Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C2C(=CC=1)N(O[S:12](O)(=O)=O)C(=O)C2.S[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=O)[CH2:21]2.[CH2:28](I)[CH3:29].P([O-])([O-])(O)=O>CO>[CH2:28]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[S:12])[CH2:21]2)[CH3:29]
Reactant: Cc1ccc2c(c1)CC(=O)N2OS(=O)(=O)O
Reactant: CCI
Reactant: O=C1Cc2cc(S)ccc2N1
Agent: O=P([O-])([O-])O
Solvent: CO
Product: CCc1ccc2c(c1)CC(=S)N2
Yield: 92.5 %

Procedure:
Under reaction conditions analogous to the preparation of 5-methylsulfoxyoxindole, alkylation of 5-mercaptooxindole 1.99 g (12.05 mmol) with ethyl iodide 1.35 mL (16.7 mmol) in aqueous methanol at 50° C. in the presence of hydrogen phosphate provided 2.152 g of 5-ethylthiooxindole (92.5%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[H-].[Na+].[CH3:54][O:55][C:56]1[CH:65]=[CH:64][C:59]([C:60](=[O:63])[CH2:61]Br)=[CH:58][CH:57]=1.O>CN(C)C=O>[CH3:54][O:55][C:56]1[CH:65]=[CH:64][C:59]([C:60](=[O:63])[CH2:61][N:2]([CH3:1])[S:3]([C:6]2[S:7][C:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:21]5[C:22]([C:45]6[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=6)=[N:23][N:24]([C:26]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:25]=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:9][CH:10]=2)(=[O:5])=[O:4])=[CH:58][CH:57]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN(C)S(=O)(=O)c2ccc(-c3ncnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5-c5ccc(F)cc5)cc34)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
50 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) was dissolved in 3 mL N,N-dimethylformamide, then 3.1 mg sodium hydride was added thereto and stirred at room temperature for 0.5 hour. Under ice-cooling, a solution of 18 mg 4-methoxyphenacyl bromide in 2 mL N,N-dimethylformamide was added thereto and stirred for 1.0 hour under ice-cooling. Water was added to the reaction solution which was then extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 47 mg of the title compound.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-:15].[K+].C(Br)C1C=CC=CC=1>O>[CH2:14]([O:15][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccccc1
Reactant: [OH-]
Reactant: O=C1CCCCO1
Agent: BrCc1ccccc1
Agent: [K+]
Solvent: O
Product: O=C(O)CCCCOCc1ccccc1
Temperature: 125 °C
Reaction time: 8 h

