Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[O:5][C:4]([C:21]([O:23]CC)=[O:22])=[CH:3]1>C(O)(=O)C.Cl>[O:1]=[C:2]1[C:7]2[N:8]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[O:5][C:4]([C:21]([OH:23])=[O:22])=[CH:3]1
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2-c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cc(=O)c2c(o1)c1ccccc1n2-c1ccccc1
Reaction time: 0.25 h

Procedure:
A mixture of 1.0 g (0.0033 mole) of ethyl 4,5-dihydro-4-oxo-5-phenylpyrano [3,2-b]indole-2-carboxylate in 10 ml glacial acetic acid and 2.0 ml conc. hydrochloric acid was stirred at reflux for 41/2 hr, then cooled and added to 75 g ice - H2O. The solid was filtered, washed with cold water, then added to a mixture of 35 ml 5% aqueous sodium carbonate and 250 ml water. After filtering by gravity, tha aqueous solution was washed three times with 75 ml chloroform, cooled in ice, and acidified with 4.0 N hydrochloric acid. The orange precipitate was filtered, digested 15 min on the steam bath with 25 ml water and re-filtered warm. Recrystallization from DMF-water yielded an off-white solid of mpt.>290°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.Cl([O-])=[O:12].[Na+].S(=O)(=O)(O)N>C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]([OH:12])=[O:9]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c(Cl)ccnc1Cl
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A solution of 0.40 g of the aldehyde from Step B was dissolved in 6 mL of THF and then added to a solution of 0.27 g of sodium chlorite and 0.29 g of sulfamic acid in 6 mL of water. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1 N sodium hydroxide (10 mL) and extracted with diethyl ether (1×). The aqueous layer was then acidified with concentrated HCl, extracted with methylene chloride (2×), and the combine methylene chloride extracts were dried over magnesium sulfate. The methylene chloride was removed under vacuum to give 0.22 g of a solid. 1H NMR (CDCl3; 300 MHz) δ 7.38 (d, 1H J is 5.4 Hz), 8.40 (d, 1H, J is 5.5 Hz), 8.60 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: O=C(O)COCCc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCOCCc1ccc(F)cc1
Yield: 91 %

Procedure:
The 2-(4-fluorophenyl)ethoxyacetic acid obtained according to the preceding paragraph was reduced with lithium aluminum hydride in a manner analogous to that described in Example 1(b) to give 6.6 g (91%) of 2-[2-(4-fluorophenyl)-ethoxy]ethanol in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH3:57])[C@H:28]([C:34]1[O:38][N:37]=[C:36]([C:39]([NH:41][C:42]2[C:43](=[O:55])[N:44]([CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[N:45]([CH3:48])[C:46]=2[CH3:47])=[O:40])[C:35]=1[CH3:56])[O:29][CH2:30][C:31]([CH3:33])=[CH2:32])(C(C)(C)C)(C)C>C1COCC1>[CH:49]1([N:44]2[C:43](=[O:55])[C:42]([NH:41][C:39]([C:36]3[C:35]([CH3:56])=[C:34]([C@H:28]([O:29][CH2:30][C:31]([CH3:33])=[CH2:32])[C@@H:27]([OH:26])[CH3:57])[O:38][N:37]=3)=[O:40])=[C:46]([CH3:47])[N:45]2[CH3:48])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: C=C(C)CO[C@@H](c1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(C)CO[C@@H](c1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C)[C@H](C)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tetrabutyl ammonium fluoride (15.16 ml, 15.16 mmol) was added dropwise to 5-((1R,2S)-2-((tert-butyldimethylsilyl)oxy)-1-((2-methylallyl)oxy)propyl)-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methylisoxazole-3-carboxamide (5.06 g, 7.58 mmol (assuming 76% purity)) in THF (160 ml) and the resulting mixture was stirred at room temperature for 18 h.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].I[C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[C:19]([N+:32]([O-:34])=[O:33])[CH:18]=1.O>C(O)C.O>[N+:32]([C:19]1[CH:18]=[C:17]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:22]=[CH:21][C:20]=1[S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])([O-:34])=[O:33]
Reactant: OB(O)c1cccnc1
Reactant: O=[N+]([O-])c1cc(I)ccc1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2cccnc2)ccc1S(=O)(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Argon was passed through a mixture of 3-pyridineboronic acid (187 mg, 1.53 mmol) and Na2CO3 (408 mg, 3.84 mmol) in water ethanol (water 3.74 ml, ethanol 14.96 ml) at stirring at 90° C. for 30 min and cooled to 80° C. 4-Iodo-2-nitro-1-(phenylsulfonyl)-benzene 4(3) (734 mg, 1.9 mmol) was added to the reaction mixture in argon current, inert gas was passed for another 10 min, then bis-triphenylphosphinepalladium dichloride (34 mg) was added and argon was passed for additional 5 min. The reaction mixture was stirred for 2 h at 85° C. in argon atmosphere, then, cooled, water was added, and precipitated solid was filtered off. The reaction product was extracted from mother liquor with CH2Cl2, organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was suspended in CH2Cl2, filtered off, mother liquor was evaporated, the residue washed with diethyl ether, it gave 460 mg (70.5%) of 3-(3-nitro-4-(phenylsulfonyl)phenyl)pyridine 5(1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([S:11]([OH:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[OH-].[Na+:16]>O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([S:11]([O-:14])(=[O:12])=[O:13])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Na+:16]
Reactant: CC(=O)Nc1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cccc(S(=O)(=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 118.6 mg (0.55 mmol) of 3-acetamidobenzenesulfonic acid in 0.5 mL of water was treated with 0.55 mL (0.55 mmol) of 1.0N NaOH at 0° C. After stirring at room temperature for 4 hours, the mixture was concentrated to dryness and used without subsequent purification.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH2:19][OH:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl>[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]=[O:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.9 %

