Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:16])[C:13](O)=[O:14])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:16])[C:13]([Cl:26])=[O:14])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a 50 ml volume four-necked flask, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetic acid (8-a) (0.94 g), toluene (anhydrous) (3.0 ml) and dimethylformamide (anhydrous) (0.2 m) were added under a nitrogen atmosphere and the internal temperature was raised to about 50° C. Thionyl chloride (0.45 ml) was added thereto and the resulting mixture was stirred at 50° C. for 2 hours. The mixture was concentrated under reduced pressure, and azeotropically distilled with toluene to give 0.96 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10]([CH:12]1[CH2:14][CH:13]1[C:15]1[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[S:18][CH:19]=1)=[O:11]>O1CCCC1>[S:18]1[CH:19]=[C:15]([C@@H:13]2[CH2:14][C@H:12]2[CH:10]=[O:11])[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]1=2
Reactant: CON(C)C(=O)C1CC1c1csc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C[C@@H]1C[C@H]1c1csc2ccccc12
Temperature: -40 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
Powdered lithium aluminum hydride (3.05 g, 80.4 mmol) was carefully added portionwise to a stirred solution of 2-benzo[b]thiophen-3-yl-cyclopropanecarboxylic acid methoxy-methyl-amide (3.50 g, 13.4 mmol) in anhydrous tetrahydrofuran (300 ml) at −40° C. under N2. The resulting mixture was stirred at −40° C. for 3 h. The reaction was quenched with ethyl acetate (100 ml) and allowed to warmed to room temperature. After 20 min, water (5 ml) was added followed by a solution of aqueous sodium hydroxide (5N, 5 ml). After stirring for 30 min at room temperature the aluminum salts were removed by vacuum filtration. The salts were washed with ethyl acetate (100 ml) and the combined filtrates were concentrated in vacuo. The crude material was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give trans-2-benzo[b]thiophen-3-yl-cyclopropanecarbaldehyde (2.02 g, 75%). 1H NMR (500 MHz, CDCl3) 9.48 (1H, d, J=4.57 Hz), 7.84 (2H, dd, J=17.09, 7.33 Hz), 7.41 (2H, m), 2.80 (1H, m), 2.17 (1H, m), 1.78 (1H, m), 1.59 (1H, m); MS m/e 203.22 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([CH3:28])=[CH:23][N:22]=1>>[Cl:20][C:21]1[N:26]=[C:25]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)[C:24]([CH3:28])=[CH:23][N:22]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: Cc1cnc(Cl)nc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
EXAMPLE 91 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2,4-dichloro-5-methyl-pyrimidine: MS (m+1)=410.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][S:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:15]=1
Reactant: ClCc1cccnc1
Reactant: Sc1ncnc2ccccc12
Product: c1cncc(CSc2ncnc3ccccc23)c1
Yield: 35.6 %

Procedure:
The title compound(3.34 g) was prepared from 4-mercaptoquinazoline(6.0 g) and 3-chloromethylpyridine(5.2 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)C(C)C)(C)C.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O>[C:7]([O:6][C:4]([C@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:2][NH:1][C:46]([NH:45][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:47])=[O:5])([CH3:9])([CH3:10])[CH3:8]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CN)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CNC(=O)Nc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.8 g of 2(R)-[2-amino-1(R)-(tert-butoxycarbonyl)ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide prepared as described in Example 33, part (i), 0.325 ml of N,N-diisopropylethylamine and 0.21 ml of phenyl isocyanate in 10 ml of dimethylformamide was stirred at 60° C. under nitrogen for 2.5 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1M hydrochloric acid. The ethyl acetate solution was separated and washed with sodium hydrogen carbonate solution and with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether and there was obtained 0.705 g of 2(R)-[1(R)-(tert-butoxycarbonyl)-2-(3-phenylureido)ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: CN1CCNCC1
Product: CC1CCN(c2nc(N3CCN(C)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 145 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
A flask was charged with 6′-chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (210 mg, 0.820 mmol) (as prepared in the previous step), and 1-methylpiperazine (182 μL, 1.65 mmol) and the mixture was stirred at 145° C. for 3 h. Purification of the resulting residue by silica gel preparative TLC eluting with 10% methanol in dichloromethane yielded 202 mg (77%) of the title compound as yellow glass. 1H-NMR (400 MHz, CDCl3): δ 8.19 (d, 1H, J=9.2 Hz), 6.03 (d, 1H, J=9.2 Hz), 3.82 (m, 2H), 3.70 (m, 4H), 2.98 (m, 2H), 2.48 (m, 2H), 2.34 (s, 3H), 1.71-1.60 (m, 3), 1.35 (m, 2H), 0.97 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z): Calcd. for C16H26N5O2, 320.2 (M+H); found: 320.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]>[Pd].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCCC=Cc1ccccn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCc1ccccn1
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A mixture of methyl 6-(pyridin-2-yl)-5-hexenoate (4.97 g, 21.0 mmol) and 10% palladium on carbon (200 mg) in methanol (100 ml) was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered. Evaporation of solvent from the filtrate yielded a target product, methyl 6-(pyridin-2-yl)-hexanoate (4.1 g, 94%).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:11]=[N:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1>S(=O)(=O)(O)O>[F:13][C:12]([F:15])([F:14])[C:9]1[N:10]=[CH:11][C:6](=[O:2])[NH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cnc(C(F)(F)F)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1cnc(C(F)(F)F)c[nH]1
Temperature: 25 °C

