Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][C:19]1(N)[CH2:24][CH2:23][N:22]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH2:21][CH2:20]1>CC(O)C.CO>[C:27]1([CH:25]([N:22]2[CH2:23][CH2:24][C:19]3([NH:16]/[C:13](=[N:12]/[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17][CH2:18]3)[CH2:20][CH2:21]2)[CH3:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(c1ccccc1)N1CCC(N)(CN)CC1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CC(C)O
Solvent: CO
Product: CC(c1ccccc1)N1CCC2(CC1)CN/C(=N\C(=O)c1nc(Cl)c(N)nc1N)N2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (1.7 g, 4.54 mmol) and 4-aminomethyl-1-(1-phenyl-ethyl)-piperidin-4-ylamine (Intermediate BM) (1.6 g, 4.59 mmol) in propan-2-ol (50 ml) is stirred at 80° C. for 16 hours. The reaction mixture is concentrated in vacuo and purified by column chromatography (basic alumina, 0-2% MeOH in DCM) to obtain pale yellow solid. The compound obtained is further dissolved in MeOH and precipitated by adding diethyl ether. The supernatant solvent mixture is decanted and the product is washed again with diethyl ether and dried under vacuum to afford the title compound as off-white solid; [M+H]+ 429
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[CH:18]=[C:19]2[C:27]([C:28]3[CH:33]=[C:32]([CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:31]=[CH:30][C:29]=3[O:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[F:47])=[CH:26][N:25]([CH3:48])[C:20]2=[C:21]([O:23][CH3:24])[N:22]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[O:39][C:29]1[CH:30]=[CH:31][C:32]([CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:28]=1[C:27]1[C:19]2[C:20](=[C:21]([O:23][CH3:24])[N:22]=[C:17]([CH:1]=[CH2:2])[CH:18]=2)[N:25]([CH3:48])[CH:26]=1
Reactant: COc1nc(Br)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c2c(OC)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
Tributyl(vinyl)tin (0.053 g, 0.167 mmol), the product from Example 91E (0.075 g, 0.140 mmol) and Pd(PPh3)2Cl2 (9.80 mg, 0.014 mmol) were combined in dioxane (1.163 mL) and sparged with argon for 15 minutes. The mixture was stirred for 2 hours at 100° C., cooled and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), treated with 3-mercaptopropyl functionalized silica gel, filtered, and concentrated. Purification by chromatography (silica gel, 0-40% ethyl acetate in heptanes) afforded the title compound (0.041 g, 61%).
Reaction SMILES: C(OC(N(C(OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH:37]3[CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>>[CH:37]1([C:33]2[CH:34]=[C:35]([CH3:36])[C:30]([N:27]3[CH2:26][CH2:25][N:24]([C:22]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][C:17]5=[O:21])=[CH:15][C:10]=4[C:9]([N:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[O:40])=[O:23])[CH2:29][CH2:28]3)=[N:31][CH:32]=2)[CH2:39][CH2:38]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Reactant: C1COCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N2CCOCC2)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 814 and morpholine (38 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (20 mg) was obtained.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[C:8]([O:11][C:12](=O)C)(=O)[CH3:9].C(O)(=O)C>C(O)C>[CH2:8]([O:11][CH:12]=[CH:2][C:1]([CH2:4][C:5](=[O:7])[CH3:6])=[O:3])[CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC=CC(=O)CC(C)=O
Reaction time: 2.5 h

Procedure:
253 g (2.5 moles) of acetylacetone, 1,110 g (7.5 moles) of orthformic acid triethyl ester and 8 g of acetic anhydride are heated to ebullition in a flask with vigorous stirring. During the reaction, about 23 g of acetic acid is added and the ethanol formed is distilled off. After 2 to 3 hours the reaction is completed. The unreacted orthoformic acid triethyl ester is distilled out at reduced pressure (5 to 1 Torr) through the top of the column and fed back to the next batch. Following this, 355 g of ethoxymethylene acetylacetone is evaporated, separated from the residue through a simple distillation bridge at 0.1 to 0.3 Torr. The yield, referred to acetylacetone, was 91% of theory.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][CH:13]=[CH2:14])(=[O:3])[CH3:2].[BrH:15].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCCCCC>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][CH2:13][CH2:14][Br:15])(=[O:3])[CH3:2]
Reactant: Br
Reactant: C=CCc1cccc(C)c1OC(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Product: CC(=O)Oc1c(C)cccc1CCCBr
Yield: 58.1 %

