Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([OH:34])=O)=[CH:31][C:26]=2[O:25][N:24]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.S(Cl)([Cl:44])=O>ClCCl>[Cl:44][C:32]([C:30]1[CH:29]=[CH:28][C:27]2[C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:24][O:25][C:26]=2[CH:31]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(C(=O)O)ccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(C(=O)Cl)ccc12

Procedure:
To a solution of 3-(2-(1(S)-(tert-butoxycarbonylamino)-2-(pyridin-2-yl)ethyl) -phenyl)benzo[d]isoxazole-6-carboxylic acid (Compound 18a) (45 mg) dissolved in dry dichloromethane (2 mL) under nitrogen, cooled with ice bath, was added triethylamine (127 μL) then thionyl chloride (35.5 μL). After 10 min the solvents were removed under reduced pressure to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:32][C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@@H:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:29]3)[CH2:27]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:51].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:51][C:16]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:14]=2)[CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:29][C@H:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:32]3)[CH2:27]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2cnccn2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3cnccn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-1-(pyrazin-2-yl)hexane-1,4-dione (284 mg) in acetic acid (2.2 mL) was added ammonium acetate (530 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (94.3 mg, yield 34%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1Br)([CH3:3])[CH3:2].[CH2:14]1[O:16][CH2:15]1.[NH4+].[Cl-]>CCOCC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[CH:15]([OH:16])[CH3:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1Br
Reactant: C1CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1C(C)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,6 diisopropylbromobenzene (see J. Org. Chem., 42(14):2426-2431 (1977) forpreparation) (30 g, 124.4 mmol) was added to a suspension of Li powder (1.9g, 273.6 mmol) in ether (100 mL) heated under reflux, the heating was continued for another 4 hours, cooled, and the mixture was poured into ethylene oxide which was precooled to -78° C. The mixture was warmed slowly to room temperature, saturated NH4Cl solution was added slowly with caution, the ether layer was separated and washed with brine, dried over MgSO4, filtered, and the solvent was evaporated to dryness. After column chromatography (3:1 hexane:ethyl acetate) pure 2,6-diisopropylphenylethanol was obtained (17 g, 6.3%); NMR (CDCl3): δ 1.2-1.3 (m, 12H) , 3.05 (t, 2H), 3.15-3.35 (m, 2H), 3.7-3.8 (t, 2H), 7.1-7.3 (m, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH:9]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: CC(=O)c1cc(Br)c(F)cc1O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1cc(Br)c(F)cc1O
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
In a bottle were combined 1-(5-bromo-4-fluoro-2-hydroxyphenyl)ethanone (8.63 g, 37.15 mmol), benzaldehyde (3.94 g, 37.15 mmol), EtOH (96%, 45 mL) and NaOH (13.08 g, 327 mmol). The mixture was stirred vigorously for 0.5 h. and then filtered. The mixture was poured into HCl (1 N, 50 mL) and filtered. The solid was dried to give 1-(5-bromo-4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (10.8 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:31](=[O:32])[C:11]3=[CH:12][NH:13][C:14]4[CH2:15][CH2:16][CH:17]([O:20]C(OCC5C=CC=CC=5)=O)[CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[H][H]>CN(C=O)C.CCO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:31](=[O:32])[C:11]3=[CH:12][NH:13][C:14]4[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)OC1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CC(O)CC3

Procedure:
2-p-chlorophenyl-8-benzyloxycarbonyloxy-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one (1.60 g) is dissolved in 100 mL of 1:1 mixture of DMF and EtOH and subjected to catalytic hydrogenation with 10% palladium on carbon (0.4 g) for 24 hours under one atmosphere pressure of hydrogen. After the reaction is complete the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is triturated with EtOH to obtain 2-p-chlorophenyl-8-hydroxy-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:22]1[N:26]=[N:25][C:24]([CH3:27])=[N:23]1)[CH2:20]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(SCC(OC)C[NH2:48])CCCCCCCCCCCCCCC.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:1]([S:17][CH2:18][CH:19]([N:22]1[N:26]=[N:25][C:24]([CH3:27])=[N:23]1)[CH2:20][NH2:48])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CO)n1nnc(C)n1
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCSCC(CN)n1nnc(C)n1

