Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[N:6]=[C:7](Cl)[NH:8][C:4]=2[CH:3]=1.Cl.[Cl:17][C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>>[Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[NH:6][C:7]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Br
Reactant: Clc1cccnc1N1CCNCC1
Agent: Cl
Product: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4Cl)CC3)nc2cc1Br

Procedure:
The reaction of 5-bromo-2-chloro-6-(trifluoromethyl)benzoimidazole (100 mg, 0.3 mmol, Example 89f) with 1-(3-chloropyridin-2-yl)piperazine hydrochloride (186 mg, 0.61 mmol, Example 3b) under the conditions of Example 3c afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 461.7, 464.0 (M+1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH2:11])[CH2:8]2.Cl.[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH:14]1[NH2:23])[CH2:20]2.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>O1CCCC1>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:24]([NH:23][CH:14]1[CH:15]3[CH2:21][CH:19]4[CH2:18][CH:17]([CH2:22][CH:13]1[CH2:20]4)[CH2:16]3)=[S:25])[CH2:8]2
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: C1CCOC1
Product: S=C(NC1C2CC3CC(C2)CC1C3)NC1C2CC3CC(C2)CC1C3

Procedure:
The 2-adamantylamine obtained from 5.0 g. (0.0266 mole) of 2-adamantylamine hydrochloride is reacted with 2.5 g. (0.014 mole) of 1,1'-thiocarbonyldiimidazole in 100 ml. of tetrahydrofuran for 20 hr. The solvent is evaporated and the residue partitioned between 5 percent hydrochloric acid and ether. The organic layer is washed with water, dried over potassium carbonate, evaporated and the residue is recrystallized from benzene-Skellysolve B: 3.65 g. (79 percent), m.p. 254-258.
Reaction SMILES: C[C:2](C)([O-:4])C.[Na+].C[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1C.[N:15]1([C:22]2[C:23]([CH3:36])=[C:24]([CH3:35])[C:25]3[O:29][C:28]([CH3:31])([CH3:30])[C:27](=[O:32])[C:26]=3[C:33]=2[CH3:34])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:2][O:4][C:13]1[CH:12]=[CH:11][C:10]([N:18]2[CH2:19][CH2:20][CH2:21][N:15]([C:22]3[C:23]([CH3:36])=[C:24]([CH3:35])[C:25]4[O:29][C:28]([CH3:31])([CH3:30])[C:27](=[O:32])[C:26]=4[C:33]=3[CH3:34])[CH2:16][CH2:17]2)=[CH:9][CH:8]=1
Reactant: Cc1ccccc1C
Reactant: CC(C)(C)[O-]
Reactant: Cc1c(C)c(N2CCCNCC2)c(C)c2c1OC(C)(C)C2=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Na+]
Solvent: O
Product: COc1ccc(N2CCCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
Bis(tri-tert-butylphosphine)palladium (20.0 mg, 0.0387 mmol) and sodium tert-butoxide (500 mg, 5.16 mmol) were added to a solution of o-xylene (20 mL) containing 5-(1,4-diazepan-1-yl)-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one synthesized in Reference Example 63, and the mixture was stirred under argon atmosphere at 120° C. for 12 hours. After cooled to room temperature, the mixture was diluted with water and extracted using ethyl acetate. It was dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0 to 90:10) to give 240 mg of the title compound (yield: 45%).
Reaction SMILES: [N-:1]=[C:2]=[O:3].CC[CH2:6][CH2:7][O:8][C@H](CO)CC.[OH-].C([N+:19](CCCC)(CCCC)CCCC)CCC>C(O)COCCO>[NH2:1][C:2]([O:8][CH2:7][CH3:6])=[O:3].[NH2:1][C:2]([NH2:19])=[O:3]
Reactant: CCCCO[C@@H](CC)CO
Reactant: [N-]=C=O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: OCCOCCO
Product: CCOC(N)=O
Product: NC(N)=O
Temperature: 85 °C
Reaction time: 0.01 h

