Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:14])[N:3]=1.[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][NH2:19]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(NCCC(C)(C)C)cc(C)nc1Cl
Yield: 79.9 %

Procedure:
A solution of ethyl 2,4-dichloro-6-methyl-3-pyridinecarboxylate (1.00 g, 4.27 mmol) in ethanol (20.0 mL) was treated with (3,3-dimethylbutyl)amine (0.570 mL, 4.27 mmol). The mixture was refluxed for 2 days, and upon cooling, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash column chromatography (20-60% ethyl acetate in hexanes) to afford the title compound as an amber oil (1.02 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.94 (t, J=4.4 Hz, 1H), 6.18 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 2.82-3.17 (m, 2H), 2.25 (s, 3H), 1.35-1.54 (m, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.84 (s, 9H). MS(ES+) m/e 299 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[N:30]1[C:37](Cl)=[N:36][C:34]([Cl:35])=[N:33][C:31]=1[Cl:32].C([O-])([O-])=O.[Na+].[Na+].O>CC(C)=O>[Cl:35][C:34]1[N:33]=[C:31]([Cl:32])[N:30]=[C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:37]4[N:36]=[C:34]([Cl:35])[N:33]=[C:31]([Cl:32])[N:30]=4)=[CH:18][CH:17]=3)([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:37]4[N:36]=[C:34]([Cl:35])[N:33]=[C:31]([Cl:32])[N:30]=4)=[CH:25][CH:24]=3)[C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:37]4[N:36]=[C:34]([Cl:35])[N:33]=[C:31]([Cl:32])[N:30]=4)=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)[N:36]=1
Reactant: Nc1ccc(C(c2ccc(N)cc2)(c2ccc(N)cc2)c2ccc(N)cc2)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Nc2ccc(C(c3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)(c3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)c3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)cc2)n1
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of tetrakis(4-aminophenyl)methane (4.57 grams, 12.0 mmol; prepared as described in Example C) in acetone (96 milliliters) was added dropwise at 0° C. to a stirred solution of cyanuric chloride (9.06 grams, 49.1 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) in acetone (144 milliliters). The resulting mixture was kept at 0° C. for 1 hour, treated with Na2CO3 (5.21 grams, 49.2 mmol), and poured into water (960 milliliters). The precipitate was separated by filtration, washed with water, and dried to give the tetrakis[4-[(2,4-dichloro-1,3,5-triazin-6-yl)amino]phenyl]methane (7.97 grams, 8.20 mmol, 68 percent yield) as a colorless solid: mp>310° C.; 1H NMR (400 MHz, DMSO-d6, 25° C.) δ7.18 (d, 8H, 3J=8.7 Hz), 7.55 (d, 8H, 3J=8.7 Hz), 11.18 (s, 4H); 13C NMR (75.4 MHz, DMSO-d6, 25° C.)δ64.1, 121.7, 131.7, 135.8, 143.8, 164.6, 169.7, 170.7; MS (FAB, 2-nitrobenzyl alcohol) m/e 969. Anal. Calcd for C37H20Cl8N16: C, 45.71; H, 2.07; N, 23.05. Found: C, 46.03; H, 2.09; N, 22.61.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([C@@H:14]2[CH2:18][N:17]([CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([F:35])[CH:37]=3)[C@H:16]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:25][CH2:26]3)=[O:20])[CH2:15]2)[N:13]=1
Reactant: O=Cc1cccc(F)c1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2cccc(F)c2)CC1
Yield: 13.3 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 3-fluoro-benzaldehyde (17 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (9.9 mg, 13.3%) as light yellow oil. MS m/e=573.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][N:19]3[C:27](=[O:28])[C:26]4[NH:25][CH:24]=[N:23][C:22]=4[N:21]=[CH:20]3)[C:12]=2[F:29])[CH:9]=1)[C:5]#[N:6].[CH2:30]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH2:32]>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>[Cl:17][C:16]1[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([CH2:32][CH:31]=[CH2:30])[CH:9]=2)[C:5]#[N:6])=[C:12]([F:29])[C:13]([CH2:18][N:19]2[C:27](=[O:28])[C:26]3[NH:25][CH:24]=[N:23][C:22]=3[N:21]=[CH:20]2)=[CH:14][CH:15]=1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1
Temperature: 160 °C
Yield: 28 %