Procedure:
3-hexadecylthio-2(5-methyl-2H-tetrazol-2-yl)propanol V h1 is allowed to react and worked up by the same procedure as described in (3). The phthalimide compound: m.p. 82°-83° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: C(Cl)Cl.C(O)(C(F)(F)F)=O.C(OC([N:18]=[C:19]([N:21](C(OC(C)(C)C)=O)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:52])[CH2:27][C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[C:30]([NH:36][CH2:37][C:38]([F:50])([F:49])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45]([CH3:48])(=[O:47])=[O:46])[C:29]=1[F:51])[NH2:20])=O)(C)(C)C>>[C:19]([NH:21][O:22][CH2:23][CH2:24][NH:25][C:26](=[O:52])[CH2:27][C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[C:30]([NH:36][CH2:37][C:38]([F:49])([F:50])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45]([CH3:48])(=[O:47])=[O:46])[C:29]=1[F:51])(=[NH:18])[NH2:20]
Reactant: CC(C)(C)OC(=O)N=C(N)N(OCCNC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2ccccc2S(C)(=O)=O)c1F)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccccc1C(F)(F)CNc1ccc(C#N)c(CC(=O)NCCONC(=N)N)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
A solution of 3:1 CH2Cl2/TFA (0.8 mL) was added to N-[2-(N′,N″-bis(tert-butoxycarbonyl)amidinoaminooxy)ethyl]-2-{3-[(2,2-difluoro-2-(2 methanesulfonylphenyl)ethyl)amino]-6-cyano-2-fluorophenyl}acetamide (34.8 mg, 0.049 mmol)(prepared essentially as described in Example 2h), and the reaction mixture was stirred at room temperature for 3 h. After evaporating the solvents, the residue was subjected to flash chromatography (DCM/MeOH saturated with gaseous NH3; 95:5→90:10) to yield 18.4 mg (74%) of the title compound as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.24 (m, 1H), 7.74 (m, 3H), 7.20 (dd, J=8.6 Hz, 1.3 Hz, 1H), 6.87 (t, J=8.7 Hz, 1H), 4.24 (t, J=14.2 Hz, 2H), 3.80 (t, J=5.2 Hz, 2H), 3.72 (d, J=1.9 Hz, 2H), 3.43 (t, J=5.5 Hz, 2H), 3.27 (s, 3H). LC/MS (m/z) [M+1]+ 513.4 (calculated for C21H24F3N6O4S, 513.5).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][O:20][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Nc1ncc2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a solution of 90 (0.68 g, 2.28 mmol) in DMF (10 mL) was added imidazole (0.54 g, 7.93 mmol) and tert-butyldimethylsilyl chloride (0.68 g, 4.56 mmol) sequentially. The reaction mixture was stirred at room temperature for 2 h, at which point it was concentrated and purified by flash column chromatography (silica, MeOH/CHCl3; gradient=5-20%) to afford 0.49 g (52%) 91 as a white solid: 1H (400 MHz, d6-DMSO) δ 8.33 (s, 1H), 6.87 (s, 2H), 5.90 (d, J=4.0 Hz, 1H), 5.33 (d, J=5.6 Hz, 1H), 5.00 (d, J=5.2 Hz, 1H), 4.79 (q, J=5.2 Hz, 1H), 4.16 (q, J=5.2 Hz, 1H), 3.77 (m, 2H), 3.64 (dd, J=12.0, 7.2 Hz, 1H), 0.84 (s, 9H), 0.00 (s, 6H); MS (+)-ES [M+H]+ m/z 415.4.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[CH3:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][O:16][CH2:17][CH2:18][C:19](OCC)=[O:20])=[CH:13][CH:12]=1>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][CH2:17][CH2:18][C:19](=[O:20])[CH2:1][C:2]#[N:3])=[CH:24][CH:25]=1
Reactant: CC#N
Reactant: CCOC(=O)CCOCc1ccc(OC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(COCCC(=O)CC#N)cc1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of MeCN (31.8 mL, 611.0 mmol) in anhydrous THF (500 mL) at −78° C. was slowly added n-BuLi (2.5 M, 244.4 mL, 611.0 mmol) The mixture was stirred at the same temperature for 1 h and to it was added a solution of at −78° C. was slowly. The mixture was stirred added n-BuLi (2.5 M, 244.4 mL, 611.0 mmol). The mixture was stirred ethyl 3-((4-methoxybenzyl)oxy)propanoate (112 g, 470.0 mmol) in THF (200 mL). The resulting mixture was stirred at −40° C. for 2 h and then quenched with 1 N aqueous HCl (300 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine, dried (Na2SO4) and then concentrated in vacuo to give 5-((4-methoxybenzyl)oxy)-3-oxo-pentanenitrile (78 g, 79%) as yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([O:15][CH3:16])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:17]([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:17]([NH:27][C@H:28]([C:36]([CH:4]1[C:3]2([NH2:2])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]1([C:13]([O:15][CH3:16])=[O:14])[CH2:6]3)[CH2:10]2)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C2
Reaction time: 24 h