Procedure:
Elastomeric urethane-urea copolymers were prepared by reacting 200 g of an isocyanate-terminated prepolymer with 35 g of 1,2-bis (2-aminophenylthio)ethane. The prepolymer had been previously prepared by reacting 2 moles of a commercially available mixture of isomeric tolylene diisocyanates for every mole of polytetramethylene glycol. The resultant product contained approximately 6.3% by weight of unreacted isocyanate groups. Prior to being combined with the diamine the prepolymer was degassed by heating it to 85° C. while maintaining the prepolymer under reduced pressure for several minutes. The diamine (85% of the stoichiometric amount) together with the catalyst was heated to 85° C., at which time it was added to the degassed prepolymer. The time at which these reagents was combined was used as the zero reference point. The resultant mixture was stirred for 40 seconds and then degassed for 1.3 minutes at 85° C. under reduced pressure, after which it was poured into a number of circular mold cavities measuring 1 inch (2.5 cm) in diameter and 3/8 inch (0.95 cm) in height. The mold had been preheated to a temperature of 85° C. The mold was then placed on the lower platen of a hydraulic press that was maintained at 85° C. The surface of the liquid was periodically probed with a metal spatula until it had solidified to the extent that the spatula would not penetrate the surface using moderate pressure. A cover was then placed on the mold and it was subjected to a pressure of 35,000 pounds (15,900 kg) using a 5 inch (12.7 cm) diameter ram. The small amount of polymer which overflowed when the press was closed was tested periodically with a spatula. When the polymer was no longer "tacky", i.e. it did not stick to the spatula, the press was opened and one of the samples was removed. If the sample could be distorted under pressure the press was closed on the mold and samples were removed periodically until the sample under test could not be distorted. The interval between combining of the reagents and removal of the distortion-free samples from the mold is referred to as the demold time in the following table, which contains the demold times obtained using (a) an uncatalyzed mixture of prepolymer and chain extender (b) a mixture of prepolymer, chain extender and 0.05% tetrabutylammonium hydroxide and (c) a mixture of prepolymer, chain extender and 0.025% of a tetrahydroxyalkylammonium hydroxide available as TMR from Air Products and Chemicals, Inc., which was added as a 50% by weight solution in diethylene glycol. The three samples are referred to as a, b and c in the table.
Reaction SMILES: [SH:1][CH:2]([CH2:8][SH:9])[CH2:3][S:4]([O-:7])(=[O:6])=[O:5].[Na+].Cl>>[SH:1][CH:2]([CH2:8][SH:9])[CH2:3][S:4]([OH:7])(=[O:6])=[O:5]
Reactant: O=S(=O)([O-])CC(S)CS
Agent: Cl
Agent: [Na+]
Product: O=S(=O)(O)CC(S)CS

Procedure:
prepared from sodium 2,3-dimercaptopropanesulfonate (Aldrich, 95% by neutralization with HCl or treatment with an acid ion-exchange resin, e.g. DOWEX™ MSC-1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11](=[CH:15]OCC)[C:12]([CH3:14])=O)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:14][C:12]1[C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=2)=[O:19])=[CH:15][NH:24][N:23]=1
Reactant: NN
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: O
Product: Cc1n[nH]cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 33.6 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-2-(ethoxymethylene)-acetoacetamide (1 g) in 3 mL of ethanol is stirred overnight with 0.3 g of hydrazine hydrate. The precipitate is collected by vacuum filtration, washed with ethanol:water 2:1 and dried to give 0.3 g of 3-methyl-4-(4-(trifluoromethyl)phenylaminocarbonyl]pyrazole as an off-white solid.
Reaction SMILES: [CH2:1]([CH:19]([CH2:23][C:24]([OH:26])=O)C(O)=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]CCC.[OH-:27].[Na+:28].[OH2:29]>CC(C)=O>[C:24]([O:26][CH2:24][CH2:23][CH2:19][CH2:1][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][CH3:15])(=[O:26])[CH2:23][CH2:19][C:1]([O-:29])=[O:27].[Na+:28]
Reactant: CCCCCCCCCCCCCCCCCCC(CC(=O)O)C(=O)O
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCC(=O)[O-]
Temperature: 40 °C
Yield: 98.5 %