Procedure:
A mixture of 3-bromo-5-({6-chloro-2-fluoro-3-[(6-oxo-6,7-dihydro-1H-purin-1-yl)methyl]phenyl}oxy)benzonitrile (78 mg, 0.164 mmol), allyltri-n-butyltin (0.082 ml, 0.263 mmol) and tetrakis(triphenylphosphine)palladium(0) (18.99 mg, 0.016 mmol) was heated in a personal microwave reactor at 160° C. for 20 min. The mixture was filtrated and was purified with reverse phase HPLC to afford a white solid 3-({6-chloro-2-fluoro-3-[(6-oxo-6,7-dihydro-1H-purin-1-yl)methyl]phenyl}oxy)-5-(2-propen-1-yl)benzonitrile (20 mg, 27.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1H) 8.06-8.20 (m, 1H) 7.35-7.52 (m, 1H) 7.23-7.32 (m, 1H) 7.18 (s, 1H) 7.12 (s, 1H) 5.79-5.98 (m, 1H) 5.27 (s, 2H) 5.02 (s, 1H) 3.38 (d, 2H). LC-MS (ES+) m/z 435.50, [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Yield: 96.5 %

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1 g, 3.3 mmol) in EtOH (25 mL) containing PtO2 (250 mg) was placed on a Parr hydrogenator at 60 psi H2. After 18 h the mixture was filtered through celite and evaporated to give 0.96 g (97%) of a white solid. TLC (silica, 50% EtOAc/hexanes): Rf=0.5. MS (electrospray): exact mass calculated for C17H23N3O22, 301.18; m/z found, 302.2 [M++H]. 1H NMR (CDCl3, 400 MHz) 10.95 (br s, 1H), 8.26 (dd, J=3.33 Hz, 1.37 Hz, 1H), 7.96 (dd, J=6.26 Hz, 1.57 Hz, 1H), 7.11 (s, 1H), 7.05 (dd, J=4.89 Hz, 3.13 Hz, 1H), 4.22 (br s, 2H), 3.00-2.79 (m, 3H), 1.99 (d, J=13.89 Hz, 2H), 1.74-1.60 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[C:15]([O:18][CH2:19][CH:20]([CH2:31][O:32][NH2:33])[O:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])(=[O:17])[CH3:16].C(N(CC)CC)C>O1CCOCC1>[C:15]([O:18][CH2:19][CH:20]([O:21][CH2:22][P:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:30])[CH2:31][O:32][NH:33][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])(=[O:17])[CH3:16]
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CCOP(=O)(COC(CON)COC(C)=O)OCC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOP(=O)(COC(CONc1nc(NC=O)nc(Cl)c1NC=O)COC(C)=O)OCC
Temperature: 120 °C
Yield: 81.4 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (0.475 mg, 2 mmol), diethyl [2-acetoxy-1-(aminooxymethyl)ethoxy)methylphosphonate (0.60 mg, 2 mmol) and triethylamine (0.54 ml, 4 mmol) in dry dioxan (20 ml) was heated at 120° C. for 5 hours. The reaction mixture was cooled to ambient temperature, filtered, and the filtrate evaporated to leave a yellow oil. The oil was chromatographed on silica gel (eluant dichloromethane:methanol 97:3) to give the title compound as a pale yellow solid (0.81 g, 80%). 1H NMR: δH [(CD3)2SO] 1.23 (2×3H, 2×t, J=7 Hz, (OCH2CH3)2), 2.03 (3H,s, COCH3), 3.80-4.35 (11H,m, CH2CHCH2 +(OCH2CH3)2 +OCH2P), 8.16 (1H,br.s, sharpens to s. on D2O, CHO), 9.26 (1H,d,J=9.9 Hz. collapses to s. on D2O. CHO), 9.45 (1H,br.s, D2O exchangeable, NH), 10.8-10.95 (2H,m, D2O exchangeable 2×NH). Found: C,37.36; H,5.37; N,13.43%; C16H25N5O9PCl.H2O requires: C,37.18; H,5.27; N,13.55%. m/z: observed 497.1082; C16H25N5O9PCl(M+) requires 497.1078.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([CH2:22][NH2:23])[CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[S:41]([NH:23][CH2:22][C:11]1[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[N:12]=1)(=[O:42])=[O:43]
Reactant: NCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)NCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of [5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-yl]methyl amine hydrochloride (391 mg, 1 mmol) was suspended in dry dichloromethane (10 mL), and diisopropylethylamine (323 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. 2-Chloro-6-methyl-benzenesulfonyl chloride (225 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solution was then washed with water, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield 2-chloro-N-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-ylmethyl]-6-methyl-benzenesulfonamide which was purified by column chromatography using dichloromethane/methanol (98:2) (440 mg, 81% as a cream solid).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([CH2:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O)=[O:21])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:26]([C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[O:23][CH2:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)COc1ccccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)COc1ccccc1-c1nc2n(C3CCCC3)[nH]c(CC)c-2c(=O)n1
Yield: 38.4 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (5.26 g, 23.7 mmol), 2-(ethoxycarbonylmethoxy)benzaldehyde (9.10 g, 47.3 mmol), p-toluenesulfonic acid (0.2 g) and xylenes (100 ml) was refluxed for 18 hours with the azeotropic removal of water. The solvent was removed in vacuo, and the residue was treated with ethanol and evaporated to dryness. The residue was partitioned between chloroform and 10% aqueous K2CO3, the layers were separated and the aqueous layer was extracted with chloroform (100 ml). The organic layers were combined, and concentrated to dryness. The residue was preloaded on silica gel and then was purified by column chromatography on silica gel eluting with hexanes (100%) to 20% ether/hexane to afford 3.74 g (38%) of 1-cyclopentyl-3-ethyl-6-[2-(ethoxycarbonylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 116-117° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C.Cl>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: CCCc1ccc(Br)cc1
Agent: [Cu]I
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCc1ccc(C#C[Si](C)(C)C)cc1
Yield: 87.1 %