Procedure:
Anhydrous CrO3 (1.94 g, 19.38 mmol) is added to a solution of anhydrous pyridine (3.07 g, 38.76 mmol) in anhydrous CH2Cl2 (50 ml). The resulting mixture is stirred at r.t. for 15 min. A solution of 1-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-2-azetidinone (0.74 g, 3.23 mmol) in anhydrous CH2Cl2 5 ml is added all at once. After stirring for 5 min, the CH2Cl2 solution is separated from a dark gummy precipitate which is washed with more CH2Cl2. The combined CH2Cl2 solution is evaporated under vacuum. The residue is taken up in ether filtered and washed with 5% NaHCO3, 5% HCl, 5%NaHCO3 and brine then dried and evaporated to give the aldehyde (0.543 g 74%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.O(C)[Na]>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:23]([OH:24])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Agent: CO[Na]
Solvent: CO
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6 (0.75 g, 1 mmol) in methanol (75 mL) was adjusted to pH 9 with NaOCH3 and stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and the residue was triturated with ether (2×75 mL). The ether insoluble solid was dissolved in water (15 mL) and acidified with acetic acid whereupon the crude product precipitated. Crystallization of this material from water gave a colorless powder: yield 0.31 g, 78%: mp 238° C. (decomp.): UV λmax (pH 1) 215 nm (ε 2280), 245 (6900), 301 (8400): UV λmax (pH 7) 215 nm (ε 22,100), 245 (6900), 301 (8000): UV λmax (pH 11) 245 nm (ε 5700), 291 (6000). NMR (DMSO-d6) δ 5.79 (1H, d, J=5.32 Hz, C1, H), 6.90 (2H, s, NH2), 11.12 (1H, s, NH), and other sugar protons. Anal Calcd. for C10H12N4O6S.H2O: C, 35.92: H, 4.22: N, 16.76: S, 9.59. Found: C, 35.82: H, 4.02: N, 16.92: S, 9.66.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([C:12]2[CH:30]=[CH:29][C:15]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[C:22]([CH2:27]O)[CH:21]=[CH:20]4)=[CH:14][CH:13]=2)=[CH:10][CH:9]=[N:8]1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[N:8]1[NH:7][C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[C:22]([CH2:27][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:21]=[CH:20]4)=[CH:29][CH:30]=2)=[CH:10][CH:9]=1
Reactant: C1CCNC1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3nc(CO)ccc3c2)cc1
Product: c1cc(-c2ccc(Oc3ccc4nc(CN5CCCC5)ccc4c3)cc2)[nH]n1

