Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Cl:10][C:11]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:12]=1[C:13]([N:15]=[C:16]=[O:17])=[O:14]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:12]=1[C:13]([NH:15][C:16]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)=[O:17])=[O:14]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccc(F)cc1Cl)Nc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3.24 g (0.02 mol) of 3,4-dichloroaniline are dissolved in 60 ml of dry toluene, and 3.99 g (0.02 mol) of 2-chloro-4-fluoro-benzoyl isocyanate are added in the absence of moisture. The mixture is stirred for one hour at 80° C. and then cooled to 20°-25° C. The precipitate which separates out is filtered off under suction and dried in vacuo at 100° C. 6.8 g (94% of theory) of 1-(2-chloro-4-fluoro-benzoyl)-3-(3,4-dichlorophenyl)-urea of melting point 208° C. are obtained.
Reaction SMILES: Cl.[CH3:2][N:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([C:11]2[N:15]=[C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[O:13][N:12]=2)[N:5]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.C(Cl)Cl>[CH2:30]([N:19]1[CH2:18][CH2:17][CH:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[N:5]=[C:4]([N:3]([CH3:2])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:9]=[C:8]([NH2:10])[N:7]=3)[N:15]=2)[CH2:21][CH2:20]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCNCC3)n2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCN(Cc4ccccc4)CC3)n2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 1.9 %

Procedure:
To 2-N-methyl-2-N-phenyl-6-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine hydrochloride (Intermediate 105, 0.100 g, 0.257 mmol) in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 0.012 g, 0.309 mmol) at 0 C and stirred for 5 min. Benzyl bromide (30.6 μL, 0.257 mmol) was added, the reaction mixture was warmed to room temperature and stirred for 18 h. The mixture was then heated at 45 C for 18 h and re-treated with benzyl bromide (30.6 L, 0.257 mmol). The mixture was then heated at 50 C for 18 h and stirred room temperature for 72 h. The reaction mixture was diluted with DCM and then washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC, Method A, to afford the title compound (2.2 mg, 1.9%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(Cl)Cl.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16](O)[C:17]([CH3:35])([CH3:34])[N:18]=[C:19]2[C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2>O>[F:7][CH:16]1[C:15]2[C:20](=[CH:21][CH:22]=[CH:23][C:14]=2[F:13])[C:19]([C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:18][C:17]1([CH3:35])[CH3:34]
Reactant: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1O
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1F
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Diethylaminosulphur trifluoride (76 mg) was added to an methylene chloride (20 mL) solution of 3-(5-fluoro-4-hydroxy-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline (50 mg, 0.16 mmol), followed by stirring for 1 hour under ice cooling, pouring water, extracting with ethyl acetate, and applying the resulting residue to chromatography to obtain 45 mg (yield 90%) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:11])[CH:12]([N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[CH2:28][CH2:27]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: O=C(c1ccc(Cl)cc1)N1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