Procedure:
Sodium nitrite (0.21 g) was added in one batch to concentrated sulphuric acid (2.5 ml) at 2° C. The reaction mixture was then stirred, allowed to warm to room temperature and then heated to 40° C. for 10 minutes. The resulting solution was then cooled to 3° C. and a solution of 2-amino-5-trifluoromethylpyrazine (prepared by the method of Miesel, U.S. Pat. No. 4,293,552, 0.5 g) in concentrated sulphuric acid (3.5 ml) added dropwise. The reaction temperature was not allowed to rise above 5° C. during the addition. After stirring at 5° C. for 10 minutes, the reaction mixture was allowed to warm to room temperature and after 10 minutes heated to 40° C. for 10 minutes. The reaction mixture was then added to ice. Vigorous gas evolution was noted. The mixture was then extracted with ethyl acetate, the organic phase washed with brine, dried with sodium sulphate and evaporated under reduced pressure to give 5-trifluoromethylpyrazine-2-one as a yellow solid.
Reaction SMILES: [N:1]([CH:4]([C:17]1[CH:21]=[CH:20][O:19][C:18]=1[Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[CH3:35][S:36]([NH:1][CH:4]([C:17]1[CH:21]=[CH:20][O:19][C:18]=1[Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCC(N=[N+]=[N-])c1ccoc1[Si](CC)(CC)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCC(NS(C)(=O)=O)c1ccoc1[Si](CC)(CC)CC

