Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[C:8]([C:9]([NH2:11])=[O:10])=[C:7](CC)[C:6]([OH:14])=[CH:5][C:4]=1[OH:15])C.[H-].[Na+].[N+:18]([C:21]1[CH:26]=[C:25]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1Cl)([O-:20])=[O:19]>C1COCC1>[N+:18]([C:21]1[CH:26]=[C:25]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[O:14][C:6]1[CH:7]=[C:8]([CH:3]=[C:4]([O:15][C:22]2[CH:23]=[CH:24][C:25]([S:27]([C:30]([F:32])([F:33])[F:31])(=[O:29])=[O:28])=[CH:26][C:21]=2[N+:18]([O-:20])=[O:19])[CH:5]=1)[C:9]([NH2:11])=[O:10])([O-:20])=[O:19]
Reactant: CCc1c(O)cc(O)c(CC)c1C(N)=O
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl 3,5-dihydroxybenzamide (100 mg, 0.6553 mmol) in THF was added sodium hydride (60 mg of 60% dispersion in mineral oil) followed by 2-nitro-4-(trifluoromethylsulfonyl) chlorobenzene (378 mg, 1.306 mmol). The mixture was stirred at room temperature for overnight. The reaction was extracted with ethyl acetate, the organic layer was washed with water and brine, dried, concentrated and purified to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.32 (br s, 1H, NH), 10.58 (br s, 1H, NH), 8.78 (d, J=2.2 Hz, 1H), 8.57 (br s, 1H), 8.47 (br d, 1H), 8.33 (dd, J=2.2 & 8.8 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.35 (m, 2H), 7.01 (br s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)=O)(C)(C)C.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17]>ClCCl>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[CH3:12][C:10]1([OH:13])[CH2:11][NH:8][CH2:9]1
Reactant: CC1(O)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CNC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, 3-hydroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.40 g, 2.13 mmol) was dissolved in dichloromethane (20 mL). The colorless solution was cooled to 0° C. and trifluoroacetic acid (6.5 ml) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to afford 3-methyl-azetidin-3-ol trifluoroacetate as light brown oil which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C:9](=[O:21])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[CH:3]=2)[CH2:13][CH2:12]1
Reactant: CC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Reactant: OB(O)c1ccncc1
Product: CC1(c2ccccc2)CCN(c2cccc(-c3ccncc3)c2)C(=O)O1

Procedure:
The title compound was prepared from 3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 4-pyridylboronic acid following procedures analogous to those in Example 1 Step 2. LC-MS Method 2, tR=1.329 min, m/z=345.1. 1H NMR (CDCl3) 1.70 (s, 3H), 2.30-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 4.10 (m, 2H), 7.27-7.50 (m, 9H), 8.60 (b, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:18](O)=[O:19]>>[CH2:11]([O:10][C:6]1[C:7]([CH3:9])=[N:8][C:3]([CH2:2][NH:1][CH:18]=[O:19])=[CH:4][CH:5]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1nc(CN)ccc1OCc1ccccc1
Reactant: O=CO
Product: Cc1nc(CNC=O)ccc1OCc1ccccc1

Procedure:
A solution of 6-aminomethyl-3-benzyloxy-2-methylpyridine (6.31 g) in 8.7 ml of formic acid is heated at 90° for 15 hours. The reaction mixture is cooled, made basic with ice-cold ammonium hydroxide solution and extracted with chloroform. (3×25 ml). The chloroform extract is dried over sodium sulfate and evaporated. Recrystallization from ether yields 3-benzyloxy-6-formylaminomethyl-2-methylpyridine, m.p. 67°-68°.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH:15](O)=O.[OH-].[Na+]>>[CH2:1]([N:8]([CH3:15])[CH2:9][C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: C[C@@H](O)CNCc1ccccc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](O)CN(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
Stir a mixture of 3.5 g (21.2 mmol) (2R)-1-(benzylamino)propan-2-ol [F. L. Delft, Synthesis 1997, 4, 450-454], 1.85 ml (2.0 g, 23.3 mmol) of a 35% aqueous formaldehyde solution and 3.6 ml (4.4 g, 95.3 mmol) formic acid for 16 h under reflux. After cooling to room temperature, first neutralize with 45% sodium hydroxide solution and then adjust to a pH value of 9. Extract with ethyl acetate. Wash the organic phase three times with 10 ml water each time, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation, and dry. 3.08 g (78% of theor.) of the desired product is obtained.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH:17]=[CH:21][N:22]([CH3:24])[CH3:23])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Product: CN(C)C=CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2