This is an example of Procedure B in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.5 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (0.6 g 1 eq) were dissolved in CH3CN (5 mL). Ca(OTf)2 (0.456 g, 0.5 eq) was added into the mixture. Reaction mixture was stirred at RT for overnight, then 80-85° C. for 8 h. After concentrating and adding EtOAc 20 mL to the residue, the organic phase was washed with H2O, dried over Na2SO4. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 1.01 g of desired product as a sticky oil (92% yield). * It is important to note that during workup, the organic phase should be washed with H2O and saturated NaCl solution, not saturated NaHCO3 solution.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>O1CCOCC1.CO.C1C=CC=CC=1>[NH2:8][C@@H:9]([CH3:12])[CH2:10][O:11][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@H](C)N)cc1

Procedure:
Following a procedure similar to that described in Preparation 27, but using 15.8 g of (S)-2-t-butoxycarbonylamino-1-propanol, 10.0 g of methyl 4-hydroxyphenylacetate, 24 g of triphenylphosphine, 70 ml of dry benzene, 15.7 g of diethyl azodicarboxylate, 50 ml of methanol and 70 ml of a 4N solution of hydrogen chloride in dioxane, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:5][CH:4]=[N:3]1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 46.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl (1-methyl-1H-pyrazol-5-yl)carbamate (243 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (140 mg, 46.8%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20](O)=[O:21])=[CH:4][CH:3]=1.O1CCCC1.C(Cl)(=O)OCC.[NH3:36]>O.C(N(CC)CC)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]([NH2:36])=[O:21])=[CH:4][CH:3]=1
Reactant: N
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(F)cc1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)cc(C(N)=O)n2Cc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a mixture of the compound obtained in Example 22 (4) (0.23 g) and tetrahydrofuran (7 ml), triethylamine (0.19 ml) and ethyl chlorocarbonate (0.1 ml) were added at 0° C. and the mixture was stirred at the same temperature for 20 minutes. An ammonia gas was blown into the mixture at 0° C. and the mixture was stirred at the same temperature for 30 minutes. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was recrystallized (ethyl acetate) to obtain 0.06 g of the desired product as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[C:16]3[O:15][CH2:14][C:13](=[O:17])[C:12]=3[CH:11]=[CH:10][C:9]=2[O:18][CH3:19])=[C:5]([CH3:20])[NH:4][N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[N:22]1.N1CCCCC1>CO>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](/[CH:30]=[C:14]2\[O:15][C:16]3[C:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][NH:4][C:5]=4[CH3:20])=[C:9]([O:18][CH3:19])[CH:10]=[CH:11][C:12]=3[C:13]\2=[O:17])=[N:22]1
Reactant: COc1ccc2c(c1Cc1c(C)n[nH]c1C)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1Cc1c(C)n[nH]c1C)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A solution of 7-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-6-methoxybenzofuran-3(2H)-one (0.0427 g, 0.157 mmol) in methanol (0.6 mL) was added with 1H-indazole-3-carboxaldehyde (0.0229 g, 0.157 mmol) and piperidine (0.0107 g, 0.126 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-7-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-6-methoxybenzofuran-3(2H)-one (0.0388 g, 61%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([O:16][CH3:17])[C:5]([C:7]1[CH:15]=[CH:14][C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH:8]=1)=[O:6].[CH3:18][S:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>CN(C=O)C>[CH3:18][S:19][C:20]1[N:25]=[C:24]([N:11]2[C:10]3[CH:14]=[CH:15][C:7]([C:5]([N:4]([CH3:3])[O:16][CH3:17])=[O:6])=[CH:8][C:9]=3[N:13]=[CH:12]2)[CH:23]=[CH:22][N:21]=1.[CH3:18][S:19][C:20]1[N:25]=[C:24]([N:13]2[C:9]3[CH:8]=[C:7]([C:5]([N:4]([CH3:3])[O:16][CH3:17])=[O:6])[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12]2)[CH:23]=[CH:22][N:21]=1
