Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([CH2:17][CH2:18][OH:19])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:20]1([C:26]([OH:28])=O)CC=CCC1.C(O)(=O)C.[N+:33]([O-:38])([N+]([O-])=O)=[O:34]>CCCCCC.C(Cl)(Cl)Cl>[C:26]([O:19][CH2:18][CH2:17][C:16]1[C:4]2[O:3][C:2]([N+:33]([O-:38])=[O:34])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1)(=[O:28])[CH3:20]
Reactant: OCCc1cccc2c(-c3ccccc3)c(Br)oc12
Reactant: O=C(O)C1CC=CCC1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(=O)OCCc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product of step A and 2 g. of 4-cyclohexenecarboxylic acid are dissolved in 25 ml. of acetic acid, and 1.8 g. of dinitrogen tetraoxide in 5 ml. of acetic acid are added dropwise. After stirring 20 minutes at room temperature, the mixture is heated at 45° C. for one hour, then at 55° C. for one hour. The mixture is then partially evaporated to remove residual dinitrogen tetraoxide, poured into water, then extracted with diethyl ether. The ether extracts are washed thrice with water, twice with sodium bicarbonate solution, once with water, and dried. Evaporation provides a residue which is dissolved in hexane-chloroform and fractionated by chromatography on silica gel, using hexane-chloroform as eluent. Thin layer chromatographic analysis determines that two relatively pure components are obtained. Recrystallization of the first main component twice from a hexanebenzene mixture provides yellow flakes of 2-(2-nitro-3-phenyl-7-benzofuranyl)ethyl acetate, m.p. 95°-98° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.N>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O1CCCC1.N1C=CC=CC=1>[N+:8]([C:7]1[C:2](=[O:1])[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1c([N+](=O)[O-])cccn1-c1ccccc1
Reaction time: 8 h
Yield: 61 %

Procedure:
5 g of 2-hydroxy-3-nitropyridine, 7.14 g of phenylboronic acid, 2.6 g of copper(II) acetate, 9.9 ml of triethylamine and 5.8 ml of pyridine were added to 100 ml of tetrahydrofuran, followed by stirring overnight. The reaction mixture was poured into aqueous ammonia, and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. The residue was suspended into ether, and collected by filtration, to give 4.71 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O-:10])=O.F[P-](F)(F)(F)(F)F.[N:41]1([O:50][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.NO>CN(C=O)C>[OH:50][NH:41][C:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1([CH3:1])[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])=[O:10]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3(C)CCCCC3C(=O)[O-])cc2)c2ccccc2n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3(C)CCCCC3C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of racemic (1S,2R)-2-methyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylate (0.075 g) in DMF (0.8 mL) was added BOP (0.1 g, 1.3 eq), diisopropylethylamine (0.122 mL, 4 eq) and hydroxylamine hydrochloride (0.024 g, 2 eq). The reaction was stirred for 8 h and purified by direct injection onto an HPLC to afford racemic (1S,2R)-N-hydroxy-2-methyl -2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxamide (0.03 g, 40%) as a white powder. MS: 484.1 (M+H)+
Reaction SMILES: O=[C:2]([C:8]1[S:12][CH:11]=[N:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>CCCCCC.C(OCC)(=O)C>[OH:23][N:22]=[C:2]([C:8]1[S:12][CH:11]=[N:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)c1cncs1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(=NO)c1cncs1
Temperature: 85 °C
Yield: 93.5 %