Procedure:
The protected monohydroxy compound, 1-acetoxy,2-(2 propenyl)-6-methylbenzene was the starting material. Halogenation was achieved by bubbling HBr through a hexane solution (250 ml.) of the starting material (61.3 g, 0.323 moles) and dibenzoyl peroxide (2 g) for 2 hours. The reaction mixture was washed twice with saturated NaHCO3 solution (2×200 ml.) and once with H2O. The hexane layer was dried over Na2SO4 and the solvent evaporated. The desired 1-acetoxy,2-(3-bromopropyl)-6-methylbenzene was isolated by distillation. The % yield was 58.1% (40.84 g, BP=164°-166° C. at 0.03 Torr).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[C:10](Cl)(=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Product: CCCCCCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Yield: 86.9 %

Procedure:
Following the procedure described in Referential Example 3, but using 4-(S)-isopropyl-2-oxazolidinone (5.39 g) and dodecanoyl chloride (9.46 g), the desired compound (11.3 g) was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH2:16])([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:16][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Nc1ccc(-c2ccncc2)cc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To a solution of 2-nitro-4-pyridin-4-ylphenylamine (1 mmol) in pyridine (3 mL), 4-chloro-benzenesulfonyl chloride (1.2 mmol) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (20 mL). The contents were washed with brine (25 mL), dried over sodium sulfate and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate (1:1) then ethyl acetate to give 156 mg of 4-chloro-N-(2-nitro-4-pyridin-4-ylphenyl)benzene sulfonamide.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][C@H:7]2[CH2:9][C@@H:4]1[C:5](=[O:10])[O:6]2)[CH3:2].[NH:11]([C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=1)[NH2:12].C[Al](C)C.Cl>O1CCOCC1>[CH2:1]([C@@H:3]1[CH2:8][C@H:7]([OH:6])[CH2:9][C@@H:4]1[C:5]([NH:12][NH:11][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=1)=[O:10])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC[C@@H]1C[C@H]2C[C@@H]1C(=O)O2
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835 g, 5.96 mmol) in 1,4-dioxane (12 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (step D, 1.810 g, 5.96 mmol). The reaction mixture was heated at about 80° C. for about 16 h then cooled to ambient temperature. 1,4-Dioxane (25 mL) and trimethylaluminum (2 N in toluene, 9 mL, 18 mmol) were added sequentially. The reaction mixture was stirred at ambient temperature for about 30 min then HCl (1 N aqueous, 50 mL) was added dropwise and the reaction mixture was stirred for about 30 min. The layers were separated and the aqueous portion was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (10 mL), saturated aqueous NaHCO3 (15 mL), brine (15 mL) and dried over anhydrous MgSO4, filtered, and coned under reduced pressure. The residue was purified using silica gel chromatography (40 g) eluting with 100% EtOAc to give (1S,2R,4S)-2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (1.887 g, 71%): LC/MS (Table 1, Method b) Rt=2.05 min; MS m/z: 444 (M+H)+.
Reaction SMILES: [CH2:1]([S:6]([OH:9])(=[O:8])=[O:7])[S:2]([OH:5])(=[O:4])=[O:3].C(=O)([O-])[O-].[Ag+2:14].C(=O)=O>O>[CH2:1]([S:6]([O-:9])(=[O:8])=[O:7])[S:2]([O-:5])(=[O:4])=[O:3].[Ag+2:14]
Reactant: O=S(=O)(O)CS(=O)(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Product: O=S(=O)([O-])CS(=O)(=O)[O-]

