Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]([C@@H:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[OH:15])[CH:7]=[N:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([O:15][C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[N:6]1[C:5]2[CH:16]=[C:17]([Cl:18])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=[CH:7]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O[C@@H]1CCCC[C@H]1n1cnc2cc(Cl)c(Cl)cc21
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CCCC[C@H]1n1cnc2cc(Cl)c(Cl)cc21
Yield: 97 %

Procedure:
(±)-trans-2-(5,6-Dichloro-1H-benzimidazol-1-yl)cyclohexanol (part a of this example, 6.25 g, 21.9 mmol) was stirred in acetic anhydride (3 ml)-pyridine (50 ml) for 18 h. Volatiles were evaporated and the residue partitioned between chloroform and saturated aqueous sodium bicarbonate. The chloroform solution was filtered through Celite/charcoal and evaporated to give title compound as an off-white solid (6.92 g, 97%), m.p. 145-147° C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:21])=O>>[Cl:21][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(SCCN2CCOCC2)ccnc1CO
Reactant: O=S(Cl)Cl
Product: Cc1c(SCCN2CCOCC2)ccnc1CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Thionyl chloride (20 ml) was dropwise added to 2-hydroxymethyl-3-methyl-4-(2-morpholinoethylthio)pyridine (2 g) under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, the thionyl chloride was distilled away. The residue was alkali-oversaturated with potassium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 2.1 g of 2-chloromethyl-3-methyl-4-(2-morpholinoethylthio)pyridine as an oily substance. The oily substance was added to ethanol (50 ml) containing a solution of 2-mercaptobenzimidazole (1.0 g) and sodium hydroxide (0.6 g) in water (10 ml) and the mixture was refluxed under heating for 5 hours. After the completion of the reaction, the ethanol was distilled away and water was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away. Acetone was added to the residue to allow crystallization. The obtained crystals were recrystallized from a mixed solvent of ethanol-acetone to give 2-((3-methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole as white crystals, melting point 201°-203° C.
Reaction SMILES: CO[CH:3](CSC(=O)NCCCCCCCCCCCCCCCCCC)[CH2:4]N.[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH:36][CH2:37][CH:38]([O:57][CH3:58])[CH2:39][S:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])(=[O:35])=[O:34]>>[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH:36][CH2:37][C:38]1([CH2:39][S:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:4][CH2:3][CH2:58][O:57]1)(=[O:34])=[O:35]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CN)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC1(CNS(=O)(=O)CCCCl)CCCO1

Procedure:
2-Aminomethyl-2-hexadecylthiomethyltetrahydrofuran IV b1 is allowed to react and worked by the same procedure as described in (4). m.p. 44.5° to 45.5° C. The summary of the experimental condition and the physical data of the product are listed in the Table 7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>>[O:30]=[S:27]1(=[O:31])[CH2:28][CH2:29][N:24]([C:20]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:25][CH2:26]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)N2CCS(=O)(=O)CC2)s1
Yield: 84 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using thiomorpholine 1,1-dioxide instead of 4-aminotetrahydropyran, to the title compound (94 mg, 84%) which was obtained as a light yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=449.1 [M+H]+.
Reaction SMILES: [C:1]([N:7]1[CH2:12][CH2:11][CH:10]([C:13](OCC)=[O:14])[CH2:9][CH2:8]1)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1CCN(C(=O)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)CN1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
20a (29.5 g, 122 mmol) was dissolved in 200 mL of tetrahydrofuran and cooled to 0° C. Lithium aluminum hydride (s) (10.6 g, 279 mmol) was added slowly and the reaction was allowed to warm to rt and stirred for 24 h. The reaction was quenched by slow addition of sodium sulfate hydrated crystals (Na2SO4.10H2O) until there was no bubbling on addition followed by 20 mL of water. The mixture was filtered through Celite®, and the Celite® washed with diethyl ether. The solvent was removed from the filtrate to provide 20 g (97%) of the desired product as a white solid. 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:15])[NH:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:16]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:11]([C:8]1[NH:7][C:6](=[O:15])[C:5]([CH:2]([NH:1][C:21]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:22])[CH2:3][CH3:4])=[N:10][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCC(N)c1nnc(C(C)(C)C)[nH]c1=O
Product: CCC(NC(=O)C1CCCC1)c1nnc(C(C)(C)C)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 110 mg (0.50 mmol) 6-(1-aminopropyl)-3-tert-butyl-1,2,4-triazin-5(4H)-one, 70 mg (0.50 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][N:5]=1)[CH3:2].[Br:12]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][Br:12])[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1cc(CO)ccn1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOc1cc(CBr)ccn1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 0.31 g of 2-ethoxy-4-(hydroxymethyl)pyridine in 6 ml of dichloromethane is added dropwise to a solution of 1.025 g of dibromotriphenylphosphorane in 12 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is continued at this temperature for about 1 hour. The reaction medium is taken up in 100 ml of dichloromethane and then washed with 3×100 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography, using a cartridge 27 mm in diameter packed with 20 g of 20-40 μm conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate)(9/1)(v/v) at a flow rate of 8 ml/minute. The fractions between 80 and 180 ml are concentrated under reduced pressure. 0.37 g of 2-ethoxy-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: C(OC([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([N:19]([CH3:30])[C@H:20]([C:27]([OH:29])=O)[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])=O)C1C=CC=CC=1.[CH3:31][C@H:32]1[CH2:36][CH2:35][NH:34][C@@H:33]1[C:37]([NH2:39])=[O:38]>CN(C)C=O>[NH:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([N:19]([CH3:30])[C@H:20]([C:27]([N:34]1[CH2:35][CH2:36][C@H:32]([CH3:31])[C@H:33]1[C:37]([NH2:39])=[O:38])=[O:29])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18]
Reactant: C[C@H]1CCN[C@@H]1C(N)=O
Reactant: CN(C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: CN(C)C=O
Product: C[C@H]1CCN(C(=O)[C@H](Cc2c[nH]cn2)N(C)C(=O)[C@@H]2CCC(=O)N2)[C@@H]1C(N)=O
Yield: 46.1 %