Procedure:
To 15.0 g (75.4 mmol) of 1-n-propyl-4-bromobenzene were added 8.8 g (89.8 mmol) of trimethylsilylacetylene and 100 ml of triethylamine (NEt3), and the reaction system was purged with argon. Next were added 81 mg (0.4 mmol) of copper (I) iodide (CuI), 324 mg (1.2 mmol) of triphenylphosphine, and 162 mg of dichlorobistriphenylphosphine palladium (II) [PdCl2(PPh3)2] to the reaction system, and the mixture was subjected to reaction for 24 hours with heating and refluxing. After completion of the reaction, the reaction mixture was poured into an iced water, and the resultant mixture was acidified by adding hydrochloric acid. After the resultant water-insoluble oil was extracted with hexane, the hexane phase was washed with water. By removing hexane from the hexane phase, 14.2 g (65.7 mmol) of 1-(4-n-propylphenyl)-2-trimethylsilylacetylene was obtained.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1C(O)=O)=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl[C:24](=[CH2:29])[C:25]([O:27][CH3:28])=[O:26].C(N(CC)CC)C>ClC(Cl)C>[C:24]1([C:25]([O:27][CH3:28])=[O:26])[CH:29]=[CH:1][N:3]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: C=C(Cl)C(=O)OC
Reactant: O=CN1CCCCC1C(=O)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccn2c1CCCC2

Procedure:
To a solution of 10 g of the carboxylic acid obtained in Step A (63.6 mmol) in 65 mL of dichloroethane there are successively added 13.4 g of tosyl chloride (70.4 mmol), 11.5 mL of methyl 2-chloroacrylate (113.5 mmol) and then, dropwise, 17.8 mL of N,N,N-triethylamine (127.2 mmol). The reaction mixture is then refluxed for 1 hour 30 minutes. It is then placed at ambient temperature, and there are then added 5 mL of methyl 2-chloroacrylate (48.9 mmol) and, dropwise, 9 mL of N,N,N-triethylamine (64 mmol). The batch is refluxed overnight.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([OH:15])=[O:14])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:21][CH2:22]O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:21][CH3:22])=[O:14])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nc2cc(O)ccc2cc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2ccc(O)cc2nc1C
Temperature: 75 °C

Procedure:
7-Hydroxy-2-methylquinoline-3-carboxylic acid (860 mg, 4.24 mmol) was dissolved in EtOH (29 mL) and H2SO4 (0.3 mL) was added. The reaction was heated at 75° C. for 23 h before being concentrated onto silica. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a yellow solid sulfate salt (1.128 g, 81%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[NH2:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:17](OC(OCC)OCC)(=O)C>>[Si:1]([O:8][C:9]1[C:10]2[NH:16][CH:17]=[N:15][C:11]=2[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1N
Reactant: CCOC(OCC)OC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2nc[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.5 %

Procedure:
To 3-{[tert-butyl(dimethyl)silyl]oxy}benzene-1,2-diamine (4.27 g, 17.9 mmol) is added diethoxymethyl acetate (8.7 g, 53.6 mmol), and the mixture is stirred at room temperature for 5 hours. The precipitated white solid is collected by filtration, and the filtrate is further stirred at room temperature for 12 hours. The precipitated white solid is collected by filtration, and washed with a small amount of hexane. The filtrate is concentrated under reduced pressure, ant the obtained residue is purified by silica gel column chromatography (ammonic chloroform) to give the title compound as white solid (1.89 g, yield: 43%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)c1ccc(CCCNCCCc2cccc(Cl)c2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(3-(3-(3-chloro-phenyl)-propylamino)-propyl)-thiophene-2-carboxylic acid methyl ester (from Preparation 8, 0.0855 g, 0.243 mmol), triethylamine (0.0541 g 0.534 mmol), and pyridine-3-sulfonyl chloride hydrochloride (from Preparation 2, 0.0572 g, 0.267 mmol) in 10 mL CH2Cl2 combined at 0° C. was stirred at room temperature overnight. The organic solution was washed with water, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step A as an oil. MS 494 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[C@@H:27]([CH2:38][O:39]C(=O)C)[O:26][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH3:16])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH3:16])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C@@H:6]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:5]1[OH:4]
Reactant: COCc1ccc(Cc2ccc(OC)cc2)c(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(Cc2ccc(OC)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of 2-(4-methoxybenzyl)-5-methoxymethyl-phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.14 g) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 0.047 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on benzenesulfonylpropyl silica gel (eluent: methanol) to give 2-(4-methoxybenzyl)-5-methoxymethylphenyl β-D-glucopyranoside (0.084 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:8]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)N1CCCCC1)CN2
Reactant: O=Cc1ccccc1
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)N1CCCCC1)CN2Cc1ccccc1