Procedure:
In a 2000 ml. Erlenmeyer flask, there were placed 150 g. of monostearyl succinic acid (acid value, 156.7) and 1200 ml. of acetone. This mixture was first warmed and stirred to effect solution and then cooled to 40°C., at which point 17.3 g. of sodium hydroxide in 100 ml. of water were slowly added. The addition step was accomplished with vigorous agitation of the mixture, while the temperature of the acetone solution was always maintained at 40°-43°C. throughout said step. The resulting reaction mixture was then stirred for a further 15 minutes, cooled down to 10°-15°C. and filtered with suction. The filter cake so obtained was washed twice with separate 100 ml. portions of cold acetone and sucked dry on the filter funnel. After drying the product in a vacuum oven at 50°C., it was found that a yield of 157.5 g. (98.5%) of sodium stearyl succinate was obtained. This particular salt, which was obtained in the form of a white powder, gave a 0.1% (W/V) aqueous dispersion at 25°C. and a 1% dispersion at 50°C.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1.Cl[C:13]1[CH:45]=[CH:44][C:16]([CH2:17][N:18]([S:30]([C:33]2[S:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:36][CH:37]=2)(=[O:32])=[O:31])C2C(C)=CC=CC=2C(NO)=O)=CC=1.[CH3:46][C:47]1C=C(C=[CH:53][C:54]=1C)CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:13][C:45]1[CH:44]=[C:16]([CH:46]=[CH:47][C:54]=1[CH3:53])[CH2:17][N:18]([S:30]([C:33]1[S:34][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])[C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([NH:2][OH:1])=[O:11]
Reactant: Cc1ccc(CO)cc1C
Reactant: Cc1cccc(C(=O)NO)c1
Reactant: Cc1cccc(C(=O)NO)c1N(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(-c2ccccn2)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CN(c2c(C)cccc2C(=O)NO)S(=O)(=O)c2ccc(-c3ccccn3)s2)cc1C
Reaction time: 1 h

Procedure:
To a suspension of (5-pyridin-2-yl-thiophene-2-sulfonyl)-amino]-N-hydroxy-3-methyl-benzamide on Wang resin, the product of Example 407 (100 mg, 0.84 mmol/g), in a solution of 3,4 dimethylbenzyl alcohol (0.485 mmol) in THF (1 mL) was added a solution of triphenylphosphine (0.485 mmol) and diethyl azodicarboxylate (0.485 mmol) in THF (1.24 mL). The resultant mixture was shaken for 4 h at room temperature. The resin was filtered, washed with THF (4×3 mL) and dichloromethane (4×3 mL), and dried under vacuum. The resin was suspended in trifluoroacetic acid/ dichloromethane (1:1, 2 mL) and allowed to sit for 1 h. The resin was filtered and washed with DCM (2×1.5 mL). The combined filtrates were evaporated to dryness, and the crude product was purified on a solid phase extraction cartridge (reverse phase) to give 18.1 mg of product Mass Spec: expected 507.1286, found 507.9.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[S:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1.[F:16][C:17]([F:28])([F:27])[S:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C1COCC1>[F:15][C:4]([F:14])([F:3])[S:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][O:11][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([S:18][C:17]([F:28])([F:16])[F:27])=[CH:20][CH:21]=2)=[CH:8][CH:7]=1
Reactant: OCc1ccc(SC(F)(F)F)cc1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)Sc1ccc(COCc2ccc(SC(F)(F)F)cc2)cc1
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
Sodium hydride (65 mg 60% dispersion oil, 1.58 mmol) was added to a solution of 4-(trifluoromethylthio)benzyl alcohol (300 mg, 1.44 mmol) in THF (10 mL) at rt. After stirring for 10 min, to the mixture was added 4-(trifluoromethylthio)benzyl bromide (410 mg, 1.51 mmol), stirring was continued overnight. The reaction was quenched with saturated ammonium chloride solution, extracted with EtOAc, washed with water and dried to give 0.5 g (85%) of bis(4-trifluoromethylthiobenzyl) ether as a yellow oil. 1HNMR (360 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 4H), 7.53 (d, J=8.1 Hz, 4H), 4.65 (s, 4H, CH2OCH2). MS-EI m/z 398 [M+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:19][C:20](=[O:34])[C:21]([NH:23][C:24]([CH3:33])([CH3:32])[CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:22])[CH:11]=[CH:12][C:13]=1[C:14]1[O:18][CH:17]=[N:16][CH:15]=1.C(N1CCOCC1)C>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][C:24]([NH:23][C:21](=[O:22])[C:20]([NH:19][C:10]2[CH:11]=[CH:12][C:13]([C:14]3[O:18][CH:17]=[N:16][CH:15]=3)=[C:8]([O:7][CH3:6])[CH:9]=2)=[O:34])([CH3:33])[CH3:32])[CH2:27][CH2:28]1)(=[O:4])=[O:3]
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CC2CCNCC2)ccc1-c1cnco1
Reactant: CS(=O)(=O)Cl
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CC2CCN(S(C)(=O)=O)CC2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
14 mg (0.12 mmol) of methanesulphonyl chloride were added to a solution of 40 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl-N′-[1,1-dimethyl-2-(4-piperidinyl)ethyl]oxalamide in 1 ml of dichloromethane followed by 17 mg (0.15 mmol) of N-ethylmorpholine and the mixture stirred at room temperature for 4 hours. The resulting solution was diluted with ethyl acetate, washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate, evaporated to dryness and the residue triturated with diethyl ether. There was obtained 23 mg of N-[2-[1-(methanesulfonyl)-4-piperidinyl]-1,1-dimethylethyl]-N′-(3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as an off-white solid. MS m/e 479 [M+]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH3:12][Si:13]([CH3:17])([CH3:16])[C:14]#[CH:15].C(Cl)Cl>C(#N)C.C1COCC1.[Cu]I.Cl[Pd]Cl>[CH3:12][Si:13]([C:14]#[C:15][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)s1

