Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH2:12]([CH:19]1[CH2:20][CH2:21][N:22]([C:25](=[O:29])[C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[NH:7][C:6]=3[CH:11]=2)=[O:27])[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Solvent: O
Product: O=C(Nc1ccc2oc(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-3H-benzoxazole-2-one and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 2. Melting Point: 187-190° C. (water)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7]/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH2:3][CH2:2]1.O[C:13]1[CH:22]=[C:21]2[C:16]([C:17]([S:23][CH3:24])=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1>>[CH3:24][S:23][C:17]1[C:16]2[C:21](=[CH:22][C:13]([O:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:14][CH:15]=2)[N:20]=[CH:19][N:18]=1
Reactant: OC/C=C/CN1CCOCC1
Reactant: CSc1ncnc2cc(O)ccc12
Product: CSc1ncnc2cc(OC/C=C/CN3CCOCC3)ccc12
Yield: 55.6 %

Procedure:
Using an analogous procedure to that described in the second last paragraph of Note [12] above, (E)-4-morpholinobut-2-en-1-ol (J. Med. Chem., 1972, 15, 110-112; 1.27 g), was reacted with 7-hydroxy-4-methylthioquinazoline (1.2 g) to give 4-methylthio-7-[(E)-4-morpholinobut-2-en-1-yloxy]quinazolin (1.15 g); NMR Spectrum: (CDCl3) 2.45 (br s, 4H), 2.7 (s, 3H), 3.05 (d, 2H), 3.7 (t, 4H), 4.7 (d, 2H), 5.9 (m, 2H), 7.15-7.25 (m, 2H), 7.95 (d, 1H), 8.9 (d, 1H); Mass Spectrum: M+H+ 332.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)=[O:18]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C1CCc2ccccc2N1
Product: O=C1CCc2cc(C(=O)CCCCCl)ccc2N1

Procedure:
Using 3,4-dihydroquinolin-2(1H)-one (2.94 g) and 5-chloropentanoyl chloride (3.7 g) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (1.59 g) having a melting point of 145 to 146° C.
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.Cl[CH2:42][CH2:43][S:44][CH3:45].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>CC#N>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:42][CH2:43][S:44][CH3:45])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CSCCN1CCC(N2Cc3cc4nc(-c5c(NCC(O)COc6ccc(C)cc6C)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 100 °C