Procedure:
The title compound was prepared from 155A and benzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 7.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 411 [M+1]+. Chiral HPLC 100% e.e.; retention time 29.7 min; Conditions: AD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 60 min at 11 mL/min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[N:3]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([NH:1][C:2]2[C:7]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=3[Cl:16])=[N:6][CH:5]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[N:3]=2)=[O:25])[CH2:23][CH2:22]1
Reactant: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Reactant: O=C(Cl)C1CC1
Product: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(NC(=O)C2CC2)n1

Procedure:
This compound was prepared in an analogous manner to Example 9 from 2-amino-6-acetamido-3-(2,3,5-trichlorophenyl)pyrazine (Example 1) and cyclopropylcarbonyl chloride (Aldrich). Yield 0.387 g (61%) N.m.r. (D6DMSO) δ: 0.53 (2H, m), 0.7 (2H, m), 1.75 (1H, m), 2.18 (3H, s), 7.43 (1H, d), 7.87 (1H, d), 9.22 (1H, s), 10.36 (1H, b), 10.83 (1H, b).
Reaction SMILES: C([SiH](CC)CC)C.O[CH:9]([C:19]1[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([O:28][CH3:29])=[C:21]([O:30][CH3:31])[C:20]=1[O:32][CH3:33])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1>C(Cl)Cl.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>[CH3:33][O:32][C:20]1[C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[C:23]([O:26][CH3:27])=[C:24]([CH3:25])[C:19]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=1
Reactant: COc1c(C)c(C(O)c2ccc(C(=O)O)cc2)c(OC)c(OC)c1OC
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(C(=O)O)cc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of triethylsilane (1.39 ml, 8.74 mmol) and TMSOTf (0.056 ml, 0.31 mmol) in methylene chloride (30 ml) was added dropwise a solution of the compound (2.26 g, 6.24 mmol) obtained in Step 1 in methylene chloride (12 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with water, dried, and then the solvent was distilled off to yield the title compound (1.98 g, 5.75 mmol, yield 96%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:35]=[CH:34][C:15]4[N:16]([C:19]5[CH:20]=[C:21]([NH:30][C:31](=[O:33])[CH3:32])[CH:22]=[C:23]([N:25]6[CH:29]=[CH:28][CH:27]=[N:26]6)[CH:24]=5)[CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[CH3:42][S:43]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:35]=[CH:34][C:15]4[N:16]([C:19]5[CH:20]=[C:21]([NH:30][C:31](=[O:33])[CH3:32])[CH:22]=[C:23]([N:25]6[CH:29]=[CH:28][CH:27]=[N:26]6)[CH:24]=5)[CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1cc(-n2cccn2)cc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-n2cccn2)cc(-n2cnc3cc(-c4cnn(C5CCN(S(C)(=O)=O)CC5)c4)ccc32)c1
Reaction time: 4 h
Yield: 19 %

Procedure:
To a solution of the compound of Example 128 (80 mg, 0.171 mmol) in DCM (10 ml) was added pyridine (27 mg, 0.34 mmol, 2 eq.) and methanesulfonyl chloride (19 mg, 0.171 mmol, 1 eq.). The mixture was stirred for 4 h and quenched and extracted as in Example 2(b). The solvent was distilled off and the residue was purified by preparative HPLC to give the product in 19% yield (18 mg). 1H NMR (300 MHz, DMSO-d6): δ 10.52 (s, 1H), 10.06 (s, 1H), 8.58 (d, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.06-8.00 (m, 3H), 7.89 (s, 1H), 7.83 (d, 1H), 7.78-7.74 (m, 2H), 6.62 (t, 1H), 4.36 (m, 1H), 3.01-2.94 (m, 6H), 2.30 (s, 3H), 2.13 (s, 3H), 2.10-2.01 (m, 2H); LC-MS (ESI): Calculated mass: 544.63; Observed mass: 545.2 [M+H]+ (rt: 0.40 min).