Procedure:
δ-Valerolactone (50 g) and toluene (500 mL) were mixed. To the mixture were added potassium hydroxide (158 g) and benzyl bromide (178 mL). The mixture was stirred at 125° C. overnight. To the reaction mixture was added water (350 mL) at ice temperature. The organic layer was removed, and the aqueous layer was washed with tert-butyl methyl ether (150 mL×3). To the resulting aqueous layer were added concentrated hydrochloric acid (75 mL) and 6 N hydrochloric acid (40 mL) at ice temperature. The mixture was extracted with ethyl acetate (250 mL, 100 mL). The combined organic layer was washed with brine (100 mL), then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (79.2 g) as a crude product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].[Cl:41][C:42]1[CH:47]=[CH:46][C:45](F)=[CH:44][CH:43]=1>CN(C)C=O>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([O:1][CH2:2][C:3]2[N:4]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][CH2:15]3)[C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:44][CH:43]=1
Reactant: OCc1cc2ccccc2n1CCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: Fc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2cc3ccccc3n2CCC2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere 2-hydroxymethyl-1-[2-(1-tritylpiperidin-4-yl)ethyl]-1H-indole (3.91 g, 7.81 mmol) was dissolved in about 10 ml of N,N-dimethylformamide. The resulting solution was then placed in an ice bath and sodium hydride (0.468 g, 11.71 mmol) was added and the resulting mixture was stirred at room temperature for about 30 minutes. To the reaction mixture 1-chloro-4-fluorobenzene (0.915 ml, 1.12 g, 8.59 mmol) was added and the resulting mixture was stirred at room temperature for about four days, protected from light.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:22])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH3:24])[CH3:23])(C)(C)C.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[NH2:7][CH:8]1[C:9]([CH3:24])([CH3:23])[C:10]2[CH:11]=[C:12]([C:20]([NH2:21])=[O:22])[CH:13]=[CH:14][C:15]=2[CH2:16][CH:17]1[O:18][CH3:19]
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC1Cc2ccc(C(N)=O)cc2C(C)(C)C1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a slurry of trans-(7-carbamoyl-3-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (9.22 g, 26.4 mmol) in DCM (100 mL) was added 4 N HCl in dioxane (25 mL, 100 mmol) slowly. The reaction mixture was stirred at RT for 15 h, concentrated to dryness, triturated with DCM (25 mL) for 30 min, filtered, rinsed with DCM (3×15 mL), and dried under vacuum. Ethanol (100 mL) was added and the reaction mixture was concentrated under vacuum to give the HCl salt of the title compound (7.17 g) as a white powder. (m/z): [M+H]+ calcd for C14H20N2O2 249.16; found 249.1. 1H NMR (d6-DMSO, 400 mHz) δ (ppm): 8.18 (s, 3H), 8.00 (s, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.66 (dd, J=8.0 Hz, 1.8 Hz, 1H), 7.32 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 3.70 (m, 1H), 3.44 (s, 3H), 3.43 (m, 1H), 3.22 (m, 1H), 2.67 (dd, J=16.4 Hz, 10.2 Hz), 1.50 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:9])=[CH:6][N:5]=[C:4](SC)[N:3]=1.Cl[C:21]1C=CC=C(C(OO)=O)C=1.[S:31]([O-:34])(O)=[O:32].[Na+]>C(Cl)(Cl)Cl>[CH3:21][S:31]([C:4]1[N:3]=[C:2]([CH3:1])[C:7]([C:8]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:9])=[CH:6][N:5]=1)(=[O:34])=[O:32]
Reactant: CSc1ncc(C(=O)OCCC(C)=C(F)F)c(C)n1
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(CCOC(=O)c1cnc(S(C)(=O)=O)nc1C)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To 20 ml of chloroform was dissolved 1.10 g (3.8 mmol) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-(methylthio)pyrimidine-5-carboxylate, followed by the addition, in three portions, of 2.00 g (8.1 mmol) of 70% m-chloroperbenzoic acid under ice-cooling and stirring for 1 hour after warming to room temperature. An aqueous solution of sodium hydrogensulfite was added under ice-cooling and the mixture was filtered to fractionate an organic layer. The organic layer was washed with a saturated sodium hydrogencarbonate solution and water in this order, followed by drying over anhydrous magnesium sulfate, the addition of “Florisil” and filtering. The solution was concentrated at 40° C. under reduced pressure to obtain 1.13 g (yield: 92%) of 4,4-difluoro-3-methyl-3-butenyl 2-methanesulfonyl-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [CH3:1][C:2](=C)[CH3:3].[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[C:15]1(C)C=CC=CC=1>>[CH3:6][C:5]1([CH3:15])[C:8]2[C:9](=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[C:2]([CH3:3])([CH3:1])[CH2:7]1
Reactant: CC(C)c1ccc(O)cc1
Reactant: C=C(C)C
Reactant: Cc1ccccc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21
Temperature: 150 °C

Procedure:
112 g (2 mol) of isobutylene were pumped for one hour into 136 g (1 mol) of 4-isopropyl-phenol in 100 ml of toluene and 30 g of an acid activated Fuller's earth in an autoclave with stirring at 150° C. The reaction mixture was then stirred for 6 hours at 150° C. After removal of the catalyst by filtration, 120 g of pure 1,1,3,3-tetramethyl-5-hydroxyindane were obtained by fractional distillation; Bp12 : 144° C.; Mp: 119° C. ##STR16##
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:10][OH:11].C1(C(C)C)C=CC=CC=1.C1(O)C=CC=CC=1.CC(C1C=CC=CC=1)=C>CC(C)=O>[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]=[O:11]
Reactant: [O-]O
Agent: C=C(C)c1ccccc1
Solvent: CC(C)=O
Solvent: CC(C)c1ccccc1
Solvent: Oc1ccccc1
Product: O=O