Procedure:
To a r.b. flask (500 cm3) was added the ethyl oxo-thiazol-5-ylacetate (6.30 g, 34.02 mmol) to ethanol (ca. 180 cm3) with stirring. Sodium acetate (3.06 g, 37.30 mmol) and hydroxylamine hydrochloride (3.78 g, 54.43 mmol) were then added to give an off-white suspension. This was brought to reflux at 85° C. for 1 hour. Reaction monitored by TLC (60% hexane/ethyl acetate; s.m. r.f 0.5, prod. r.f. 0.3.). Reaction cooled and concentrated in vacuo. Product taken up in ethyl acetate (c.a. 200 cm3) and washed with 5% hydrochloric acid solution. Ethyl acetate layer was dried over magnesium sulphate and evaporated to dryness to give a cream solid (6.372 g, 31.825 mmol) [94% Yield].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:47])[C:19]2[CH:20]=[C:21]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:38]=3)[S:22][C:23]=2[C:24]2[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:25]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:19]2[CH:20]=[C:21]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:38]=3)[S:22][C:23]=2[C:24]2[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:25]=2)=[O:47])=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1cc(-c2cc(C(O)c3ccc(Cl)cc3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)Nc1cc(-c2cc(C(=O)c3ccc(Cl)cc3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (63.1 uL, 0.746 mmol) in methylene chloride (1.50 mL, 23.4 mmol) was cooled to −78° C. To this solution was added dimethyl sulfoxide (65.1 uL, 0.918 mmol) in methylene chloride (1.00 mL) dropwise. The reaction was stirred for 10 min under an atmosphere of Nitrogen. To this mixture was added a solution of N-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (319 mg, 0.574 mmol) in methylene chloride (1.50 mL) dropwise. In 1 hr, triethylamine (0.400 mL, 2.87 mmol) was added dropwise to the reaction and the resulting mixture was warmed to rt. In 1 hr, the solution was diluted with CH2Cl2 and washed with water. The aqueous layer was extracted with CH2Cl2(×2). The combined org layer was washed with NaHCO3(aq) saturated solution, dried, and concentrated to provide N-{4-[4-(4-chlorobenzoyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide as a yellow solid (325 mg, quantative). LCMS: (AA) 554, 556; 1H NMR (400 MHz, CDCl3) δ 8.56-8.47 (s, 1H), 8.32-8.24 (m, 1H), 8.11-8.03 (s, 1H), 8.03-7.92 (s, 1H), 7.87-7.77 (m, 2H), 7.63-7.57 (s, 1H), 7.42-7.32 (m, 3H), 5.37-5.32 (s, 2H), 3.53-3.40 (t, J=8.1 Hz, 2H), 2.27-2.19 (s, 3H), 0.94-0.80 (t, J=8.1 Hz, 2H), 0.02-−0.04 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[CH3:14][N:15]([CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)[CH3:16]>>[CH3:16][N:15]([CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][CH2:1][C:3]2[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=2)[CH2:20][CH2:19]1)[CH3:14]
Reactant: CCOC(=O)c1ccnc(C=O)c1
Reactant: CN(C)CC1CCC(CN)CC1
Product: CCOC(=O)c1ccnc(CNCC2CCC(CN(C)C)CC2)c1

Procedure:
By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and {4-[(dimethylamino)methyl]cyclohexyl}methanamine. Aqueous work up gave the title compound as a yellow oil. Used without further purification. 1H NMR (300 MHz, chloroform-d): δ ppm 8.41 (d, 1H), 8.04 (s, 1H), 7.49 (d, 1H), 4.04 (q, 2H), 3.39 (s, 2H), 2.46 (m, 4H), 2.38 (d, 6H), 1.60 (m, 4H), 1.34 (t, 3H), 1.03 (m, 2H), 0.68 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[CH:22]=3)=[O:17])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].I[CH3:31]>CN(C=O)C>[CH3:31][N:15]([C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:27])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[C:16]([C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=1)=[O:17]
Reactant: CI
Reactant: CC1(C)OB(c2ccc(NC(=O)c3cc4ccccc4o3)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2ccccc2o1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 12 h
Yield: 40.7 %

Procedure:
To a solution of benzofuran-2-carboxylic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (195 mg, 0.54 mmol, 1 eq) in 3.5 mL of DMF under nitrogen atmosphere was added NaH (60% in mineral oil, 23 mg, 0.58 mmol, 1.1 eq). After 30 min of reaction, iodomethane (0.05 mL, 0.8 mmol, 1.5 eq) was added and the reaction was allowed to go for 12 h. After work up and column chromatography, benzofuran-2-carboxylic acid methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (83 mg) was obtained in 41% yield. 1H NMR (400 MHz, Benzene-d6) δ ppm 1.3 (s, 12 H) 3.4 (s, 3 H) 6.9 (d, J=0.8 Hz, 1 H) 7.0 (m, 4 H) 7.2 (m, 2 H) 8.1 (d, J=8.3 Hz, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[C:9](C)=C[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.FO[C:22]([F:25])(F)F.BrBr.[C:28](Cl)(Cl)(Cl)Cl>C(O)(=O)C>[F:25][C:22]1[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6][N:5]([C:4]([CH3:17])([CH3:28])[C:3]([N:2]([CH3:1])[CH3:19])=[O:18])[CH:9]=1
Reactant: FOC(F)(F)F
Reactant: Cc1cc(-c2ccccc2)nn1C(C)C(=O)N(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: BrBr
Solvent: CC(=O)O
Product: CN(C)C(=O)C(C)(C)n1cc(F)c(-c2ccccc2)n1

Procedure:
Following the procedure of Example 108, but substituting N,N,α,α,-tetramethyl-3-phenylpyrazole-1-acetamide for N,N,α,5-tetramethyl-3-phenylpyrazole-1-acetamide, trifluoromethyl hypofluorite for bromine, and carbon tetrachloride for acetic acid as the reaction solvent there was obtained 4-fluoro-N,N,α,α-tetramethyl-3-phenylpyrazole-1-acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6](C(O)=O)=[C:5]2[OH:15].C1(OC2C=CC=CC=2)C=CC=CC=1>CO.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:15]
Reactant: O=C(O)c1cnc2ccc(Br)cc2c1O
Solvent: CCOCC
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2ccc(Br)cc12
Temperature: 25 °C
Yield: 95.7 %