Procedure:
A 50% solution of methanedisulfonic acid in water (2.5 grams) was diluted in 25 mL of water into which, while stirring, silver carbonate (3.91 grams) was added slowly. The silver carbonate dissolved with effervescence of carbon dioxide. After the reaction was complete remaining insoluble material was removed by filtration and the filtrate was stripped of water and dried under high vacuum at 45° C. to give 4.9 grams of white crystals.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: O=Cc1c(N2CCOCC2)n(-c2ccccc2)c2ccccc12

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with morpholine as described in Step 2 of Example 29 to afford 2-(morpholin-4-yl)-1-phenyl-1H-indole-3-carboxaldehyde (885 yield) as a fluffy, creamy solid. ESI/MS 307 (M+H); RT=2.99 min; NMR 10.15 (1H, s); 8.14 (1H, d, J=6 Hz); 7.69 (5H, m); 7.22 (2H, m); 6.94 (1H, d, J=9 Hz); 3.45 (4H, m); 3.28 (4H, m).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>C(O)(=O)C>[N+:17]([CH:20]=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)([O-:19])=[O:18]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To piperonal (15.55 kg, 103.5 mol) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70° C. After about 30 minutes, the yellow product began to crystallize. The reaction temperature was raised to 80° C. and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was cooled to 10° C. and filtered. The precipitate was washed with acetic acid (2×8 kg) and then water (2×90 kg). The product was dried under a nitrogen purge and then in a vacuum oven at 50° C. for 2 days to afford 15.94 kg (80%) of the title compound as a bright yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)(=O)C>[C:24]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:5][CH2:6]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(CCC(=O)c2cc3c4c(c2)CCN4C(=O)CC3)CC1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A mixed solution of 8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (free base, 0.30 g, 0.96 mmol) and acetic anhydride (0.11 ml, 1.16 mmol) in ethyl acetate (25 ml) was heated at 55-60° C. with stirring for 1 hour. The solvent was then distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=10:1) to provide the title compound (0.185 g) as colorless powders melting at 160-161° C.
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4](SC)[S:5][CH3:6])#[N:2].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][NH:17][NH2:18]>C(O)C>[NH2:10][C:9]1[N:17]([CH2:16][C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:22])([F:23])[F:11])[CH:14]=2)[N:18]=[C:4]([S:5][CH3:6])[C:3]=1[C:1]#[N:2]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: NNCc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: CSc1nn(Cc2cccc(C(F)(F)F)c2)c(N)c1C#N
Yield: 79.4 %

Procedure:
8.5 g (0.05 mol) of 1,1-dicyano-2,2-bis(methylthio)-ethylene and 9.5 g (0.06 mol) of 3-trifluoromethylbenzyl-hydrazine (compare DE-OS (German Published Specification) No. 2,230,675) are stirred in 100 ml of ethanol at 20° C. for 15 hours. For working up, the solvent is removed in vacuo and the residue is triturated with petroleum ether. Filtration with suction gives 12.4 g (80% of theory) of 5-amino-4-cyano-3-methylthio-1-(3-trifluoromethylbenzyl)-pyrazole of melting point 142° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][CH2:17][NH:18][C:19]1[C:20](=[O:30])[N:21]([CH2:26][C:27]([OH:29])=O)[C:22]([CH3:25])=[CH:23][N:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([CH2:44][NH2:45])[CH:42]=2)[NH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O>[CH3:25][C:22]1[N:21]([CH2:26][C:27]([NH:45][CH2:44][C:41]2[CH:42]=[C:43]3[C:38](=[CH:39][CH:40]=2)[NH:37][CH:36]=[C:35]3[CH3:34])=[O:29])[C:20](=[O:30])[C:19]([NH:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([CH:33]=[CH:32][CH:31]=2)[CH2:12][O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:24][CH:23]=1
Reactant: Cc1cnc(NCCc2cccc(COCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(COCCNC(=O)OC(C)(C)C)c4)c3=O)cc12
Yield: 96.1 %