Reactant: CON(C)C(=O)c1ccc2nc[nH]c2c1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2c(c1)ncn2-c1ccnc(SC)n1
Product: CON(C)C(=O)c1ccc2ncn(-c3ccnc(SC)n3)c2c1
Temperature: 100 °C

Procedure:
To a suspension of NaH (210 mg, 60% suspension in oil, 5.21 mmol) in DMF (10 mL) at 0° C. was added 5-(N-methyl-N-methoxyaminocarbonyl)-benzimidazole (890 mg, 4.34 mmol) dissolved in DMF (10 mL) dropwise. The ice bath was removed, and the reaction mixture was stirred until the mixture became homogeneous (10 min) then added 2-methylthio-4-chloropyrimidine (610 μL, 5.21 mmol). The mixture was heated at 100° C. for 1.5 h then cooled down to 0° C. and quenched with H2O carefully. The reaction mixture was poured in to a separatory funnel and extracted with EtOAc. The combined extracts were washed with H2O followed by brine and dried over Na2SO4. The crude material was purified by flash chromatography (1:200 crude material: silica gel) using 1% MeOH/EtOAc system to obtain 516 mg of 2-methylthio-4-[5-(N-methyl-N-methoxyaminocarbonyl)-benzimidazol-1-yl]pyrimidine and 429 mg of 2-methylthio-4-[6-(N-methyl-N-methoxyaminocarbonyl)benzimidazol-1-yl]pyrimidine. 2-methylthio-4-[5-(N-methyl-N-methoxyaminocarbonyl)-benzimidazol-1-yl]pyrimidine. Partial 1H NMR (500 MHz, CDCl3): δ 8.71 (s, 1H); 8.65 (d, J=5.5 Hz, 1H); 8.25 (s, 1H); 8.24 d, J=8.5 Hz, 1H); 7.82 (d, J=5.5 Hz, 1H); 7.22 (d, J=5.5 Hz, 1H); 3.58 (s, 3H); 3.42 (s, 3H); 2.68 (s, 3H). 2-methylthio-4-[6-(N-methyl-N-methoxyaminocarbonyl)-benzimidazol-1-yl]pyrimidine: Partial 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H); 8.64 (d, J=5.5 Hz, 1H); 8.63 (s, 1H); 7.87 (d, J=8.5 Hz, 1H); 7.77 (d, J=8.5 Hz, 1H); 7.23 (d, 5.5 Hz, 1H); 3.6 (s, 3H); 3.42 (s, 3H); 2.68 (s, 3H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.[CH3:21][N:22]1[CH2:28][C:27]2[CH:29]=[C:30](/[CH:33]=[CH:34]/[C:35](O)=O)C=N[C:26]=2[NH:25][C:24](=O)[CH2:23]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:25]([CH3:26])[CH2:24][C:23]2[N:22]([CH3:21])[C:28]3[C:34]([CH:35]=2)=[CH:33][CH:30]=[CH:29][CH:27]=3)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCCC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(CN2CCCC2)c1
Yield: 82 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(6-amino-5-pyrrolidin-1-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (223 mg, 82%) was prepared as a light, yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.2 (br s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.52-7.39 (m, 3H), 7.24-7.01 (m, 4H), 6.41-6.16 (m, 1H), 5.05-4.85 (m, 2H), 4.29 (s, 2H), 3.74-3.68 (m, 3H), 3.10-3.00 (m, 6H), 2.10-1.82 (m, 5H); MS (ESI) m/e 404 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:29])([CH2:22][CH2:23][CH2:24][S:25]([OH:28])(=[O:27])=[O:26])[C:10]=1/[CH:30]=[CH:31]/NC1C=CC=CC=1)([OH:3])=[O:2].[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][N+:49]1[C:57]2[C:52](=[CH:53][C:54]([S:58]([OH:61])(=[O:60])=[O:59])=[CH:55][CH:56]=2)[C:51]([CH3:69])([CH2:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:67])=[O:66])[C:50]=1[CH3:70].C([O-])(=O)C.[Na+:75].COCCOCC[N+]1C2C(=CC(S(O)(=O)=O)=CC=2)C(C)(CCCS(O)(=O)=O)C=1C>C(O)(=O)C.C(OC(=O)C)(=O)C.C(OCC)C>[Na+:75].[Na+:75].[Na+:75].[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:29])([CH2:22][CH2:23][CH2:24][S:25]([OH:28])(=[O:26])=[O:27])/[C:10]/1=[CH:30]\[CH:31]=[CH:70]\[C:50]1[C:51]([CH3:69])([CH2:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:67])=[O:66])[C:52]2[C:57](=[CH:56][CH:55]=[C:54]([S:58]([OH:61])(=[O:59])=[O:60])[CH:53]=2)[N+:49]=1[CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH3:39])([OH:3])=[O:2]