Procedure:
The solid 6-bromo-4-hydroxy-quinoline-3-carboxylic acid (102.59 g, 337.7 mmol) was added to hot diphenyl ether (508 g) and then the mixture was heated to reflux for 9 h to afford a light brown suspension. After cooling to room temperature, the mixture was diluted with methanol (20 mL) and diethyl ether (300 mL). Then, the solids were collected by filtration and washed with diethyl ether. After drying in air, 72.43 g (95% yield) of 6-bromo-quinolin-4-ol was isolated as a white solid: EI-HRMS m/e calcd for C9H6BrNO (M+) 222.9633, found 222.9630.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[CH:6][N:5]([CH2:13][CH2:14][F:15])[C:4]=2[CH:3]=1.[BH4-].[Na+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][N:5]([CH2:13][CH2:14][F:15])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=CN(CCF)c2cc(Cl)sc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=S1(=O)NCN(CCF)c2cc(Cl)sc21
Temperature: 60 °C

Procedure:
100 mg of the compound obtained in Step A above are dissolved in 4 ml of isopropanol. The mixture is heated to 60° C., then 200 mg of sodium borohydride are added. After minutes at that temperature, the solvent is evaporated off under reduced pressure. The residue that is obtained is taken up in 10 ml of water, cooled in an ice bath and adjusted to pH 4 by addition of 6N hydrochloric acid. The insoluble material is collected by filtration and washed with water. The product is then dissolved in a minimum of chloroform and precipitated by addition of n-hexane. The precipitate is then collected by filtration.
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC.[C:23]([O:44]C)(=[O:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]CC>>[C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:23]([OH:44])(=[O:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCC=CCC=CCCCCCCC(=O)OC
Reactant: CCCCCCCCC=CCC=CCCCCCCC(=O)O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
The lipid thus obtained contains 8,11-eicosadienoic acid as a component of the lipid such as fat. Although 8,11-eicosadienoic can be directly isolated, preferably it is isolated as an ester with a lower alcohol, for example, as methyl 8,11-eicosadienoate. The esterification accelerates the separation of the target fatty acid from other lipid components, and from other fatty acids produced during the culturing, such as parmitic acid, oleic acid and linoleic acid (these fatty acids are also esterified simultaneously with the esterification of 8,11-eicosadienoic acid). For example, to obtain methyl ester of 8,11-eicosadienoic acid, the above-mentioned extract is treated with anhydrous methanol/HCl 5 to 10%, or BF3 /methanol 10 to 50% at room temperature for 1 to 24 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][CH2:32][CH3:33])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: CCCBr
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imdazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 1-bromopropane using potassium carbonate as a base in DMF at 80° C. Mass: 452.08 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[O:8][CH2:7]2)(=[O:3])[CH3:2].[F:23][C:24]([F:37])([F:36])[C:25]([C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[C:29]([Cl:35])[CH:28]=1)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.FC(C1C=CC=CC=1)(F)F.COC(C)(C)C>[F:37][C:24]([F:23])([F:36])[C:25]([C:27]1[CH:28]=[C:29]([Cl:35])[C:30]([Cl:34])=[C:31]([Cl:33])[CH:32]=1)=[CH:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]1)[O:8][CH2:7]2)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)COC21CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: FC(F)(F)c1ccccc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
In 100 mL two neck RBF fitted with dean-stark apparatus, a stirred solution of tert-butyl 5′-acetyl-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 1, 7 g, 23.1mmol) in toluene (21 mL) and trifluoro methyl benzene (21 mL) was added followed by addition of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone (7.37 g, 26.6 mmol) and Cs2CO3 (0.751 g, 2.31 mmol) at room temperature. Resulting reaction mixture was stirred at 110° C. for 16 hours. Reaction was monitored by TLC, after complete consumption of starting material; reaction mixture was dissolved in tert-butyl methyl ether (50 mL), and filtered through celite bed. The filtrate was concentrated under reduced pressure to get crude compound as brown sticky oil 14.1 g. Purification was done by column chromatography using silica gel 230-400 mesh. Desired compound was eluted in 20% ethyl acetate in n-hexane to give compound as light yellow solid (8.6 g, 66.15%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.11 (d, J=9.6 Hz, 2H), 4.32 (d, J=9.52 Hz, 2H), 5.12 (s, 2H), 7.28 (s, 1H), 7.40 (m, 1H), 7.54-7.56 (m, 1H), 7.66 (s, 1H), 7.83 (d, J=7.92 Hz, 1H). VETERINARY (m/z): 560.0 (M−H).
Reaction SMILES: N1C=CC=CC=1.C(O[C:11](=[O:13])[CH3:12])(=O)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[N:22]2[CH2:25][C:24](=[CH:26][S:27]([CH2:30][C:31]3[CH:32]=[C:33]([N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH:34]=[CH:35][CH:36]=3)(=[O:29])=[O:28])[CH2:23]2)=[CH:17][CH:16]=1>C(OCC)(=O)C.O>[C:11]([N:40]1[CH2:41][CH2:42][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH2:30][S:27]([CH:26]=[C:24]3[CH2:23][N:22]([CH:21]([C:18]4[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=4)[C:43]4[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=4)[CH2:25]3)(=[O:28])=[O:29])[CH:32]=2)[CH2:38][CH2:39]1)(=[O:13])[CH3:12]
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 23 h
Yield: 89.4 %