Procedure:
A mixture of 2-[3-{[3-({2-[(tert-butoxycarbonyl)amino]ethoxy}methyl)phenethyl]amino}-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 107) (174 mg, 0.38 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (67 mg, 0.42 mmol), HOBT (77 mg, 0.57 mmol), WSCDl.HCl (91 mg, 0.47 mmol) and N-methylmorpholine (124 ml, 1.13 mmol) in N,N-dimethylformamide (5 ml), was stirred at room temperature for 20 hrs. The reaction mixture was partitioned between ethyl acetate and water and the phases separated. The organic layer was dried over MgSO4 and evaporated under reduced pressure to give the title compound as a white solid, (220 mg, 96%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>N1C=CC=CC=1>[CH2:29]([NH:31][C:32]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1)=[O:33])[CH3:30]
Reactant: CCN=C=O
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)cn3c2)c1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cn2cc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
A mixture of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (301 mg, 0.800 mmol), ethyl isocyanate (100 μL, 1.27 mmol) and pyridine (10 mL) was stirred at 50° C. for 18 hr. The mixture was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→0/100) and recrystallized from ethyl acetate-hexane to give the title compound (78.0 mg, 22%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 117 mg of 4-Isopropoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.01 (d, 6H, J=5.6 Hz), 4.27 (m, 1H), 6.51 (d, 2H, J=8.8 Hz), 6.87 (d, 1H, J=8.8 Hz), 7.15-7.25 (m, 4H), 7.60 (d, 2H, J=6.0 Hz), 8.64 (d, 2H, J=6 Hz), 9.60 (s, 1H). MS: m/z 431.9 (M++1).
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)C.[I:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26]CCI>>[I:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=1
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1
Reactant: ICCOCCOCCI
Product: CCCC(=O)c1ccc(OCCOCCOCCI)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 21 except that 1,2-bis-(2-iodoethyloxy)ethane was used instead of 2-(diethylamino)ethyl chloride hydrochloride. This produced the crude product which was purified by flash silica gel column chromatography, eluting with 4:1 hexanes/ethyl acetate to give 43 (3.85 g, 52%) as a clear oil: MS (ES+) m/z 407.0 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:42]=[CH:41][C:18]([C:19]([NH:21][N:22]=[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([I:32])[CH:30]=5)[N:25]([CH2:33][CH2:34][CH2:35][C:36]([O:38]C)=[O:37])[C:24]4=[O:40])=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+]>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:21]/[N:22]=[C:23]4\[C:24](=[O:40])[N:25]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:26]5[C:31]\4=[CH:30][C:29]([I:32])=[CH:28][CH:27]=5)=[O:20])=[CH:41][CH:42]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)CCCN1C(=O)C(=NNC(=O)c2ccc(NC(=O)CCc3ccc4c(c3)OCO4)cc2)c2cc(I)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCN1C(=O)/C(=N\NC(=O)c2ccc(NC(=O)CCc3ccc4c(c3)OCO4)cc2)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
Into a suspension of methyl 4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoate (150 mg, 0.22 mmol) in THF/H2O (2/1) (10 mL) was added NaOH (1.0 N, 1.1 mL). The resulting solution was stirred at rt for 2 hr and quenched with HCl (5 N, 4 mL). A yellow solid precipitated out. Filtration, washing with water (4×10 mL) and drying under vacuo at 60° C. for 15 hrs gave the title compound as a yellow powder (90 mg, 58%) in 95.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:14]=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:9]
Reactant: COc1ccc(Oc2ccc(C(F)(F)F)cc2N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: COc1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)c2cc(Cl)ccc2O)cc1
Yield: 88.1 %

Procedure:
Using 5-chlorosalicylic acid and 3-amino-4-(4-methoxyphenoxy)-benzotrifluoride as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C(C)(C)C)ccc1O
Solvent: CC(=O)O
Product: Cc1cc(C(C)(C)C)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
4-tert-Butyl-2-methyl-phenol (1.64 g, 10 mmol) was dissolved in 15 mL acetic acid, fuming nitric acid (0.47 mL, 10 mmol) was added and the resulting solution was stirred at rt overnight. The reaction mixture was then poured onto crushed ice, and extracted with chloroform. The organic phase was washed with water, and dried over sodium sulfate. Evaporation gave 2.02 g the nitration product as a red oil.