Procedure:
Reducing 3-(1-azidotridecyl)-2-triethylsilylfuran with lithium aluminum hydride, as in Example 8, followed by reacting the intermediate with methanesulfonyl chloride, gives 3-(1-methanesulfonamidotridecyl)-2-triethylsilylfuran. Oxidizing this sulfonamide followed by reduction with sodium borohydride gives 3-(1-methanesulfonamidotridecyl)-2(5H)-furanone.
Reaction SMILES: [Mg].[C:2]([C:6]1[CH:7]=[C:8](Br)[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].II.[B:15](OC)([O:18]C)[O:16]C>C1COCC1>[C:2]([C:6]1[CH:7]=[C:8]([B:15]([OH:18])[OH:16])[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(C)(C)c1cccc(Br)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(B(O)O)c1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of dry THF (10 mL) was added magnesium (1.25 g, 52 mmol), 3-t-butyl bromobenzene (2.0 g, 9.4 mmol) and a crystal of iodine. The reaction was first heated slightly until the reaction started and then removed. The remaining 3-t-butyl bromobenzene (8.0 g, 37.7 mmol) was added via an addition funnel until the spontaneous refluxing stopped. The reaction mixture was heated to reflux for 2 hours. The Grignard was transferred via a syringe into a cooled solution (−40° C.) of trimethyl borate dissolved in THF and added over a 10 minute period. The reaction mixture was warmed to room temperature overnight. Ethyl acetate and distilled water were added to the reaction mixture and the layers separated. The organics were washed with brine and dried over magnesium sulfate. The solvent was concentrated and the product purified by a silica gel column using 10% ethyl acetate and hexanes as the eluants to give 3-t-butylphenyl boronic acid (4.0 g, 46% yield) as a white solid. The product was confirmed by GCMS and was used directly in the next step.
Reaction SMILES: C([O:9][C@H:10]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[C:25]1([C@@H:10]([OH:9])[C@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O[C@H](c1ccccc1)[C@@H](OC1CCCCO1)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O[C@H](c1ccccc1)[C@@H](OC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To 7S (2.11 g, 5.24 mmol) was added a solution of sodium hydroxide (295 mg, 7.38 mmol) in methanol (10.5 ml). After stirring for 18 h at rt, the reaction mixture was concentrated in vacuo. After addition of water, the product was extracted with dichloromethane twice and the organic layer was dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified by silica gel chromatography (eluted with 8:1 hexane:AcOEt) to give 8S (1.25 g, 80%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][CH:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccccc1C(C)OC(=O)Nc1c(C)noc1-c1ccc(Br)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)c4ccccc4OC)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-methoxy-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:6](=[O:21])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:28]([O:34][C@@H:35]1[C@@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@H:39]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:38]([CH2:55][O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[O:37][C@@H:36]1Br)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(#N)C.O1CCCC1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([CH3:19])[CH3:20])=[CH:15][CH:16]=2)[C:6]([O:21][C@@H:36]2[O:37][C@H:38]([CH2:55][O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[C@@H:39]([O:48][C:49](=[O:54])[C:50]([CH3:51])([CH3:52])[CH3:53])[C@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:44])([CH3:45])[CH3:46])[C@H:35]2[O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccc(OC(C)C)cc2)c1C
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccc(OC(C)C)cc2)c1C
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a suspension of 1-acetyl-1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (1.00 g) in acetonitrile (5 mL) and tetrahydrofuran (3 mL) was added potassium carbonate (0.719 g) under stirring at room temperature. After stirring the mixture at 50° C. for 1 hour, 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (2.35 g) was added to the mixture. The mixture was stirred at 50° C. for 12 hours. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. 2-Propanol was added to the residue, and the mixture was re-concentrated under reduced pressure. The residue was recrystallized in the mixed solvent of water and methanol, the obtained crystals were dried under reduced pressure to give 1-acetyl-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2.19 g).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)C.[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[C:17]([CH3:19])=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl.CO>[CH2:22]([O:21][C:16](=[O:20])/[C:17](=[N:12]/[C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)/[CH3:19])[CH3:23]
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)/C(C)=N/c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-imidazol-1-yl-phenyl amine (637 mg) was dissolved in 2 M hydrochloric acid/MeOH (3 ml), and this was concentrated under reduced pressure. The residue was suspended in concentrated hydrochloric acid (1 ml), and an aqueous solution of sodium nitrite (304 mg, 2.5 ml) was added dropwise thereto over 30 minutes at 0° C. on ice. The reaction mixture was slowly added dropwise to an aqueous solution prepared in advance from aqueous solutions of sodium hydrosulfite (2.3 g, 13 ml) and 5 M sodium hydroxide (400 μl), while keeping the temperature of the reaction mixture at 5° C. or lower. Then, the mixture was stirred at 25° C. for one hour. An ethanol solution (5 ml) of ethyl pyruvate (465 μl) was added dropwise to the reaction mixture. After stirring at 50° C. for 30 minutes, the mixture was further stirred at 25° C. for 10 hours. The pH of the mixture was adjusted to 11 using an aqueous solution (about 10 ml) of 20% potassium phosphate. The resulting precipitate was collected by filtration, and dried. Thus, 2-[(E)-4-imidazol-1-yl-phenylimino]-propionic acid ethyl ester was obtained as a pale yellow powder (1.1 g, 99%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2[NH:15][C:16]3[C:21]([C:13]=2[CH:12]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:10]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3>C(O)(=O)C>[Br:1][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:9]=[N:10][C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][C:13]2=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(Br)cc12
Temperature: 25 °C
Yield: 98 %