Procedure:
2 cm3 of pyridine and then 11.5 mg of acetic anhydride are successively added, at a temperature close to 20° C., to 54 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 23 hours at a temperature close to 20° C., the reaction medium is concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 30° C. The residue obtained is taken up in 5 cm3 of ethyl acetate and 2 cm3 of water. After separating after settling out, the organic phase is washed with 2 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 52 mg of 4-acetyl 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine are thus obtained in the form of a beige foam [1H NMR spectrum (300 MHz, CDCl3), δ in ppm): 2.16 (s, 3H), 2.77 (s, 3H), from 3.10 to 3.25 (mt, 4H), 3.63 (broad t, J=5.5 Hz, 2H), 3.78 (broad t, J=5.5 Hz, 2H), 3.82 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (broad d, J=8 Hz, 1H), 6.92 (dd, J=8 and 2 Hz, 1H), 7.02 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:19]S(C)(=O)=O)[C:6]2[O:10][C:9]([N:11]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][C:7]=2[CH:18]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[ClH:2].[C:31]([NH:19][C:5]1[C:6]2[O:10][C:9]([N:11]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][C:7]=2[CH:18]=[C:3]([Cl:2])[CH:4]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CS(=O)(=O)Nc1cc(Cl)cc2nc(N3CCCNCC3)oc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)cc2nc(N3CCCNCC3)oc12)c1ccccc1
Reaction time: 3 h

Procedure:
The compound of Example 14 (a) (7-amino-5-chloro-2-[1-(4-tert-butyloxycarbonyl) homopiperazinyl]benzoxazole, 48 mg, 0.130 mmol) was dissolved in methylene chloride (2 ml), and the solution was successively added with triethylamine (0.056 ml) and benzoyl chloride (0.031 ml) at 0° C. After the reaction mixture was stirred for 3 hours, the reaction was stopped by using saturated aqueous solution of sodium hydrogencarbonate. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solution was added with 4 N hydrochloric acid in ethyl acetate (1 ml), and the deposited solids were collected by filtration to obtain the title compound (20 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:16]I>CC(C)=O>[CH3:16][O:11][C:10](=[O:12])[CH2:9][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:13]#[C:14][CH3:15]
Reactant: CI
Reactant: CC#C[C@@H](CC(=O)O)c1ccc(O)cc1
Solvent: CC(C)=O
Product: CC#C[C@@H](CC(=O)OC)c1ccc(O)cc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 123.1 %

Procedure:
Phenol 1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHCO3 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction stirred at 40° C. for 14 hours. An additional portion of methyl iodide (3 mL, 48 mmol) was added, and heating was continued for 24 hours. Potassium salts were removed by filtration and thoroughly rinsed with acetone. The filtrate was concentrated to an oil which was filtered through a 1 cm plug of silica gel. Elution with 2.5% MeOH in DCM followed by concentration provided phenol 1 (21.5 g) as a light yellow oil. 1H NMR (500 MHz, acetone-d6) δ 8.2 (br s, 1H); 7.20 (d, 2H, J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, 1H); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 219.1 (M+H); 241.1 (M+Na).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:17])[OH:16])=O)C1C=CC=CC=1>Cl>[NH2:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:16])[OH:17]
Reactant: CCCCCCCCCCCCP(=O)(O)CCCNC(=O)OCc1ccccc1
Agent: Cl
Product: CCCCCCCCCCCCP(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A solution of 2.4 g of 3-benzyloxycarbonylaminopropyl(dodecyl)phosphinic acid in 50 ml of 36% hydrochloric acid is refluxed for 3 hours. During this time, a white precipitate is formed. After cooling to room temperature the acid is removed by co-evaporation with 6×50 ml of water on a rotary evaporator. The crude product is then dissolved in 50 ml of ethanol and stirred with 5 ml of propylene oxide. Filtration and drying gives 3-aminopropyl(dodecyl)phosphinic acid as a white solid m.p. 175°-7°. 31P-NMR=43.0 ppm (NaOD).