature for 1 hour. Then, the solvent was distilled away under reduced pressure and the residue was added to a mixture of chloroform, water, and a 1M sodium hydroxide aqueous solution, followed by extraction with chloroform. The resultant was dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a light brown solid of 5-(1H-pyrrol-1-yl)pyridin-3-amine (23 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5]Br.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5][N:15]=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: ClC(Cl)=C(Cl)c1cc(Cl)cc(CBr)c1
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Cl)cc(C(Cl)=C(Cl)Cl)c1
Yield: 70.7 %

Procedure:
A solution of 3-chloro-5-(trichlorovinyl)benzyl bromide (3.57 g) and sodium azide (813 mg) in 50 ml of ethanol was heated at reflux for 30 minutes. The reaction was then concentrated and the residue chromatographed on silica gel with petroleum ether as eluant to afford 2.24 g of pure 3-chloro-5-(trichlorovinyl)benzyl azide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]1=2.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:24]1([S:30]([NH:1][CH2:2][CH2:3][S:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]2=3)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2c(c1)C(SCCN)c1ccccc1CO2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of pyridine was dissolved 9.00 g of methyl 11-(2-aminoethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound f) obtained in Reference Example 6. Under ice cooling, 4.2 ml of benzenesulfonyl chloride was dropwise added to the solution and the mixture was stirred at room temperature overnight. Pieces of ice were added to the mixture. After stirring for further an hour, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate and the extract was washed in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=7:3) to give 9.90 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([NH:16][C:17]1[C:25]([Br:26])=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1)(=[O:15])[CH3:14]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([Br:26])[C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:18][C:19]=2[O:27][CH3:28])[CH2:7]1
Reactant: COc1cc(NC(C)=O)c(Br)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc(NC(C)=O)c(Br)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-acetylamino-5-bromo-2-methoxybenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[N:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH2:25][CH:26]2[O:28][CH2:27]2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>CO>[C:29]([NH:33][CH2:27][CH:26]([OH:28])[CH2:25][O:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[C:13]1[N:14]=[N:15][C:10]([NH:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][CH:12]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(OCC2CO2)c1
Reactant: CC(C)(C)N
Solvent: CO
Product: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(OCC(O)CNC(C)(C)C)c1
Reaction time: 48 h

Procedure:
A solution of 6-(2-t-butyloxycarbonylhydrazino)-3-[2-(2,3-epoxypropoxy)-4-methoxyphenyl]pyridazine and t-butylamine in methanol was allowed to stand at room temperature for 48 hours. Evaporation of the reaction mixture gave 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-(2-t-butyloxycarbonylhydrazino)pyridazine.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.ClCCl>S([O-])([O-])(=O)=S.[Na+].[Na+]>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[N+:24]([O-:9])=[CH:23][CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2nccc(-c3c(F)cc(F)cc3F)c2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(-c1c(F)cc(F)cc1F)cc[n+]2[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.2 %

Procedure:
m-Chloroperbenzoic acid (425 mg) was added to a mixture of methyl 4-(2,4,6-trifluorophenyl)quinoline-6-carboxylate (710 mg) and dichloromethane (20 mL), followed by stirring at room temperature for 3 days. The reaction mixture was diluted with aqueous sodium thiosulfate solution, and extracted with chloroform. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain methyl 4-(2,4,6-trifluorophenyl)quinoline-6-carboxylate 1-oxide (680 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[N:6][C:7]=1[CH3:8].[Se](=O)=[O:21]>COCCOC>[Br:1][C:2]1[C:7]([CH:8]=[O:21])=[N:6][CH:5]=[C:4]([N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[CH:3]=1
Reactant: O=[Se]=O
Reactant: Cc1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Solvent: COCCOC
Product: O=Cc1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 130 °C
Yield: 383.1 %

Procedure:
To 2-(5-bromo-6-methylpyridin-3-yl)isoindoline-1,3-dione (30A, 1.5 g, 4.73 mmol) and selenium dioxide (682 mg, 6.15 mmol) was added 14 mL of DME. The reaction mixture was heated in a 130° C. heating bath for 20 hours. The reaction was repeated on identical scale 4×. The combined reaction mixtures were cooled and the solids filtered off. The filtrate was concentrated to afford 6 g of the title compound. 1H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 8.95 (d, J=1.9 Hz, 1H), 8.41 (d, J=1.7 Hz, 1H), 8.07-7.84 (m, 4H).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:25]N(C=O)C>ClC(Cl)C>[C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:25])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Sc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1

Procedure:
A solution of 2-(phenylsulphenyl)-4-trifluoromethylbenzoic acid (11.5 g) and thionyl chloride (11.4 g) in dichloroethane containing a few drops of DMF was heated at reflux for 1.5 hours. The mixture was evaporated to dryness and methanol was added. The mixture was heated at reflux for 1 hour and evaporated to dryness. It was treated with water and extracted with ether, washed with sodium carbonate solution (2M), water, dried (Na2SO4) and filtered. The flitrate was evaporated to dryness and the residue was triturated with cyclohexane and filtered to give methyl 2-(phenylsulphenyl)-4-trifluoromethylbenzoate (10.5g) as a white solid, m.p. 55°-60° C.