Procedure:
Under an argon atmosphere a solution of 32.5 g (138.0 mmol) ethyl 5-bromo-thiophene-2-carboxylate in 320 ml acetonitrile and 640 ml THF is combined with 1.3 g (7.0 mmol) copper-(I)-iodide and 39.0 g (276.0 mmol) trimethyl-silylacetylene with stirring, the mixture is stirred for 5 min and then 5.6 g (7.0 mmol) 1,1-bis-(diphenylphosphino)-ferrocene-dichloropalladium(II))-PdCl2 in a complex with CH2Cl2 1/1 and 57.4 ml (414.0 mmol) TEA are added. The reaction mixture is stirred overnight at room temperature, evaporated down i. vac., the residue is combined with ethyl acetate and washed with ammonia solution (5%) and water. The organic phase is dried on sodium sulphate and evaporated to dryness i. vac. The residue is combined with diethyl ether, the precipitate is suction filtered and dried.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)=[CH:35][CH:34]=1>>[N:39]1([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][N:18]3[C:14]4=[N:15][C:16]([CH3:17])=[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([OH:9])=[O:8])[C:12]([C:21]5[CH:22]=[C:23]6[C:28](=[CH:29][CH:30]=5)[O:27][CH2:26][CH2:25][CH2:24]6)=[C:13]4[CH:20]=[CH:19]3)=[CH:34][CH:35]=2)[CH:43]=[N:42][CH:41]=[N:40]1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: BrCc1ccc(-n2cncn2)cc1
Product: Cc1nc2c(ccn2Cc2ccc(-n3cncn3)cc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.61 (br. s., 1 H), 8.13 (br. s., 1 H), 7.67 (d, J=8.4 Hz, 2 H), 7.52-7.39 (m, 3 H), 7.24-7.17 (m, 1 H), 7.12 (t, J=3.1 Hz, 1 H), 6.95 (dd, J=4.7, 8.4 Hz, 1 H), 6.37 (dd, J=3.5, 11.3 Hz, 1 H), 5.80-5.70 (m, 1 H), 5.64-5.52 (m, 2 H), 4.30 (t, J=4.2 Hz, 2 H), 2.96-2.77 (m, 5 H), 2.16-2.05 (m, 2 H), 1.05-0.91 (s, 9 H); LC/MS (m/z) ES+=552.39 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[S:19])[S:15][CH:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2].[CH3:21][I:22]>CO>[IH:22].[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][C:18](=[NH:20])[S:19][CH3:21])[S:15][CH:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccc(-c2csc(NC(N)=S)n2)c1
Reactant: CI
Solvent: CO
Product: CSC(=N)Nc1nc(-c2cccc(CNC(C)=O)c2)cs1
Product: I
Yield: 74.9 %