Procedure:
This was prepared from benzyloxycarbonyl-L-pyroglutamyl-Nα -methyl-L-histidine (207 mg) and trans-3-methyl-L-prolineamide (77 mg) by the method of Example 2(vi) to yield a white hydroscopic solid (90 mg) RF 3A m.p. 135°-140° RF 3B 0.60 (Found C, 55.0; H, 7.0; N, 21.2; C18H23N6O4 requires C, 55.4; H, 6.7; N, 21.5%) [α]D22 - 23.9° (c = 1, dimethylformamide).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:7]=[C:8]([C:13]([OH:15])=O)[NH:9][C:10]=1[CH2:11][CH3:12]>>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([Cl:3])=[O:15])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Product: CCc1[nH]c(C(=O)Cl)nc1Cl
Temperature: 85 °C
Reaction time: 0.67 h

Procedure:
Thionyl chloride (4 mL) was added to 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1c, 200 mg, 0.8 mmol), and the mixture was stirred at 85° C. for 40 minutes. Following concentration under reduced pressure, the residue was azeotropically distilled with toluene twice to obtain crude 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid chloride. 5 mL pyridine was added and then ethyl 2-(4-aminophenyl)-1,3-thiazole-5-carboxylate obtained in Example (91b) was added. The mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate. The precipitated solid was collected by filtration and washed with ethyl acetate, to obtain 214 mg of the title compound as a white solid (73%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[C:22]([C:29]4[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=4[Cl:27])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CC1(C)OB(c2ccc(F)cc2Cl)OC1(C)C
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccccc3-c3ccc(F)cc3Cl)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.20 g, 0.42 mmol) and 2-(2-chloro-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.18 g, 0.71 mmol) to afford 0.072 g (35%). LC/MS, Retention time 4.98 min; (m/z): calcd for C25H24ClFN4OS: 483.0; found: 483.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CC(C)CCBr
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of 4-benzyloxy-1H-pyridin-2-one (1.0 g, 4.97 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.86 mL, 12.43 mmol) and 1-bromo-3-methyl butane (0.715 mL, 5.96 mmol) in N,N-dimethylacetamide (20 mL) was heated at 65° C. for 5 days. The solution was cooled to about 25° C. and partitioned between 10% aqueous ammonium chloride and dichloromethane, the organic layer separated and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 1% methanol in dichloromethane to provide the title compound (0.569 g, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:16]([OH:17])[CH2:15][CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[CH:4][CH:3]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1)[C:30]([O:17][C@H:16]1[CH2:15][CH2:14][C@@H:13]2[C@@H:9]([CH2:10][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]2)[C@@H:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](O)[C@@H](c3ccc(F)cc3)[C@@H]2C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](OC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.75 g (14.0 mmol) of the intermediate of step B in dry methylene chloride under nitrogen atmosphere at RT was added 4.71 g (17.0 mmol) of 3,5-bis(trifluoromethyl)-benzoyl chloride, 2.4 mL (17.3 mmol) TEA and a catalytic amount of DMAP. The resulting mixture was stirred at RT for 2 hr then transferred to a separatory funnel, washed with saturated. aq. NaHCO3 and brine. The combined organic layers dried over magnesium sulfate, filtered and the solvent evaporated under vacuum to afford the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 8.63 (1H, s), 8.19 (2H, s), 7.25 (2H, m), 7.00 (2H, m), 5.22 (1H, m), 3.59–3.33 (2H, m), 3.30–3.20 (2H, m), 2.83 (1H, t,J=12.7 Hz), 2.62 (1H, m), 2.43 (1H, m), 2.20 (1H, m), 2.02 (1H, m), 1.90–1.70 (2H, m), 1.55, 1.47 (9H, two singlets).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C=O)c(O)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
