Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([OH:4])=[O:3].[CH3:13]O>>[CH3:13][O:3][C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: CO
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Methanol (50 ml) was cooled (0°) and saturated with hydrogen chloride gas. p-Carboxybenzaldehyde (5.0 g) was added and the resulting solution stirred at room temperature for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 5M hydrochloric acid. The organic layer was washed twice with water and dried. The solvent was removed to afford the product as a white solid (5.40 g, 100%). δH (CDCl3) 3.96 (3H, s), 7.96 (2H, dd, J 6.8 and 1.7 Hz), 8.20 (2H, dd, J 6.8 and 1.7 Hz), 10.11 (1H, s) ppm.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([CH3:23])(Br)[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]=[C:17]([CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(Br)CCc1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: COC(=O)C(C)=CCc1cccc(C(=O)c2ccccc2)c1
Temperature: 160 °C
Yield: 53.7 %

Procedure:
A mixture of 1.46 g of methyl 4-(m-benzoyl-phenyl)-2-methyl-2-bromo-butanoate and 7.3 ml of quinoline was heated at 160° C for 3 hours and after cooling to room temperature, 73 ml of 2N hydrochloric acid were added thereto. The mixture was extracted with methylene chloride and the organic phase was washed with 2N hydrochloric acid, with aqueous saturated sodium bicarbonate solution and then with water. The solution was dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over magnesium silicate and eluted with methylene chloride to obtain 615 mg of methyl 4-(m-benzoylphenyl)-2-methyl-2-butenoate in the form of an oil.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1)[CH2:7][CH2:8][CH3:9].[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>ClC(Cl)C>[CH2:6]([C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[C:14]=1[C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1cc2cc([N+](=O)[O-])ccc2o1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1
Temperature: 23 °C
Reaction time: 24 h

Procedure:
59.8 ml (0.50 mole) of tin tetrachloride are added gradually to a solution of 44.5 g (0.2 mole) of 2-n-butyl 5-nitro benzofuran and 44.3 g (0.26 mole) of anisoyl chloride in 308 ml of dichloroethane. The temperature is maintained at 23° C. and stirring is continued for 24 hours. The mixture is poured onto 770 ml of ice-water and extracted 3 times with 150 ml of dichloroethane. The solution is washed with water, 5% sodium hydrogen carbonate solution and again with water. It is evaporated to dryness and the product thus obtained crystallizes rapidly [purity on high performance liquid chromatography (HPLC): 91.69%]. It is recrystallized from 250 ml of isopropanol and 59 g of 2-n-butyl 3-(4-methoxy benzoyl) 5-nitro benzofuran are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1ccc(Cl)cc1

Procedure:
100 ml of benzene was added to 18.3 grams of p-chlorocinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 80° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12](O)=[O:13])=[CH:8][CH:7]=1>ClCCl>[Cl:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([Cl:3])=[O:13])=[CH:8][CH:7]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccc(Cl)cc1
Temperature: 43 °C
Reaction time: 3 h

Procedure:
7 ml of thionyl chloride are added dropwise to a suspension of 1.75 g of 4-chlorocinnamic acid in 40 ml of anhydrous dichloromethane, with stirring at 43° C. After reacting for 3 hours, the excess acid that has not reacted remains undissolved and is removed by decanting. The filtrate is evaporated to dryness, yielding 4-chlorocinnamic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:20][CH:21]=O)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([BH3-])#N.[Na+].C(O)(=O)C>CO.CCOC(C)=O>[C:15]([O:14][C:13]([N:12]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:20][CH2:21][NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNCCN(CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-Butyl [2-(4-nitrophenyl)ethyl](2-oxoethyl)carbamate (0.95 g, 3.1 mmol) in MeOH (20 mL) was added ethyl aminoacetate hydrochloride (480 mg, 3.4 mmol), sodium cyanoborohydride (590 mg, 9.3 mmol) and a drop of acetic acid. The mixture was allowed to stir at RT for 16 hours. LC showed good reaction. The reaction was diluted with EtOAc, washed with aqueous sodium carbonate, dried over sodium sulfate, and purified by silica gel chromatography to furnish the title compound. LC-MS (IE, m/z): 393 [M+1]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]([F:20])[CH:17]=[CH:18][CH:19]=1.[Cl-].[NH4+].[O:23]1CCC[CH2:24]1>O.CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:24]=[O:23]
Reactant: Fc1cccc(Br)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(F)cccc1Br
Reaction time: 0.08 h

Procedure:
To a solution of diisopropylamine (2.65 mL) in tetrahydrofuran (30 mL) was added n-butyllithium (2.44 mol/L n-hexane solution, 7.03 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added 3-bromofluorobenzene (3 g), and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added N,N-dimethylformamide (1.45 mL), and the mixture was stirred at the same temperature for 10 minutes, then a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was stirred under ice-cooling for 5 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (3.43 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21].[C:24]1([CH2:30][C:31]([OH:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:30][C:31]([OH:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=C(O)Cc1ccccc1
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O