Procedure:
To 30 ml of a 1 N sodium hydroxide solution is added 4.95 g of L-phenylalanine. The solution is cooled and stirred in an ice bath and 5.4 ml of a 6.1 M solution of carbobenzoxychloride is added dropwise along with additional 1 N sodium hydroxide solution so that the pH remains at 11.0-11.5. The reaction mixture is washed with ether. The aqueous layer is acidified to pH 1.0 with 12 N hydrochloric acid, then the solution is extracted with ethyl acetate. The ethyl acetate extract is separated and is washed three times with water then dried over magnesium sulfate. The solvent is removed under vacuum. The residue crystallizes on rubbing with water to give N-carbobenzoxy-L-phenylalanine. 3.99 Grams of methyl 3-amino-1-adamantanecarboxylate hydrochloride and 4.78 g of carbobenzoxy-L-phenylalanine are dissolved in 40 ml methylene chloride. To this solution is added 1.8 ml of N-methylmorpholine followed immediately by 2.19 g of dicyclohexylcarbodiimide. The reaction mixture is allowed to stand for 24 hours at room temperature, then the treatment with carbobenzoxy-L-phenylalanine and dicyclohexylcarbodiimide is repeated. The reaction mixture is again allowed to stand for 24 hours at room temperature. The dicyclohexylurea is removed by filtration and washed with methylene chloride. The combined filtrates are washed twice with 0.5 M potassium bisulfate, water and 1 M solution of potassium bicarbonate and dried over magnesium sulfate. The dicloromethane is removed under vacuum and the residue is purified by low pressure chromatography on silica gel using mixtures of hexane and chloroform as eluting solvent to give methyl carbobenzoxy-L-phenylalanyl-3-amino-1-adamantanecarboxylate which has the following structural formula ##STR13## wherein Cbz represents carbobenzoxy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:10]([CH3:20])=[C:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:12]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:10]([CH3:20])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)nc(-c2ccccc2Cl)n1-c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)nc(-c2ccccc2Cl)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl 2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-1H-imidazole-4-carboxylate (69 mg, 0.17 mmol) was dissolved in dry dichloromethane (2 mL) and treated dropwise with trifluoroacetic acid (2 mL). After stirring at rt for 2 h, the solution was concentrated to give 2-(2-chlorophenyl)-5-methyl-1-(4-nitrophenyl)-1H-imidazole-4-carboxylic acid as a yellow foam, which was used without purification in the preparation of Example 23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH:32][C:33](=[O:35])[CH3:34])=[CH:24][CH:23]=1.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[C:16]([O:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([NH:32][C:33](=[O:35])[CH3:34])=[CH:24][CH:23]=3)[CH:17]=[N:18][CH:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CC(=O)Nc1ccc(O)c2ccccc12
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccc(NC(C)=O)c4ccccc34)n2)cc(OC)c1OC
Yield: 6.7 %