Procedure:
A solution of 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-ethan-1-one (Example 2) (1.54 g, 6.25 mmol) in dimethylformamide dimethylacetal (15 mL) is heated at reflux for 17 h. The reaction mixture is evaporated, and the yellow residue is crystallized from hexanes to give 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-3-(N,N-dimethylamino)propen-1-one.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([F:17])=[C:9]([NH:15][NH2:16])[C:10]([F:14])=[C:11]([F:13])[CH2:12][C:6]=2[C:5]([F:18])=[C:4]([F:19])[C:3]=1[F:20].[CH3:21][CH:22]([CH3:26])[C:23](=O)[CH3:24]>C(O)C>[F:1][C:2]1[C:7]2[C:8]([F:17])=[C:9]([NH:15][N:16]=[C:23]([CH:22]([CH3:26])[CH3:21])[CH3:24])[C:10]([F:14])=[C:11]([F:13])[CH2:12][C:6]=2[C:5]([F:18])=[C:4]([F:19])[C:3]=1[F:20]
Reactant: NNC1=C(F)c2c(F)c(F)c(F)c(F)c2CC(F)=C1F
Reactant: CC(=O)C(C)C
Solvent: CCO
Product: CC(=NNC1=C(F)c2c(F)c(F)c(F)c(F)c2CC(F)=C1F)C(C)C
Yield: 81.4 %

Procedure:
To (1,2,3,4,6,7,9-heptafluoro-5H-benzo[7]annulen-8-yl)hydrazine (1 g) was added ethanol (20 ml) and 3-methyl-2-butanone (0.38 g). The mixture was heated to reflux for 3 hours after which time the volatiles were removed on a rotary evaporator to give a solid (1 g) which was used in the next step. M+=352
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[C:10]([O:11][CH3:12])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH:7]([C:8]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[C:10]([O:11][CH3:12])[CH:9]=1)[Br:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CC(=O)OC(C)(C)C)cc1OC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(Br)C(=O)OC(C)(C)C)cc1OC

Procedure:
Heat 58.2 g of homoveratric acid tert.-butyl ester and 43.3 g of N-bromosuccinimide under reflux for 2 hours in 1.3 liters of carbon tetrachloride under irradiation with a 500-watt immersion lamp. After cooling, filter out the succinimide and concentrate the filtrate. Dissolve the resulting concentrate in 250 ml of diethyl ether and extract the produced solution by shaking it with water. Free the ether solution from the solvent under a vacuum to obtain 50 g (66% of theory) of the title compound as a non-distillable oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccccc1F
Product: Fc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-fluorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 487.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][C:20]4[N:24]5[N:25]=[C:26]([C:29]6[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=6)[CH:27]=[CH:28][C:23]5=[N:22][N:21]=4)[CH:15]=3)[N:10]=[CH:9]2)=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]3[N:24]([C:20]([CH2:19][C:14]4[CH:15]=[C:16]5[C:11](=[CH:12][CH:13]=4)[N:10]=[CH:9][NH:8][C:17]5=[O:18])=[N:21][N:22]=3)[N:25]=2)[CH:30]=1
Reactant: COc1ccc(Cn2cnc3ccc(Cc4nnc5ccc(-c6cccnc6)nn45)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=c1[nH]cnc2ccc(Cc3nnc4ccc(-c5cccnc5)nn34)cc12
Temperature: 90 °C
Yield: 34.8 %

Procedure:
3-(4-Methoxy-benzyl)-6-(6-pyridin-3-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3H quinazolin-4-one (0.010 mg, 0.021 mmol) was treated with trifluoroacetic acid (1 mL) and anisole (0.1 mL) and heated to 90° C. for 18 hours. The compound was purified via reverse phase HPLC on a C18 column eluting with acetonitrile in water (0.1% TFA) to give 0.0026 g (35%) of 6-(6-pyridin-3-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3H-quinazolin-4-one. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (m, 1H), 8.79 (m, 1H), 8.53 (m, 2H), 8.20 (m, 1H), 8.10 (s, 1H), 8.03 (d, 1H, J=10.0 Hz), 7.89 (d, 1H, J=8.4 Hz), 7.66 (m, 2H), 4.80 (s, 2H). Mass spectrum (LCMS, ESI pos.): Calcd for C19H13N7O; found: 356.3, 357.3 (M+H).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.[CH3:14]I>CS(C)=O>[CH3:14][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1
Reactant: CI
Reactant: OCc1ccc2sccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCc1ccc2sccc2c1
Yield: 69.9 %