Procedure:
A mixture of the 2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (542 mg, 1.0 mmol), 1-chloro-2-methylsulfanyl-ethane (122 mg, 1.1 mmol), Na2CO3 (318 mg, 3.0 mmol) and NaI (150 mg, 1.0 mmol) in CH3CN (20 mL) was heated at 100° C. for 22 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (200:10:1) afforded the title compound. 1H NMR (DMSO-d6) δ 1.69-1.82 (4H), 2.09 (s, 3H, CH3), 2.09 (m, 2H), 2.19 (s, 3H, CH3), 2.20 (s, 3H, CH3), 2.50-2.59 (4H), 3.00 (m, 2H), 3.38 (m, 2H), 3.53 (m, 1H), 3.70 (m, 1H), 3.98-4.08 (3H), 4.15 (m, 1H), 4.43 (s, 1H), 4.47 (s, 1H), 5.47 (br s, 0.5H, NH), 5.53 (br s, 0.5H, NH), 6.20 (m, 1H), 6.80-6.99 (3H), 7.30-7.36 (1.5H), 7.68 (s, 0.5H), 7.79 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (br d, J=6 Hz, 1H, NH), 11.21 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 617.5 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][SH:21])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[N:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([NH:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)[S:32][CH:33]=2)=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[N:30]=[C:31]([NH:34][CH2:35][CH:36]5[CH2:37][CH2:38]5)[S:32][CH:33]=4)=[CH:27][N:28]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccc(-c2csc(NCC3CC3)n2)cn1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CS)c2CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccc(-c4csc(NCC5CC5)n4)cn3)c2CC1
Temperature: 100 °C
Yield: 93 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-mercaptomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.078 g, 0.239 mmol) in anhydrous dioxane (1.1 mL), add N-[4-(6-bromo-pyridin-3-yl)-thiazol-2-yl]-cyclopropylmethylamine (0.067 g, 0.218 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.0055 mmol), Xantphos (6.3 mg, 0.011 mmol) and diisopropylethylamine (0.076 mL, 0.44 mmol) at room temperature. Purge the reaction mixture with nitrogen and heat the mixture at 100° C. overnight. Cool the reaction mixture to room temperature. Dilute with DCM (50 mL) and filter through Celite®. Concentrate the filtrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (0:100 to 25:75 EtOAc/hexane over 33 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-{5-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-pyridin-2-ylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.113 g, 94%) as a pale yellow foam. MS (ES+) m/z: 557.2 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=O.[C:17]([NH:20][C:21]([NH2:23])=[S:22])(=[NH:19])[NH2:18]>C(O)C>[BrH:1].[NH:20]([C:21]1[S:22][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=2)[N:23]=1)[C:17]([NH2:19])=[NH:18]
Reactant: N=C(N)NC(N)=S
Reactant: CCOC(=O)Nc1cccc(C(=O)CBr)c1
Solvent: CCO
Product: Br
Product: CCOC(=O)Nc1cccc(-c2csc(NC(=N)N)n2)c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of 17.17 gm of ethyl N-[3-(2-bromoacetyl)-phenyl]-carbamate, 7.1 gm of amidinothiourea and 45 ml of ethanol was refluxed for 4 hours and then cooled to room temperature. The precipitate formed thereby was filtered off and washed with cold ethanol, yielding 22 gm of the title compound, m.p. 240°-2° C.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:21][OH:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C[O:31][C:32]([CH:34]1[CH2:36][CH2:35]1)=O.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:32]([CH:34]3[CH2:36][CH2:35]3)([OH:31])[O:22][N:21]=2)=[CH:9][CH:8]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Reactant: COC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2=NOC(O)(C3CC3)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a mixture consisting of Example 1, Compound B (3.0 g) in anhydrous tetrahydrofuran (14 mL) at −5° C. under a nitrogen atmosphere is added a solution consisting of 1.6 M n-butyllithium in hexanes (12 mL.) The mixture is stirred between −5 and 0° C. for 30 minutes. To the stirring mixture at 0° C. is added a mixture consisting of cyclopropanecarboxylic acid methyl ester (1.3 g) in tetrahydrofuran (7 mL) and the resultant mixture is stirred for two hours. The mixture is raised to room temperature and is stirred for 18 hours. The mixture is then treated with saturated aqueous ammonium chloride (50 mL) and diluted with ethyl acetate (300 mL.) The organic layer is separated and is washed sequentially with an additional portion of saturated aqueous ammonium chloride (50 mL) and brine solution (50 mL.) The organic layer is separated and is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with dichloromethane then with a mixture of hexanes-ethyl acetate (4:1 v/v) afforded the synthetic intermediate 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-cyclopropyl-4-phenyl-4,5-dihydro-isoxazol-5-ol (1.15 g.)
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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH:45]([N:48]([CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50][NH2:51])([CH3:47])[CH3:46]>C(Cl)(Cl)Cl.O>[CH:45]([N:48]([CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50][NH:51][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])=[O:43])([CH3:47])[CH3:46]
Reactant: CC(C)N(CCN)C(C)C
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN(C(C)C)C(C)C)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diisopropyl-1,2-ethanediamine (63 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (71 mg, yield 48%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([CH:24]4[CH2:26][CH2:25]4)[CH:23]=2)[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]3([CH3:30])[CH3:29])=[CH:8][C:7]=1[F:31])C.CO.[OH-].[Na+].O>C(#N)C>[CH:24]1([C:22]2[CH:23]=[C:14]([CH2:13][CH2:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[C:7]([F:31])[CH:8]=3)[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([CH3:27])([CH3:28])[CH2:18][C:17]3([CH3:30])[CH3:29])[CH2:25][CH2:26]1
Reactant: CCOC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(C)(C)c2cc(CCc3ccc(CC(=O)O)c(F)c3)cc(C3CC3)c2O1

Procedure:
Following general procedure L and using [4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl]acetic acid ethyl ester (Compound 37, 0.14 g, 0.323 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.110 g, 80%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][CH:14](O)[CH3:15])[CH2:7][CH2:8][CH3:9]>>[C:1]([O:5][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][SH:3]
Reactant: O=C(O)CS
Reactant: CCCCOCCOC(C)O
Product: CCCCOCCOCCOC(=O)CS
Temperature: 6 °C
Yield: 92.4 %