Procedure:
Using Method X, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and N-(4-hydroxynaphthalen-1-yl)acetamide (CJS 704), using an identical workup and chromatography using a mixture of ethyl acetate and dichloromethane (7:3) furnished 31 mg of the title compound. Yield: 6.7%. 1H NMR (250 MHz, DMSO-d6) δ 2.21 (s, 3H), 3.20 (s, 9H), 3.48 (s, 3H), 6.61 (s, 2H), 7.31 (d, 1H, J=8.2 Hz), 7.59 (t, 2H, J=7.6 Hz), 7.70 (d, 1H, J=8.3 Hz), 7.91 (s, 1H), 7.96-7.99 (m, 2H), 8.13 (d, 1H, J=7.8 Hz), 9.49 (s, 1H), 9.93 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6) δ 23.44, 55.10, 59.95, 95.38, 116.77, 120.89, 121.48, 121.61, 123.18, 126.38, 126.53, 127.11, 128.23, 128.71, 130.90, 131.98, 136.18, 146.44, 150.64, 152.59, 158.26, 168.93. m/z [(M+H)+ calcd for C25H24N4O5 460.2].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:15])=[CH:7]2.[OH:34]OS([O-])=O.[K+].O>CN(C=O)C>[CH:22]1[C:21]2[CH:20]([CH2:19][O:18][C:17]([NH:16][C@H:14]([C:8]3[N:9]=[C:10]([C:12]([OH:34])=[O:13])[C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[CH:3][C:2]=4[Cl:1])[CH3:15])=[O:33])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C=O)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C(=O)O)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-formylisoquinolin-3-yl)ethylcarbamate (348) (12.0 g, 26.3 mmol, 1.0 eq) in DMF (150 mL), OXONE (30 g, 48.78 mmol, 1.85 eq) was added and the resulting mixture was stirred at RT over night. The mixture was poured into water (600 mL) and then filtered. The solid was dissolved in ethyl acetate (100 mL), and then PE (300 mL) was added dropwise to this solution. The precipitate was collected by filtration to afford (S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylic acid (349).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:21][CH2:22][CH2:23][CH2:24][S:25]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4S(=O)(=O)CCCCl)c2n1

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (270 mg, 1.03 mmol) (Intermediate 10.1), 3-chloropropanesulfonyl chloride (0.25 ml, 2.06 mmol), and N,N-diisopropylethylamine (1.08 ml, 6.18 mmol) in dichloromethane (15 ml) is stirred for 10 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 351 mg (85%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 8.44 min (tR(SM) 6.59 min). MS (ESI) m/z (C19H19ClN4O2S) 403.0 (m, 100), 294.9 (65) Finnegan LCQ.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]1([C:14]2[O:18][N:17]=[CH:16][C:15]=2[CH2:19][CH2:20][C:21](O)=[O:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:21](=[O:22])[CH2:20][CH2:19][C:15]1[CH:16]=[N:17][O:18][C:14]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A mixture of 2-aminopyrazine (0.26 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.58 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(2-pyrazinyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.46 g, yield 58%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 163–164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2C=O.[N+:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[NH:27][NH2:28])([O-:17])=[O:16].O>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[N:28][NH:27][C:19]3[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=3[N+:15]([O-:17])=[O:16])[CH:7]([Cl:12])[CH:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Reactant: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(NN=C2c3ncc(Cl)cc3C=CC2Cl)c([N+](=O)[O-])c1
Yield: 85.5 %

Procedure:
23 g of 3,7-dichloroquinoline-8-carbaldehyde and 20 g of 2,4-dinitrophenylhydrazine in 500 ml of ethanol were heated at 80° C. for 5 hours. Water was added to the reaction mixture, and the precipitated solid was filtered off under suction and recrystallized from dimethylformamide to give 34 g (85% of theory) of 3,7-dichloro-8-(2,4-dinitrophenylhydrazono)-quinoline of melting point >280° C.