Reactant: COCCOCCOCC[N+]1=C(C)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Reactant: CC1(CCCS(=O)(=O)O)C(/C=C/Nc2ccccc2)=[N+](CCCCCC(=O)O)c2ccc(S(=O)(=O)O)cc21
Agent: CC(=O)[O-]
Agent: COCCOCC[N+]1=C(C)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COCCOCCOCC[N+]1=C(/C=C/C=C2/N(CCCCCC(=O)O)c3ccc(S(=O)(=O)O)cc3C2(C)CCCS(=O)(=O)O)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Temperature: 25 °C

Procedure:
One mmol 1-(5-carboxypentyl)-3-methyl-2-((E)-2-phenylamino-vinyl)-5-sulfo-3-(3-sulfopropyl)-3H-indolium and 1 mmol 1-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-2,3-dimethyl-5-sulfo-3-(3-sulfo-propyl)-3H-indolium were dissolved in 20 ml acetic acid/acetic anhydride (1/1) followed by the addition of 200 mg sodium acetate. The solution was stirred under reflux for 15 min. After cooling to room temperature, 20 ml diethylether was added. The resulting precipitate (mixture of the diastereomers 550-1 compound 2 and 550-2 compound 2) was extracted by suction, washed with ether and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:16](=[O:17])[C:15]2[N:18]3[C:8](=[C:9]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#N)=[CH:21][CH:20]=4)[N:10]=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:7]1.C(O)=[O:34]>O=[Pt]=O.C1COCC1>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:16](=[O:17])[C:15]2[N:18]3[C:8](=[C:9]([C:19]4[CH:20]=[CH:21][C:22]([CH:23]=[O:34])=[CH:25][CH:26]=4)[N:10]=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:7]1
Reactant: O=CO
Reactant: COc1ccc(CN2Cc3c(-c4ccc(C#N)cc4)nc4cccc(n34)C2=O)c(OC)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3c(-c4ccc(C=O)cc4)nc4cccc(n34)C2=O)c(OC)c1
Temperature: 60 °C

Procedure:
A suspension of (B2) and PtO2 (0.1 eq.) in a solvent mixture of HCO2H (80% sol. in water)/THF=2.5:1 (0.2 M) was heated to 60° C. for 4 h. After cooling, the catalyst was filtered through a pad of celite and the solvent was reduced in vacuo and the residue pardoned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave the title compound which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6, 300K) δ 10.0 (1H, s), 8.00 (4H, m), 7.75 (1H, d, J=9.0 Hz), 7.49 (1H, d, J=7.0 Hz), 7.38 (1H, dd, J=8.4, 7.0 Hz), 7.23 (1H, d, J=8.3 Hz), 6.61 (1H, d, J=2.0 Hz), 6.48 (1H, dd, J=8.3, 2.0 Hz), 5.40 (2H, s), 4.71 (2H, s), 3.86 (3H, s), 3.73 (3H, s). MS (ES+) C25H21N3O4 requires: 427, found: 428 (M+H)+.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[Cl:31][C:32]1[CH:33]=[C:34]([O:43][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:35]=[CH:36][C:37]=1[O:38][CH2:39][C@@H:40]1[CH2:42][O:41]1>C(Cl)(Cl)Cl.CO>[Cl:31][C:32]1[CH:33]=[C:34]([OH:43])[CH:35]=[CH:36][C:37]=1[O:38][CH2:39][C@@H:40]([OH:41])[CH2:42][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:29][CH:30]=1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)c(Cl)c1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3Cl)cc2)CC1
Yield: 17 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.57 g, 1.35 mmol) was reacted with tert-butyl(diphenyl)silyl 3-chloro-4-[(2S)oxiranyl-methoxy]phenyl ether (0.59 g, 1.35 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.185 g, 0.23 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]2I.CN(C=O)C.C([Sn](CCCC)(CCCC)[C:29]1[N:34]=[C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[CH:31][CH:30]=1)CCC.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]2[C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[N:34]=1