A mixture of 2,4-Dihydroxybenzaldehyde (5.52 g), potassium carbonate (6.08 g) and octyl bromide (7.73 g) in acetonitrile (55 ml) was stirred for 16 hours at 60° C. The solvent of reaction mixture was removed under reduced pressure, and the residue was dissolved in ethyl acetate, and washed with water and brine. The separated organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with (hexane:ethyl acetate=9:1) to give 2-Hydroxy-4-octyloxybenzaldehyde (6.73 g).
Reaction SMILES: C(N(CC)CC)C.C1C(=O)OCC1=[O:10].[CH:15]([N:18]=[C:19]=[N:20][CH:21]([CH3:23])[CH3:22])([CH3:17])[CH3:16]>ClCCl>[CH:15]([NH:18][C:19]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:10])([CH3:17])[CH3:16]
Reactant: CC(C)N=C=NC(C)C
Reactant: O=C1COC(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.75 mL, 5.5 mmol) was added to a suspension of tetronic acid (500 mg, 5.00 mmol) in dichloromethane (25 mL) to obtain a homogeneous solution. The solution was cooled to 0° C., mixed with 4-N,N-dimethylaminopyridine (200 mg, 1.7 mmol), 3-cyclohexne-1-carboxylic acid (0.65 mL, 5.6 mmol), and then, diisopropylcarbodiimide (1.0 mL, 6.3 mmol), followed by stirring for 30 min. The resulting mixture was removed from the ice bath, stirred for 14 hours at room temperature, and filtered to remove thus-produced insoluble diisopropyl urea; the reaction solution was washed twice with 5% hydrochloric acid (20 mL) and the water layer was extracted twice with dichloromethane (10 mL). The organic layers were combined, dried over sodium sulfate anhydride, and concentrated; the thus-obtained residue was purified by silica gel column chromatography (silica gel, ethyl acetate:methanol=15:1). The resultant was arranged to be a sodium salt by adding an excess amount of sodium hydrogencarbonate and distilled water (100 mL), and then washed with dichloromethane; the water layer was acidified by adding 5% hydrochloric acid and extracted four times with dichloromethane (20 mL). The resultant was dried over sodium sulfate anhydride and concentrated to give pale yellow crystals (394 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I.CCCCCCC>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:19][CH2:18][Cl:17])[C:9]#[N:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: N#CCc1ccc(Br)cc1C(F)(F)F
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: N#CC(CCCCl)c1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of (4-bromo-2-trifluoromethylphenyl)acetonitrile (2.28 g) in tetrahydrofuran (6 mL) was added to a suspension of sodium hydride (containing 60% in mineral oil, 362 mg) in tetrahydrofuran (12 mL) under ice-cooling. The mixture was stirred at the same temperature for 20 minutes. 1-Chloro-3-iodopropane (0.94 mL) was added dropwise to the reaction solution, and then the reaction solution was stirred at room temperature for 40 minutes. Ice water and heptane were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel™ C-200; elution solvent:heptane:ethyl acetate=49:1→19:1) to obtain 2.67 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([N:1]([N:16]=[O:17])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1
Reactant: Cc1cc(C)nc(Nc2ccccc2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)nc(N(N=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 2.0 g of 2-anilino-4,6-dimethylpyrimidine in 15 ml of acetic acid was added dropwise a solution of 1.4 g of sodium nitrite in 10 ml of water. After 30 minute's stirring, 50 ml of water was added to the mixture. The resulting crystals were collected by filtration and dried. Recrystallization from ethanol afforded 1.7 g (yield: 74%) of 4,6-dimethyl-2-(N-nitrosoanilino)pyrimidine having a melting point of 117°-121° C.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15]([O:17][C:18]([C:20]#[C:21][C:22](OCC)=[O:23])=[O:19])[CH3:16].Cl>C(O)C.O>[OH:23][C:22]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH:21]=1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(O)n(-c2ccccc2)n1
Temperature: 85 °C