Procedure:
It has been discovered that when a cumene oxidation product mixture containing cumene hydroperoxide (CHP) and DMPC is decomposed to produce phenol, acetone and alpha-methyl styrene by passing the cumene oxidation product mixture into a decomposing vessel containing indirect heat exchange surfaces wherein the cumene oxidation product mixture and an incoming circulating stream comprising cumene hydroperoxide, phenol, acetone and an acid catalyst are admixed, reacted and cooled by passage around the indirect heat exchange surfaces and then circulating a cooled stream comprising unreacted cumene hydroperoxide, phenol and acetone from the decomposing vessel to provide the circulating stream referred to hereinabove, an improved yield of alpha-methyl styrene is realized. A net reacted stream preferably comprising a cumene hydroperoxide concentration from about 0.5 to about 5 weight percent is removed from the circulating stream and recovered. The cumene oxidation product mixture is the result of cumene oxidation with oxygen and preferably comprises a cumene hydroperoxide concentration from about 60 to about 95 weight percent. The ratio of the flow rate of the cumene oxidation product mixture to the flow rate of the circulating stream is preferably from about 1:10 to about 1:100 in the decomposing vessel. In accordance with the present invention, a suitable and preferred acid catalyst is sulfuric acid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH3:13][CH:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][C:16](=O)[CH2:15]1.[CH2:22](N(CC)CC)C.C=O>ClCCCl>[CH3:22][N:10]([CH:16]1[CH2:15][CH:14]([CH3:13])[CH2:19][CH:18]([CH3:20])[CH2:17]1)[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=1
Reactant: CC1CC(=O)CC(C)C1
Reactant: CCN(CC)CC
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: C=O
Agent: Cl
Solvent: ClCCCl
Product: CC1CC(C)CC(N(C)Cc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C

Procedure:
In 1,2-dichloroethane (70 ml) were suspended p-nitrobenzylamine hydrochloride (3.8 g), 3,5-dimethylcyclohexanone (2.5 g) and triethylamine (2.8 ml). Under ice-cooling, to the mixture was added sodium triacetoxy boron hydride (5.9 g). Under nitrogen atmosphere, the mixture was stirred at room temperature over night. Under ice-cooling, to the mixture were added 37% formalin (1.8 ml) and sodium triacetoxy boron hydride (5.9 g). Under nitrogen atmosphere, the mixture was stirred at room temperature over night. The solvent was evaporated, and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give 3 isomers of N-methyl-N-(3,5-dimethylcyclohexyl)-N-(4-nitrobenzyl)-amine (4.3 g; (31-a), 0.7 g; (31-b), 0.2 g; (31-c)) as each yellow oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=[CH:16]4)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:32]([O:34][CH3:35])=[O:33].O>O1CCOCC1>[C:23]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:12]=[CH:11][C:7]1[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=1)[CH2:1][N:2]([C:32]([O:34][CH3:35])=[O:33])[CH2:3][CH2:4]3)[CH:22]=[CH:21]2)#[N:24]
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc2cc(C=Cc3ccc4c(c3)CCNC4)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N1CCc2cc(C=Cc3ccc4cc(C#N)ccc4c3)ccc2C1
Reaction time: 16 h

Procedure:
A solution of Example 42J (650 mg, 1.53 mmol) in dioxane (30 mL) at room temperature was treated with 10% K2CO3 (10 mL) and methyl chloroformate (700 mg) and stirred for 16 hours. The mixture was treated with water and extracted with dichloromethane. The combined extracts were washed sequentially with 5% HCl, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([C:14](=O)[CH:15]=[N+]=[N-])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:20](OCC)(=[O:22])C.[O:26]1CCCC1>C(N(CC)CC)C.CO.FC(F)(F)C([O-])=O.[Ag+]>[CH3:20][O:22][C:15](=[O:26])[CH2:14][C@@H:11]1[CH2:12][CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:19])[CH2:9][O:10]1
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)C=[N+]=[N-])OC1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of silver trifluoroacetate (124 mg, 0.56 mmol, 0.4 eq) in triethylamine (0.5 mL) is added at 0° C. to a stirred solution of (3R,6S)-[6-(2-diazo-acetyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (380 mg, 1.41 mmol, 1.0 eq) in tetrahydrofuran (20 mL) and methanol (20 mL). After 1 hour stirring at room temperature, solvents are removed and the crude product is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 3:1, v/v) to afford (2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-yl)-acetic acid methyl ester as a white solid (200 mg, 52% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]1>>[OH:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:36][C:16]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]2[C:6]([C:30]2[CH:29]=[CH:28][C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[CH:32][CH:31]=2)=[O:7])=[O:18])[CH2:38][CH2:39]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N[C@H]2CC[C@H](O)CC2)N(C(=O)c2ccc(-c3ccccc3OC)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methoxy[1,1′-biphenyl]-4carboxylic acid, and trans-4-aminocyclohexanol, the title compound was obtained in 61% purity by HPLC. MS(ESI+): m/z=466.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>>[Cl:1][C:2]1[C:3]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[F:27])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccccc1F
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Product: Fc1ccccc1Nc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc12
Yield: 56 %