Procedure:
A suspension of 4-(3-acetylaminomethylphenyl)-2-thioureidothiazole (5.75 g) and methyl iodide (3.73 g) in methanol (100 ml) was refluxed for 2.5 hours. The solvent was removed under reduced pressure. The residue was crystallized from a mixture of methanol and ethyl acetate to afford 4-(3-acetylaminomethylphenyl)-2-(2-methyl-1-isothioureido)thiazole hydriodide (6.3 g).
Reaction SMILES: [N:1]12[CH2:8][CH2:7]N(CC1)CC2.[CH:9](=[O:13])[CH:10]([CH3:12])[CH3:11].[C:14](#N)C=C.Cl>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.O>[OH:13][CH:9]([CH:10]([CH3:12])[CH3:11])[C:7](=[CH2:14])[C:8]#[N:1]
Reactant: C=CC#N
Reactant: CC(C)C=O
Reactant: C1CN2CCN1CC2
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: O
Product: C=C(C#N)C(O)C(C)C
Temperature: 25 °C
Yield: 193.4 %

Procedure:
A 250 mL, three-necked, round-bottom flask with overhead stirring is charged with 0.36 g (1.6 mmol) of 2,6-di-tert-butyl-4-methylphenol, 37 g (0.33 mol) of 1,4-diazabicyclo[2,2,2]octane, 60 mL (0.66 mol) of isobutyraldehyde, 52 mL (0.79 mol) of acrylonitrile, and 7.2 mL (0.4 mol) of water. The reaction mixture is stirred at 50° C. for 24 hours, cooled to 25° C., and quenched into a solution of 33 mL (0.38 mol) of hydrochloric acid and 100 mL of water. The product is extracted with 120 mL of methylene chloride. The aqueous acid layer is extracted again with 25 mL of methylene chloride. The combined methylene chloride layers are concentrated by rotary evaporation to provide 79.9 g (96.7%) of 3-hydroxy-4-methyl-2-methylenepentanenitrile as a yellow oil (which may solidify to a white solid on standing), 96.7% (area under the curve) by HPLC assay, which may be used in the next step without further purification. Carbonic acid 2-cyano-1-isopropyl-allyl ester ethyl ester
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25]N)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C=O.[C:31]([BH3-])#[N:32].[Na+].[C:35](O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:32]([CH3:31])[CH3:35])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1
Reactant: [BH3-]C#N
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The compound (27.7 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (1.1 ml). Then, the solution was added with a 36% formaldehyde aqueous solution (manufactured by Kanto Kagaku) (0.0160 ml) and sodium cyanoborohydride (13.2 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 22 hours. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by washing with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution and drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through a solid-phase extraction column (Sep-Pack®, tC18, manufactured by Waters Corporation), thereby obtaining hydrochloride (16.4 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:15][CH:16]=1)#[N:10]>O.CO>[OH:8]/[N:7]=[C:9](/[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([O:23][CH3:1])=[O:22])=[N:15][CH:16]=1)\[NH2:10]
Reactant: N#Cc1ccc(NC(=O)CCC(=O)O)nc1
Reactant: O=C([O-])O
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCC(=O)Nc1ccc(/C(N)=N/O)cn1
Temperature: 80 °C
Yield: 40.3 %

Procedure:
A solution of sodium bicarbonate (1.81 g, 21.4 mmol, 5 equiv.) and hydroxylamine hydrochloride (1.50 g, 21.4 mmol, 5 equiv.) in water (12 mL) was added to an solution of 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoic acid A2 (1.00 g, 4.29 mmol, 1 equiv.) in methanol (120 mL) at 80° C. The solution was heated at 80° C. overnight, before being concentrated under vacuum. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried on magnesium sulfate, and then concentrated under vacuum to give 760 mg of crude product. This crude product was adsorbed over isolute before purification by flash chromatography eluted with a gradient of methanol and dichloromethane (0 to 10% in methanol) to give methyl 4-[[5-[(Z)—N′-hydroxycarbamimidoyl]-2-pyridyl]amino]-4-oxo-butanoate (0.46 g, 1.73 mmol, 40% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37](O)[CH:38]=C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH:37]=[CH2:38])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 88.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-propen-1-ol (13 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (56 mg, yield 84%).