Procedure:
Thioglycolic acid (40.9 ml, 0.589 mole) obtained from Evans Chemetics, Inc. was added dropwise with stirring to butoxyethoxyethanol (butyl Carbitol) (95.53 g, 0.589 mole) obtained from Fisher Scientific Company with 12% Dowex cation exchange resin HGR-W (10% crosslinking, 11.46 g) as a catalyst. A temperature increase of 6° C. occurred immediately upon addition of the reactants. The solution was further heated and the byproduct, water, was distilled over at 89° C. and collected. When 50% of the water had been collected, a 30% excess of butoxyethoxyethanol (33 mls) was added to increase the rate of product formation. After 3.5 hours a 92.4% yield of butoxyethoxyethyl thioglycolate was obtained and thereafter vacuum distilled at 10 mm Hg and a temperature range of 25°-100° C. in order to remove the unreacted starting materials.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]1=3)[CH2:30][CH2:29][O:28]4)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N:33]1[CH:38]=[C:37]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]2=4)[CH2:30][CH2:29][O:28]5)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)[CH:36]=[N:35][CH:34]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(-c3cncnc3)c2C12COc1cc3c(cc12)CCO3
Yield: 28.3 %

Procedure:
A mixture of 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.11 g, 0.21 mmol), pyrimidine-5-boronic acid (0.04 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol), 2.00 M sodium carbonate (1.00 mL) and 1,2-dimethoxyethane (10.0 mL) was heated at reflux for 16 h under nitrogen. After the organic solvent was evaporated in vacuo, the black residue was extracted with ethyl acetate (3×35.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluting with ethyl acetate:hexane (35%) to afford the title compound (0.03 g, 26%): mp 263-266° C.; 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.14 (s, 2H), 7.39 (t, 1H), 7.10, (d, 1H), 6.87 (d, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 6.46 (s, 1H), 6.07 (s, 1H), 5.03 (ABq, 2H), 4.62-4.48 (m, 21-1), 4.58 (ABq, 2H), 3.01 (t, 2H); 13C NMR (75 MHz, CDCl3) δ 177.3, 162.5, 161.0, 157.4, 155.9, 151.6, 142.2, 141.7, 132.8, 132.3, 131.3, 129.3, 125.7, 120.6, 120.2, 118.3, 117.0, 112.7, 109.7, 109.4, 93.5, 78.9, 72.5, 57.7, 37.1, 28.9; MS (ES+) m/z 506.5 (M+1).
Reaction SMILES: CO[C:3](=[O:22])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)=[N:5][O:6][CH3:7].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+:37]=[CH:36]C=1.[O:40]1[CH:45]=[CH:44][CH2:43][CH2:42][CH2:41]1>ClCCl>[CH3:36][NH:37][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:45]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH:16]=1)=[N:5]/[O:6][CH3:7]
Reactant: c1cc[nH+]cc1
Reactant: C1=COCCC1
Reactant: CON=C(C(=O)OC)c1ccccc1Oc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of methyl-2-[2-(3-hydroxyphenoxy)phenyl]-2-methoxyiminoacetate (0.25 g) in dichloromethane (10 ml), dihydropyrane (0.3 ml) and PPTS (20 mg) were added, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous sodium hydrogencarbonate solution, followed by removal of the solvent. The residue was dissolved in methanol (3 ml), and 40% methanolic methylamine (0.5 ml) was added thereto. The resultant mixture was stirred at room temperature for 15 hours. The solvent and excess methylamine were removed, and the residue was purified by silica gel column chromatography to give 0.27 g of the objective compound.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[C:14]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1)=[CH2:20]
Reactant: CC(C)(C)CC(C)(O)c1ccc(C#N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(CC(C)(C)C)c1ccc(C#N)cc1
Temperature: 100 °C
Yield: 61.9 %