Procedure:
To a stirred mixture of powdered KOH (18.9 g, 0.336 mol) in dimethylsulfoxide (100 ml) was added 5-hydroxymethylbenzo[b]thiophene (13.8 g, 0.084 mol) in 25 ml of dimethylsulfoxide. Then methyl iodide (23.9 g, 0.168 mol) was added dropwise at ambient temperature over several minutes. Stirring was continued for 11/2 hours. The mixture was filtered, diluted with water (150 ml) and extracted with methylene chloride (200 ml) in three portions. The combined extracts were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. This gave 14.1 g of amber liquid. Distillation gave 10.47 g of colorless liquid, b.p. 2.2 mm Hg 110°-111° C. (Yield 70%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[S:30](=[O:33])(=[O:32])[CH2:31][C:22]=3[C:21]([C:34](OCC)=[O:35])=[N:20]2)[CH:16]=[CH:17][CH:18]=1.O>C1COCC1>[N:5]1([C:34]([C:21]2[C:22]3[CH2:31][S:30](=[O:32])(=[O:33])[C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:23]=3[N:19]([C:15]3[CH:14]=[C:13]([CH2:12][OH:11])[CH:18]=[CH:17][CH:16]=3)[N:20]=2)=[O:35])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1nn(-c2cccc(CO)c2)c2c1CS(=O)(=O)c1ccccc1-2
Reactant: C1COCCN1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1nn(-c2cccc(CO)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of aluminium chloride (5.13 g; 38.49 mmol; 4.93 eq.) in THF (30 mL) stirred for 25 min at 4° C. is added morpholine (5.40 ml; 61.36 mmol; 7.86 eq.) and the reaction mixture is stirred at 4° C. for 1 h. Ethyl 1-[3-(hydroxymethyl)phenyl]-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (3.11 g; 7.81 mmol; 1 eq.) is added and the reaction mixture is allowed to warm up to rt. After 22 h, the reaction mixture is cooled down to 0° C. then water is added slowly (total volume 25 mL). After 30 min stirring, the product is extracted with DCM. The organic phase is washed with an aqueous solution of Rochelle salts (˜0.7 m; pH=5), brine then dried over MgSO4. The solvent is removed under reduced pressure to afford 3.39 g (99%) of the title compound as a pale yellow solid. HPLC (max plot) 95.6%; Rt 3.08 min. MS (ESI+): 440.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:14][C:13]1[C:6]([Br:5])=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][C:12]=1[Br:15]
Reactant: BrCCBr
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)c(OCCBr)c(Br)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
1,2-Dibromoethane (62 mL, 0.72 moles) was added to a mixture of 3,5-dibromo-4-hydroxybenzaldehyde (10 g, 36 mmoles) and potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred vigorously at 70° C. for 16 hours. After cooling, the mixture was poured into water (300 mL) and extracted with ethyl acetate (400 mL). Water (200 mL) was added to the aqueous phase and this was extracted with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium chloride (3×150 mL), dried over MgSO4 and evaporated in vacuo. The residue was dissolved in refluxing 96% ethanol (60 mL). Water (15 mL) was added and after cooling, filtration, washing with 60% ethanol and drying 10.7 g (77%) of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde was isolated in two crops. M.p. 84-85° C.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCOCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 34.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-morpholin-4-ylethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.4 mg) was obtained.
Reaction SMILES: O[CH:2]1[C:6]2[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:23])[CH3:22].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C.CCCCCC>[CH3:17][C:16]([CH3:18])([CH3:19])[CH2:15][C:14]([NH:13][C:8]1[C:7]([CH3:21])=[C:6]([CH3:2])[C:5]2[O:4][C:3]([CH3:23])([CH3:22])[CH:11]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]=2[C:9]=1[CH3:12])=[O:20]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(N1CCCC1)C(C)(C)O2
Yield: 36 %