Procedure:
The title product (243) is synthesized from intermediate E (75 mg, 0.17 mmol) and pyrrolidine according to procedure described for the synthesis of Example 250 from intermediate AU.
Reaction SMILES: OCC1SSC(CO)=CC=1.C[C@:12]1([O:25][CH2:26][C:27]2[S:28][S:29][C:30]([CH2:33][O:34][C@@:35]3(C)[O:44][C@H:43]([C:45]([O-])=[O:46])[C@@H:38]([O:39]C(=O)C)[CH:37]=[CH:36]3)=[CH:31][CH:32]=2)[O:21][C@H:20]([C:22]([O-])=[O:23])[C@@H:15]([O:16]C(=O)C)[CH:14]=[CH:13]1.[OH-].[Na+]>C1COCC1>[C@H:12]1([O:25][CH2:26][C:27]2[S:28][S:29][C:30]([CH2:33][O:34][C@H:35]3[O:44][C@H:43]([CH2:45][OH:46])[C@@H:38]([OH:39])[CH:37]=[CH:36]3)=[CH:31][CH:32]=2)[O:21][C@H:20]([CH2:22][OH:23])[C@@H:15]([OH:16])[CH:14]=[CH:13]1
Reactant: CC(=O)O[C@H]1C=C[C@@](C)(OCC2=CC=C(CO[C@]3(C)C=C[C@H](OC(C)=O)[C@@H](C(=O)[O-])O3)SS2)O[C@@H]1C(=O)[O-]
Agent: OCC1=CC=C(CO)SS1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC[C@H]1O[C@H](OCC2=CC=C(CO[C@@H]3C=C[C@H](O)[C@@H](CO)O3)SS2)C=C[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
By the above procedure for glycosylation of 3,6-bis(hydroxymethyl)-1,2-dithiin but using methyl 3,4-diacetyl-1,2-dideoxy-D-arabinohexenopyranosyluronate instead of triacetyl D-glucal, the product obtained after work-up is 3,6-di[methyl 4-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranosyluronate]oxymethyl-1,2-dithiin (17B). This diacetate dimethyl ester (20 mg) dissolved in 1 mL of THF is treated with 3 mL of 0.1M aqueous NaOH, and the resulting solution is stirred at room temperature for three hours. The hydrolyzed product is extracted, the extract layers are combined and dried, and the solvent removed. After purification by silica gel chromatography, the product is 3,6-di[sodium 2,3-dideoxy-α-D-erythro-hex-2-enopyranosyluronate]oxymethyl-1,2-dithiin (8B).
Reaction SMILES: [NH:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=1)[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27](Cl)=O)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>N1C=CC=CC=1.CO>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:4]4[N:5]=[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:7](=[O:9])[NH:8][C:3]4=[N:1][N:2]=3)[CH2:25][CH2:26]2)=[CH:20][CH:19]=1
Reactant: NNc1nnc(-c2ccccc2)c(=O)[nH]1
Reactant: COc1ccc(C2(C(=O)Cl)CC2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C2(c3nnc4[nH]c(=O)c(-c5ccccc5)nn34)CC2)cc1
Yield: 70.6 %

Procedure:
To a solution of 3-hydrazino-6-phenyl-1,2,4-triazin-5(4H)-one (40.0 mg, 0.197 mmol) in pyridine (0.5 mL) was added 1-(4-methoxyphenyl)cyclopropanecarbonyl chloride (0.062 g, 0.30 mmol) and the resulting mixture was irradiated under microwave at 150° C. for 15 min. The reaction mixture was diluted with methanol and purified by RP-HPLC to afford the desired product (50 mg, 70%). Analytical LCMS: (M+H)+=360.2.
Reaction SMILES: O[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][N:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[Cl:23][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][N:4]=1
Reactant: O=C(c1ccc(CO)nc1)N(C1CCCC1)C1CCCC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(CCl)nc1)N(C1CCCC1)C1CCCC1
Reaction time: 0.17 h