Procedure:
Add p-toluenesulfonic acid monohydrate (308 mg, 1.62 mmol) to a solution of 4-(1-hydroxy-1,3,3-trimethyl-butyl)-benzonitrile (352 mg, 1.62 mmol) in toluene (10 mL). Heat the solution to 100° C. for 30 min. Cool the reaction mixture to room temperature, dilute the reaction mixture with EtOAc and wash the organic phase with saturated aqueous NaHCO3. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (98:2, 19:1) to give the desired intermediate as an oil (200 mg, 62%).
Reaction SMILES: [P:1]([O-:39])([O:35][CH2:36][CH2:37]Br)([O:3][CH2:4][CH:5]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:10][N:9]=1)=[O:2].[S:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>>[P:1]([O-:39])([O:35][CH2:36][CH2:37][C:41]1[S:40][CH:44]=[CH:43][NH+:42]=1)([O:3][CH2:4][CH:5]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:10][N:9]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCc1cc(OCC(COP(=O)([O-])OCCBr)Oc2ccon2)no1
Reactant: c1cscn1
Product: CCCCCCCCCCCCCCCCc1cc(OCC(COP(=O)([O-])OCCc2[nH+]ccs2)Oc2ccon2)no1

Procedure:
0.779 g of (2RS)-3-(5-hexadecyl-3-isoxazolyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in Example 21(a)] was reacted with 0.86 ml of thiazole in a similar manner to that described in Example 13, to give 0.288 g of the title compound as a white powder melting at 94°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:29])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][N:20]=[C:19]1[CH2:27]O.CS(Cl)(=O)=O.[CH2:35]([NH2:38])[C:36]#[CH:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:29])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][N:20]=[C:19]1[CH2:27][NH:38][CH2:35][C:36]#[CH:37]
Reactant: C#CCN
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: CS(=O)(=O)Cl
Product: C#CCNCc1nnc(CN(C)C)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 47, 2'-chloro-5-nitro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with methanesulfonyl chloride followed by propargylamine, to give 2'-chloro-5-nitro-2-[3-[[(2-propynyl)amino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: Cl.Cl.[OH:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CS(C)=O.C(N(CC)CC)C.[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:36])=[C:31](F)[C:32]=3[F:34])[C:27](=[O:37])[C:26]([C:38]#[N:39])=[CH:25]2)[CH2:23][CH2:22]1>O>[C:38]([C:26]1[C:27](=[O:37])[C:28]2[C:33](=[C:32]([F:34])[C:31]([N:7]3[CH2:8][CH2:9][N:4]([OH:3])[CH2:5][CH2:6]3)=[C:30]([F:36])[CH:29]=2)[N:24]([CH:21]2[CH2:22][CH2:23]2)[CH:25]=1)#[N:39]
Reactant: ON1CCNCC1
Reactant: N#Cc1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cn(C2CC2)c2c(F)c(N3CCN(O)CC3)c(F)cc2c1=O
Temperature: 100 °C
Yield: 82.1 %

Procedure:
1-Hydroxypiperazine dihydrochloride (2.45 g) (which is prepared in Preparation 1), dimethylsulfoxide (20 ml) and triethylamine (5.05 g) are added to 1-cyclopropyl-3-cyano-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline (2.64 g), which is prepared in Preparation 3, and the mixture is stirred with heating at 100° C. for 4 hours. After cooling to room temperature, water (300 ml) is added to the reaction mixture, and the resulting precipitate is filtered and washed with water to afford 3-cyano-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline (2.84 g) as pale yellow powder. The powder is recrystallized from dimethylsulfoxide to yield light brown needles, m.p. about 214° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH2:22]([N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-:36].[Na+]>O1CCCC1>[ClH:36].[ClH:36].[CH2:22]([N:29]1[CH2:30][CH:31]=[C:32]([C:2]2[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=2)[CH2:33][CH2:34]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Product: Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 10 g of p-bromo-N,N-dimethylaniline in 100 ml of tetrahydrofuran was chilled to -78° C., followed by addition of a hexane solution containing an equimolar amount of n-butyllithium. The mixture was stirred at -78° C. for 10 minutes, after which 9.5 g of N-benzyl-4-piperidone was added. The mixture was further stirred for 1 hour. The reaction mixture was then diluted with 100 ml of saturated aqueous sodium chloride solution and the organic layer was taken. From this layer, the solvent was distilled off, and 200 ml of concentrated hydrochloric acid was added to the oily residue. The mixture was heated at 100° C. with stirring for 6 hours. Finally, the solvent was distilled off and the residue was recrystallized from methanol to give 14 g of colorless crystals melting at 229°-232° C.