Procedure:
By a procedure similar to that of Example 219 but using 6,7-dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) and 2-flouroaniline, the title compound was obtained in 56% yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[P:11]([O:16]C)([O:14][CH3:15])[O:12][CH3:13]>>[CH:6]([C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH2:2][P:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13])=[O:7]
Reactant: O=Cc1cccc(CBr)c1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1cccc(C=O)c1)OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 0.60 g of 3-(bromomethyl)benzaldehyde and 0.45 ml of trimethyl phosphite was stirred at 100° C. for 3 hours. The reaction mixture was subjected to silica gel column chromatography to obtain 0.62 g of oily dimethyl (3-formylbenzyl)phosphonate [Compound No. (x)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[N:19][N:18]=[C:17]1[CH3:21].[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH3:21])=[N:18][N:19]=[C:20]1[CH2:23][OH:24]
Reactant: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: C=O
Solvent: Cc1ccccc1C
Product: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 4, 2',5-dichloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone is heated with paraformaldehyde in xylene at 125° C. to give 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 193.5°-195° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH2:10])=[NH:9])[N:7]=1.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O.C([O-])(=O)C.[Na+]>C(O)C>[Cl:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[NH:10][C:23]([CH3:25])=[C:22]([C:21]([O:27][CH2:28][CH3:29])=[O:26])[CH:14]([C:13]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=3[Cl:11])[N:9]=2)[N:7]=1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)c1csc(Cl)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2csc(Cl)n2)=NC1c1ccc(F)cc1Cl
Yield: 33.8 %

Procedure:
2 mmol 2-chloro-4-thiazolformamidine hydrochloride, 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol ethyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.28 g of a yellowish crystal with mp 141-143° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.01-1.05 (3H, m); 2.42 (3H, s); 3.92-3.95 (2H, m); 5.97 (1H, br); 7.16-7.40 (3H, m); 8.09 (1H, s); 9.52 (1H, s); MS (EI) 413.0 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 99.5 %

Procedure:
To a mixture of ethyl 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate (1.80 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (15 mL), and the mixture was heated under reflux for 4 hrs. 1N Hydrochloric acid (15 mL) and water were added to the reaction mixture, and the precipitated crystals were collected by filtration to give 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylic acid as crystals (1.70 g, yield 98%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 162-163° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].N1CCCCC1>C1C=CC=CC=1.O>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccc(C)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A mixture of 19.6 mL (166.4 mmol) of p-tolualdehyde, 23.8 mL (158.8 mmol) of diethyl malonate, 0.5 mL of piperidine and 50 mL of benzene was heated at reflux for 18 h using a Dean-Stark water separator. The mixture was allowed to cool to room temperature, benzene was added and it was washed with water (2×), 1N HCl (2×) and NaHCO3. The aqueous phase was extracted with ethyl acetate, the organic phase was dried and the solvent was removed, to yield 41.2 g of the desired product (yield: 99%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([Cl:19])[CH:10]=1)#N.[OH-:20].[K+].[OH2:22]>>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([C:1]([OH:22])=[O:20])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:10][C:11]=1[Cl:19]
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1ccccc1-c1ccc(C(F)(F)F)c(Cl)c1
Agent: [K+]
Product: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
60 g of 2-cyano-3′-chloro-4′-trifluoromethylbiphenyl were mixed with a solution of 38.7 g of potassium hydroxide in 325 ml of water and stirred at 160° C. under autogenous pressure in an autoclave for 24 hours. The autoclave was then cooled and the aqueous reaction mixture was filtered through Celite and subsequently extracted twice with 200 ml of toluene each time. The aqueous phase was brought to a pH of 6 to 7 with 10% strength hydrochloric acid. The precipitated solid was filtered off, washed with water, and dried. 30 g (47% of theory) of a bale beige solid of melting point 181 to 184° C. were obtained in a purity of 92.7% (HPLC, area percent).