Procedure:
Following a procedure in Chem. Bio. Chem, 2009, 10, 889-895, N-bromosuccinimide (37 mg, 0.208 mmol) was added to a solution of ethyl 9H-pyrido[3,4-b]indole-3-carboxylate (50 mg, 0.208 mmol) in acetic acid (1.5 ml) and stirred at room temperature. After 45 minutes the acetic acid was removed and the solid material was partitioned between EtOAc and NaHCO3. The organic layer was washed with water, brine, and dried over Na2SO4 to afford the desired compound in 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH:11]=[CH2:12]>[C].[Pd].CCOC(C)=O.CO>[CH2:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:2]=1[F:1])[CH3:12]
Reactant: C=Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cnccc1Oc1ccc(N)cc1F
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A solution of 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridine (80 mg, 0.30 mmol) in 1:1 EtOAc/MeOH (2 mL) was hydrogenated over 10% palladium-carbon (30 mg) for 1 h using H2 from a latex balloon. Pt2O (10 mg) was added to the mixture and the reaction continued for 1 h. The mixture was filtered through Celite® and concentrated in vacuo to give the title compound (50 mg, 63%) as a yellow oil. 1H NMR (DMSO-d6) δ 8.33 (s, 1H), 8.22 (d, 1H, J=5.6 Hz), 6.96 (dd, 1H, J=8.7, 9.1 Hz), 6.50 (dd, 1H, J=2.0, 13.7 Hz), 6.56 (d, 1H, J=5.6 Hz), 6.41 (dd, 1H, J=2.5, 6.1 Hz), 2.69 (q, 2H, J=7.6 Hz), 1.21 (t, 31H, J=7.6 Hz).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([N:23]1[CH2:47][CH2:46][CH2:45][C@H:24]1[C:25]([NH:27][C@H:28]([C:34]([NH:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:35])[CH2:29][CH2:30][C:31](=[O:33])[NH2:32])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:12])[OH:11])=[O:6])[CH2:3][OH:4]>CO.[Pd]>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([N:23]1[CH2:47][CH2:46][CH2:45][C@H:24]1[C:25]([NH:27][C@H:28]([C:34]([NH:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])=[O:35])[CH2:29][CH2:30][C:31](=[O:33])[NH2:32])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:11])[OH:12])=[O:6])[CH2:3][OH:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C

Procedure:
1.03 Grams of Z-Ser-Asp-Leu-Pro-Gln-NHNHBoc was dissolved in 50 ml of methanol and was catalytically reduced by using palladium as the catalyst to obtain H-Ser-Asp-Leu-Pro-Gln-NHNHBoc.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH3:14])=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:15]([CH3:18])([O-:17])=[O:16].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:14][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH2:18][N+:15]([O-:17])=[O:16])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C(C)c1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CC(C)(C[N+](=O)[O-])c1ccccn1

Procedure:
A solution of 6 g of the compound obtained in Step 1, 3.36 ml of nitromethane and 4.26 ml of DBU dissolved in 120 ml of acetonitrile was heated to reflux for 36 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure. The residue thus obtained was purified by a silica gel column chromatography using a mixture of ethyl acetate and n-hexane of 1:9 to obtain 1.8 g of the title compound as a syrup.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:63][N:64]1[CH:68]=[C:67]([C:69]2[CH:70]=[CH:71][C:72]3[N:73]([C:75]([SH:78])=[N:76][N:77]=3)[N:74]=2)[CH:66]=[N:65]1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:63][N:64]1[CH:68]=[C:67]([C:69]2[CH:70]=[CH:71][C:72]3[N:73]([C:75]([S:78][C:2]4[CH:3]=[C:4]5[C:9](=[CH:10][CH:11]=4)[N:8]=[CH:7][CH:6]=[CH:5]5)=[N:76][N:77]=3)[N:74]=2)[CH:66]=[N:65]1
Reactant: Brc1ccc2ncccc2c1
Reactant: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4)n3n2)cn1
Temperature: 100 °C
Reaction time: 23 h
Yield: 58.2 %

Procedure:
A solution of 6-bromoquinoline (45 mg, 0.215 mmol), diisopropylethylamine (0.075 mL, 0.43 mmol) in DMF (1 mL) under nitrogen was degassed by bubbling in nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium (11 mg, 0.011 mmol), Xantphos (13 mg, 0.022 mmol), and 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (50 mg, 0.215 mmol) were added, and the mixture was degassed for another 5 min. The reaction mixture was stirred at 100° C. for 23 h. More palladium catalyst (11 mg) and ligand (13 mg) were added after 6 h. The reaction mixture was cooled to room temperature, filtered through a 0.45 um filter, and the crude mixture was purified directly by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) to provide 45 mg of 6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-quinoline as a yellow solid (58% yield).