Procedure:
The presence of benzylpenicillin (Pen G) in the fermentation broth is confirmed by different methods. The first method comprises measuring the difference in free phenylacetic acid before and after enzymatically hydrolyzing the product to give phenylacetic acid and 6-APA. The amounts of phenylacetic acid are determined by gas chromatography as described above by Neidermayer. The following procedure is employed. 200 ml. of fermentation broth is centrifuged. A small amount of the supernatant fluid is removed and treated as set forth above to determine the amount of phenylacetic acid. The pH of 100 ml. of remaining supernatant fluid is adjusted to 8.0 by the addition of 0.1N NaOH solution. The temperature of the supernatant fluid is increased to 37° C. and 5 ml. of penicillin acylase preparation (derived from Bacillus megaterium) is added. Then the temperature and the pH are maintained at 37° and 8, respectively, for two hours. After this, 2 ml. of the mixture is adjusted to pH 1.8 with 60% (w/v) H2SO4 and extracted with 2 ml. of toluene. The toluene phase is analyzed for phenylacetic acid in a gas chromatographic system.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O>>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:5]1[CH:4]1[CH2:3][CH2:2][NH:1][CH2:9][CH2:8]1
Reactant: Nc1ccccc1O
Reactant: O=C(O)C1CCNCC1
Product: c1ccc2oc(C3CCNCC3)nc2c1

Procedure:
The title compound was prepared from isonipecotic acid and 2-aminophenol using the method described in Description 14. MH+ 203.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[NH:10]1[CH:14]=[CH:13]N=[CH:11]1>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH3:1][Si:2]([CH3:9])([CH3:8])[N:3]1[CH:13]=[CH:14][N:10]=[CH:11]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: c1c[nH]cn1
Agent: O=C1NS(=O)(=O)c2ccccc21
Product: C[Si](C)(C)n1ccnc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 105.8 %

Procedure:
31.5 ml (0.15 mole) of hexamethyldisilazane were added dropwise over the course of 45 minutes to 13.62 g (0.2 mole) of imidazole and 28 mg (0.15 mmoles) of saccharin heated to 100° C. and during this addition, the bath temperature was raised from 100° to 140° C. After addition of the hexamethyldisilazane, the mixture was stirred for 30 minutes at a bath temperature of 140° C. Excess hexamethyldisilazane was evaporated under reduced pressure and the residue was vacuum distilled to obtain 22,25 g (79.5%) of N-trimethylsilylimidazole boiling at 103°-105° C. at 22 mm Hg and nD 23.5°=1.4740.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C(N(CC)CC)C.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>C(O)C>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate (160 g, 0.752 mol) prepared in the Step 1-1-1 was suspended in ethanol (500 ml). Triethylamine (91.4 g, 0.903 mol) was added to the suspension, and under an ice cooling, piperidine (76.9 g, 0.903 mol) was slowly added thereto. After the mixture was stirred at a room temperature for 2 hours, a saturated sodium bicarbonate solution was added to the mixture, and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and a saturated saline solution in order, and then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 to 3:1) to give the title compound (222 g, quantitative) as a poppy-red oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:22])([OH:21])[C:19]#[CH:20]>ClCCl.[Cu]I>[NH2:1][C:2]1[C:7]([C:20]#[C:19][C:18]([CH3:22])([OH:21])[CH3:17])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)C#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A suspension of 2-amino-5-bromo-3-iodopyridine (10.0 g, 33.5 mmol), bis-(triphenyl-phosphine)-palladium(II)-dichloride (117 mg, 0.17 mmol), copper(I)iodide (79 mg, 0.41 mmol) and triethylamine (6.1 mL, 43.5 mmol) in dichloromethane (40 mL) was treated at 23 to 30° C. within 1 to 2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (3.70 g, 44 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at 25° C. for 3 hours. The mixture was diluted with dichloromethane (20 mL) and washed with water (2×50 mL). The organic phase was then treated with 1 M HCl (80 mL). The layers were separated and the organic layer was extracted with 1 M HCl (20 mL). The combined product containing aqueous layers were washed with dichloromethane (2×10 mL). The pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water, 18 g). The resulting suspension was stirred at 20° C. for 2 hours and the crystals were then filtered off and washed with water (2×20 mL). The wet crystals were dried at 50° C./<30 mbar affording 6.99 g (82%) of 4-(2-amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol as a melted mass with a purity of 99.5% (HPLC, area%). 1H NMR (400 MHz, CDCl3): δ ppm 1.63 (s, 6H); 4.0 (br., 3H); 7.59 (d, J=2.4, 1H); 8.03 (d, J=2.4, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([O:16][CH3:15])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cccc(C=CC(=O)O)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3)nc2n(CC)c1=O
Yield: 49 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.48 g (13.9 mmol) of 3-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 2.10 g (yield 49%) of Compound 139 as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CN(Cc2ccccc2)CCC1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
Benzyl-3- methyl-piperidin-4-one (2.0 g, 10 mmol) was dissolved in MeOH (10 ml), cooled to 0° C. and sodium borohydride (0.2 g, 5 mmol) was added portionwise. The reaction was allowed to reach room temperature and stirred overnight after which time the solvent was removed under vacuum, the residue redissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated to afford the title compound (2.1 g, quant), a 3:1 mixture of diasteriomers (trans:cis) as gum. MS: 206.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:10](Cl)(=[O:12])[CH3:11]>N1C=CC=CC=1.O>[C:10]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])(=[O:12])[CH3:11]
Reactant: NC(=O)c1ccsc1N
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1sccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-Amino-thiophene-3-carboxylic acid amide (20.3 g, 143 mmol) in dry pyridine (150 mL) is cooled to 0° C. Acetylchloride (11 mL, 156 mmol) is added dropwise to the solution. The resulting mixture was stirred at room temperature overnight. The mixture is then diluted with water and the resulting suspension is filtered. The cake is dried overnight in a vacuum-oven at 50° C. to yield the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([CH:17]=O)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:17][C:11]1[CH:10]=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Additionally, 2-phenylquinoline-7-carbaldehyde could be prepared as follows: To a solution of(2-phenylquinolin-7-yl)methanol (75 mg, 0.319 mmol) in chloroform (1 mL) was added MnO2 (277 mg, 3.19 mmol). The mixture was stirred at rt for 20 h and filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography. (1% MeOH in dichloromethane) to afford the title compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12]>>[CH2:11]([O:9][C:8]([C:5]1[CH:6]=[CH:7][N:2]=[N:3][CH:4]=1)=[O:10])[CH3:12]
Reactant: O=C(O)c1ccnnc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccnnc1
Yield: 49 %