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(Br)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCOCC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(Br)ccc21
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a mixture of Pd(PPh3)4 (255.0 mg, 220.6 μmol), tert-butyl 5-bromo-3-iodo-1H-indole-1-carboxylate (1000 mg, 2369 μmol) and CuI (546.2 mg, 2868 μmol) was added DMF (12 mL) followed by 4-(6-(tributylstannyl)pyridin-2-yl)morpholine (1000 mg, 2206 μmol). The mixture was heated at 100° C. for 20 min. After cooled to RT, the reaction was added H2O (5 mL) and DCM (5 mL). The organic layer was separated. The aqueous layer was extracted with DCM (10 mL×2). The organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. The brown crude oil was purified with silica gel chromatography (eluting with 100% DCM) to give tert-butyl 5-bromo-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (537.3 mg, 53.13%) as a white solid. MS (ESI, pos. ion) m/z: 458 (M+1). 1H NMR (400 MHz, DMSO-d6) ppm 1.66 (s, 9H), 3.50-3.62 (m, 4H), 3.74-3.83 (m, 4H), 6.80 (d, J=8.4 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.54 (dd, J=8.9, 2.1 Hz, 1H), 7.64 (dd, J=8.4, 7.6 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 8.29 (s, 1H), 8.68 (d, J=2.2 Hz, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[N:8][CH:9]=1)([O-])=O>C(O)(=O)C.CCOC(C)=O.[Zn]>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=[N:13][N:12]=[N:11]1
Reactant: O=[N+]([O-])c1ccc(-n2cnnn2)nc1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(-n2cnnn2)nc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
5-Nitro-2-(1H-tetrazol-1-yl)pyridine (1020 mg, 5.31 mmol) was suspended in acetic acid (10 ml). Zinc (3472 mg, 53.1 mmol) was added slowly (exothermic reaction). The mixture was stirred at 50° C. for 1 hour, cooled, diluted with EtOAc. The mixture was filtered, rinsed with ethyl acetate. The filtrate was concentrated to dryness to give crude 6-(1H-tetrazol-1-yl)pyridin-3-amine: LC/MS: [(M+1-28)]+=135.1.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([NH2:15])[CH:5]=1.[NH2:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[C:32](N1C=CN=C1)(N1C=CN=C1)=S.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:32]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:29])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:15][C:6]=2[CH:5]=1)=[O:16]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(NCC(C)C)c(N)c1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC(C)C
Yield: 36.2 %

Procedure:
1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (660.0 mg) was prepared by following General Procedure D starting from 3-amino-4-isobutylamino-benzoic acid methyl ester (790.0 g), 2-amino-6-(trifluoromethoxy)benzothiazole (930.0 mg), 1,1′-thiocarbonyldiimidazole (700.0 mg), and EDC (770.0 mg) in DMF (8.0 mL). LCMS: m/z 466; and 1H NMR (DMSO-d6, 400 MHz): δ 8.25 and 8.05 (0.6 and 0.46, 1H, m), 7.98-7.88 (2H, m), 7.75-7.73 (1H, m), 7.60-7.58 (1H, m), 7.38-7.37 (1H, m), 4.00-3.98 (2H, m), 3.88 (3H, s), 2.29-2.28 (1H, m), 0.92-0.86 (6H, m), —NH proton signal was not observed.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:21]=[C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:18][C:14]=1[C:15](O)=O>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[N:9]=[C:15]([C:14]3[CH:18]=[CH:19][C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:13]=3[O:12][CH3:11])[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2cc(C)c(C)cc2[nH]1

Procedure:
Prepared analogously to Example 14 from 4,5-dimethyl-1,2-phenylenediamine and 2-methoxy-4-methanesulfonylaminobenzoic acid.