Procedure:
To a solution of phenyl hydrazine (10 g, 92.6 mmol) in absolute ethanol (100 mL) is added dry K2CO3 (15.3 g, 111 mmol) and followed by slow addition of diethylacetylene dicarboxylate (10.6 g, 62.03 mmol) and the reaction mixture is heated at 85° C. for 12 h. The reaction mixture is then cooled to rt and 38 mL of 6N HCl is added dropwise. The reaction mixture is diluted with 150 mL water, extracted with ethylacetate. The organic layer is washed with water twice, dried over Na2SO4 and concentrated under vacuum. The residue is triturated with MTBE and the solid formed is filtered, washed with MTBE and dried to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 12.12 (bs, 1H), 7.72-7.70 (m, 2H), 7.51-7.47 (m, 2H), 7.37-7.34 (m, 1H), 5.93 (s, 1H), 4.26 (q, J=4.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H). MS (ESI+): 233.2.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:12]C(=O)C)[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[ClH:16]>>[ClH:16].[NH2:12][CH:3]([CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1)[CH2:2][OH:1]
Reactant: CC(=O)NC(CO)CN1CCN(C)CC1
Agent: Cl
Product: CN1CCN(CC(N)CO)CC1
Temperature: 100 °C

Procedure:
A suspension of 0.89 g of N-[2-hydroxy-1-(4-methyl-piperazin-1-ylmethyl)ethyl]acetamide in 10.3 mL of an aqueous acid solution of 6N hydrochloric acid is heated at a temperature of about 100° C. for 3 hours. After cooling at a temperature of about 60° C., the reaction medium is filtered and the filtrate is concentrated under reduced pressure (2 kPa) at a temperature of about 60° C. About 1 g of 2-amino-3-(4-methyl-piperazinyl)-1-propanol, hydrochloride is obtained in the form of a tacky beige-colored paste. [Infrared spectrum (KBr) 3337; 2955; 2637; 2522; 1617; 1457; 1062; 1009 and 962 cm−1].
Reaction SMILES: [ClH:1].N[N:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[ClH:1].[CH3:13][C:11]1[CH:10]=[C:9]2[C:8]3[N:3]([C:18]4[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][C:17]=42)[CH2:4][CH2:5][O:6][C:7]=3[CH:12]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc2c(c1)OCCN2N
Agent: Cl
Product: Cc1cc2c3c(c1)c1c(n3CCO2)CCN(C)C1

Procedure:
4-Amino-3,4-dihydro-7-methyl-2H-1,4-benzoxazine hydrochloride is reacted with 1-methyl-4-piperidone according to the procedure of Example 110 to yield the title compound, m.p. 248°-249°.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([Cl:10])=[CH:8][N:9]=1)(=[O:3])[CH3:2].CN(C=O)C.[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21]Br>C(OCC)(=O)C>[Cl:10][C:7]1[S:6][C:5](=[N:4][C:1](=[O:3])[CH3:2])[N:9]([CH2:21][CH2:20][O:19][CH3:18])[CH:8]=1
Reactant: COCCBr
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1cc(Cl)sc1=NC(C)=O
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A flask was charged with 2-acetamido-5-chlorothiazole (Lancaster, 19.3 g, 110 mmol) in 200 mL of 2:1 THE/DMF. To the solution was added sodium hydride (60% dispersion in mineral oil, 5.44 g, 142 mmol). The mixture was stinred at room temperature for 15 minutes and then 2-bromoethyl methyl ether (18.3 g, 131 mmol) was added. The mixture was warmed to 85° C. and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on SiO2 using a gradient of 0% to 100% ethyl acetate:hexane to provide 10.3 g (42%) of the title compound as the more polar regioisomer: 1H NMR (300 MHz, CDCl3) δ 2.28 (s, 3 H) 3.35 (s, 3 H) 3.65-3.71 (m, 2 H) 4.28-4.36 (m, 2 H) 7.00 (s, 1 H); MS (ESI+) m/z 235 (M+H)+.