Procedure:
To a solution of the title product of Example C (1.44 g, 5 mmol) in chloroform (30 mL), phosphorus pentachloride (1.04, 5 mmol) was added. The contents were immersed in an oil-bath at 70° C. and the temperature raised to reflux. After 18h, the pinkish colored reaction solution was cooled to room temperature. The reaction was diluted with water (75 mL) and solid potassium carbonate (2.2 g) added. The contents were stirred for about 10 min until no more effervescence was observed. More water (100 mL) was added and the reaction solution extracted with methylene chloride. The organic layer was separated, dried (MgSO4) and filtered. After removal of solvent, 1 6 g of the title product was isolated as an off-white solid. The compound was used in Example 1 without any further purification. 1H NMR (CDCl3) 1,2-2.2 (m, 16H), 3.6-3.9 (m, 2H), 4.7 (s, 2H), 7.53 (d,J=8 Hz, 1H), 7.74 (dd,J=3,8 Hz, 1H), and 8.56 ppm (d,J=3 Hz, 1H).
Reaction SMILES: OC1O[C@H](CO)[C@@H]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H](O)[C@H]1O.CC(N[C@H]1[C@@H](OP(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)O[C@H](CO)[C@@H](O)[C@@H]1O)=O>>[OH:8][CH:9]1[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
Lactose was contacted with UDP-N-acetylglucosamine and a β-galactoside β1-3 N-acetylglucosaminyl transferase purified from pig serum in a 0.1M HEPS buffered aqueous solution at 37° C. The product tetrasaccharide was then contacted with UDP--Gal and a β-N-acetylglucosaminoside β1-4 Galactosyltransferase isolated from bovine milk, in a 0.1M HEPS buffered aqueous solution at 37° C. The product tetrasaccharide was then contacted with CMP--NAN and a β-galactoside α2-6 sialyltransferase isolated from rat liver in a 0.1M HEPES buffered aqueous solution at 37° C. The title pentasaccharide was isolated by conventional methods.
Reaction SMILES: [C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[Cl:17]>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[Cl:17].[C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)c1ccccc1
Agent: COC(=O)C(CC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: C[C@H](N)c1ccccc1
Temperature: 100 °C