Procedure:
In a 250 mL round bottom flask, 1 mL concentrated HCl and 70 mL ethanol was added to pyridazine-4-carboxylic acid (3.78 g, 30.4 mmol). The mixture was refluxed overnight. The reaction was 80% complete based on HPLC. The reaction mixture was concentrated down. The residue was purified (silica gel, 2-10% MeOH/DCM) to give light yellow oil (1.8 g, 49%). 1H NMR (300 MHz, CD3OD): δ 9.62 (s, 1H), 9.43 (d, 1H), 8.08 (d, 1H), 4.52 (dd, 2H), 1.43 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9]O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:29]=[N+:30]=[N-:31])[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OCCc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
2-(3-Bromophenyl)ethyl alcohol (2.01 g, 10 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. After addition of triethylamine (1.52 g, 15 mmol) and tosyl chloride (1.91 g, 10 mmol) the reaction was stirred at room temperature overnight. TLC indicated complete conversion of the starting material. DCM was evaporated, the mixture was diluted with EtOAc and washed subsequently with aqueous hydrochloric acid (1 N), water, saturated sodium hydrogen carbonate and brine. Drying and evaporation afforded an oil, which was dissolved in anhydrous DMF (10 mL). Sodium azide (1.3 g, 20 mmol) was added and the mixture heated to 40° C. for 16 h. After cooling to room temperature, EtOAc was added and the solution was washed with water (4×) and brine. The resulting oil was filtered over (100 g) with the aid of PE/EtOAc (10:1) to obtain 2-(3-bromophenyl)ethyl azide (1.63 g, 72% ) as a colorless oil. 1H-NMR (CDCl3) δ 7.39 (m, 2 H), 7.16–7.22 (m, 2 H), 4.51 (bs, 1 H), 3.50 (d, J=6.6 Hz, 2 H), 2.83 (t, J=6.6 Hz, 2 H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1)CCC.BrC1C=CC(=O)N(CC2C=CC(CC)=CC=2)C=1>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[N:48]=[CH:47][CH:46]=[CH:45][N:44]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ncccn2)s1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and tri-n-butyl (2-pyrimidinyl) tin 54 were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 429 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.Cl.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Yield: 3.9 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (270 mg) described in Preparation Example 25 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 170, the title compound (17 mg) was obtained.
Reaction SMILES: O.[Cl:2][C:3]1[N:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([CH:7](C(OCC)=O)C(OCC)=O)=[O:6].Cl>CS(C)=O>[Cl:2][C:3]1[C:4]([C:5](=[O:6])[CH3:7])=[CH:18][CH:19]=[CH:20][N:21]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cccnc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1cccnc1Cl
Temperature: 130 °C
Yield: 56 %

Procedure:
Water (1.3 mL) was added to a solution of diethyl 2-(2-chloronicotinoyl)malonate (31.7 mmol) in dimethylsulfoxide (50 mL). The pH of the reaction mixture was added adjusted to 5-6 by the addition of hydrochloric acid and the reaction mixture was heated at 130° C. for 2 h. The reaction mixture was then quenched with ice water (300 mL) and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by chromatography (1/20 ethyl acetate/petroleum ether to provide 1-(2-chloropyridin-3-yl)ethanone in 56% yield as light yellow oil.