Procedure:
1.21 g (10.0 mmol) of (−)-1-phenylethylamine and 20 ml of ethanol were added to 2.77 g (10.0 mmol) of (±)-3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid, and the mixture was stirred in a suspended state under heating at a bath temperature of 90 to 110° C. for 4 hours. Then the internal temperature was lowered to 20° C. and the suspension was stirred at this temperature for one hour. The precipitated crystals were filtered out, washed with a small quantity of ethanol and dried to harvest 2.70 g (68.0% yield) of (+)-3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid·(S)-1-phenylethylamine salt.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.C(#N)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH2:28])=[S:27].O>C(OCC)(=O)C>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]1[S:27][C:2]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)[N:28]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(C)cc2)cc1
Reactant: NC(=S)c1ccccc1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A 100 mL one-neck round-bottom flask equipped for magnetic stirring was charged with 2-bromo-2-(4-methylthiophenyl)-1(4-methylphenyl)ethanone from Step 3 (0.300 g, 0.895 mmol) and acetonitrile (20 mL). 2-Chlorothiobenzamide (0.154 g, 0.895 mmol) was added, and the suspension was heated and held at reflux for three hours. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL) and poured into water(50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic solution was dried over MgSO4, filtered and evaporated in vacuo. The residue was purified via flash chromatography (silica gel; 5% ethyl acetate in hexane) to yield 2-(2-chlorophenyl)-4-(4-methylphenyl)-5-(4-methylthiophenyl)thiazole (0.284 g, 78%) as a white solid: mp 125°-126° C. 1H NMR (CDCl3) 300 MHz 8.40(m, 1H), 7.62-7.11(m, 11H), 2.50 (s, 3H), 3.36(s, 3H). Mass spectrum: MH+ =407.
Reaction SMILES: C(Cl)(=O)C.[CH:5]1([O:8][C:9]2[CH:10]=[C:11]([C:19]3[NH:36][C:22]4[CH:23]=[N:24][N:25](COCC[Si](C)(C)C)[C:26](=[O:27])[C:21]=4[C:20]=3[CH2:37][O:38][CH3:39])[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH2:7][CH2:6]1.C[O-].[Na+]>CO>[CH:5]1([O:8][C:9]2[CH:10]=[C:11]([C:19]3[NH:36][C:22]4[CH:23]=[N:24][NH:25][C:26](=[O:27])[C:21]=4[C:20]=3[CH2:37][O:38][CH3:39])[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:17])[F:18])[CH2:6][CH2:7]1
Reactant: COCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Product: COCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
To 8 ml of methanol was added 1.3 ml (18.3 mmol) of acetyl chloride, and the mixture was stirred at 50° C. for 15 minutes, and then, cooled to room temperature. To the solution was added 140 mg (0.276 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methoxymethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 11-(b), and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, to the reaction mixture were successively added 18.4 ml of methanol solution containing 1M sodium methoxide and then water, and the mixture was extracted with a mixed solvent (chloroform:methano1=9:1 (UV)). The organic layer after separation of liquids was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Water was added to the obtained concentrate, and precipitated solid was collected by filtration and dried under reduced pressure to obtain 58 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=O)[CH:10]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH2:29][CH2:30][NH2:31])[CH3:27])([CH3:19])([CH3:18])[CH3:17]>C(O)C>[C:16]([O:20][C:21](=[O:32])[NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH2:29][CH2:30][N:31]1[C:11](=[O:13])[CH:9]2[CH:10]=[CH:1][CH:2]=[C:3]3[CH:8]2[C:7](=[CH:6][CH:5]=[CH:4]3)[C:14]1=[O:15])[CH3:27])([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(CCCN)CCCNC(=O)OC(C)(C)C
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Solvent: CCO
Product: CN(CCCNC(=O)OC(C)(C)C)CCCN1C(=O)C2=CC=CC3=CC=CC(C1=O)C32
Yield: 90 %

Procedure:
1,8-naphthalic anhydride (0.18 g, 0.9 mmol) was added to a solution of [3-[(3-aminopropyl)methylamino]propyl]carbamic acid tert-butyl ester previously prepared (Spicer at el., Bioorg. Med. Chem. 2002, vol. 10, p. 19) (0.2 g, 0.8 mmol) in absolute ethanol (20 ml). The reaction mixture was heated at reflux overnight. Removal of the solvent and purification by chromatography on alumina (CH2Cl2/MeOH, 50:1) yielded [3-[[3-(1,3-dioxo-3a,9b-dihydro-1H,3H-benzo[de]isoquinolin-2-yl)propyl]methylamino]propyl]carbamic acid tert-butyl ester (0.37 g, 90%) as a foam.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:30])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:38]1([CH2:41][NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:40][CH2:39]1>C(O)C>[CH:43]1([N:42]([CH2:41][CH:38]2[CH2:39][CH2:40]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:30])=[O:9])[CH:3]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: C1CCC(NCC2CC2)CC1
Reactant: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 160 °C

Procedure:
A solution of tert-butyl 3-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate (Intermediate 34, 140 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (56.6 mg, 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent reduced to one tenth of the volume in vacuo. The solid formed was triturated with water and the residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate which was used directly without any further purification. The residue was redissolved in DCM (4.5 ml) and treated with TFA (0.5 ml). After stirring at RT for 2 hours the solvent was removed in vacuo to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][NH:7][C:17]([NH:16][CH2:15][CH2:14][Cl:13])=[O:18])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=C=NCCCl
Reactant: COc1ccc(CN)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)NCCCl)cc1OC
Yield: 89 %

Procedure:
To a solution of 3,4-dimethoxybenzylamine (2 g, 12 mmol) in anh. THF (25 mL), at r.t., under N2, was added 2-chloroethyl isocyanate (1.02 mL, 1 eq). The reaction was complete after the addition. It was concentrated and the residue was purified by flash chromatography (silica gel, cHex/EtOAc 1:1→7:3 EtOAc/NH3 (0.5 in MeOH)) to give the title compound as a white solid (2.9 g, 89%).