Procedure:
Using N-(3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 234 and pyrrolidine, the title compound was synthesized in the same manner as in Example 297. Yield: 36%. Melting point: 197-198° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH2:12]O)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Br:14][Si](C)(C)C>C(Cl)Cl>[Br:14][CH2:12][C:9]1[S:8][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:11][CH:10]=1
Reactant: OCc1ccc(-c2ccc(Cl)s2)s1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: Clc1ccc(-c2ccc(CBr)s2)s1
Reaction time: 4 h
Yield: 58.9 %

Procedure:
To a solution of (5′-chloro-[2,2′]bithiophenyl-5-yl)-methanol (2.23 g, 9.66 mmol) in 65 mL of CH2Cl2 is added bromotrimethylsilane (3.82 mL, 29.0 mmol). After 4 h, the solution is concentrated in vacuo. The crude product is stirred in hot hexanes and filtered. The filtrate is concentrated and the title compound (1.67 g, 5.69 mmol) is obtained as a green solid. 1H NMR (CDCl3, 300 MHz) δ7.00 (d, 1H), 6.94 (m, 2H), 6.85 (d, 2H), 4.71 (s, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10].[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22]O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][O:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:9])[C:3]=1[S:2][CH3:1])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: CSc1c(O)cccc1O
Product: CSc1c(O)cccc1OCCCCNC(=O)OC(C)(C)C

Procedure:
The title compound is prepared from 2-methylsulfanylbenzene-1,3-diol and 4-(Boc-amino)-1-butanol analogous to Example 1101 step A.
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([OH:19])=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1.CCCCCC>[OH:5][P:4]([CH2:16][C:17]([OH:19])=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)CP(=O)(O)CCCCc1ccccc1

Procedure:
[Ethoxy(4-phenylbutyl)phosphinyl]acetic acid from Example 1(b), is further saponified by heating with excess sodium hydroxide, acidification and recrystallization of the product from tetrahydrofuran/hexane to obtain [hydroxy(4-phenylbutyl)phosphinyl]acetic acid; m.p. 109.5°-110°.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15]2OC(=O)[S:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]([F:33])([F:32])[F:31])=[CH2:29])[CH:25]=[C:24]([Cl:34])[CH:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]2([C:30]([F:31])([F:32])[F:33])[S:17][N:16]=[C:15]([C:13]3[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])=[C:2]([CH3:1])[CH:14]=3)[CH2:29]2)[CH:25]=[C:24]([Cl:34])[CH:23]=1
Reactant: Cc1cc(-c2nsc(=O)o2)ccc1C(=O)OC(C)(C)C
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C

Procedure:
A solution of tert-butyl 2-methyl-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoate (50 mg) in 1,3-dichloro-5-[1-(trifluoromethyl)vinyl]benzene (5 mL, prepared according to WO 2005085216) was heated 190° C. during 10 minutes in a microwave. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) then on preparative HPLC to give tert-butyl 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-2-methyl-benzoate (18.5 mg) as a solid. 1H-NMR (CDCl3, 400 MHz): δ=7.86 (d, 1 H), 7.54-7.64 (m, 2 H), 7.41 (t, 1 H), 7.31 (s, 2 H), 4.23 (d, 1 H), 3.88 (d, 1 H), 2.61 (s, 3 H), 1.61 ppm (s, 9 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].Br[CH:30]([Cl:33])[CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[Cl:33][CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: CCC(Cl)Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OCCCCl)c1

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.646 ml (5.181 mmol) of 1-bromo-chloropropane, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 206 mg (0.4454 mmol, 86%) of 2-(3-chloropropoxy-2' -hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.8-2.2 (6H, m, 3CH2), 2.36 (4H, t, 2CH2), 2.5-2.8 (4H, m, 2CH2), 3.51 (2H, t, CH2), 3.66 (6H, s, 2CH3), 4.16 (2H, t, CH2), 6.05 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 461 (M-H)-
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10]C)=[O:8])(=[O:3])[CH3:2].[Br:12]Br>CO>[Br:12][CH2:2][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(=O)CCCC(C)=O
Reactant: BrBr
Solvent: CO
Product: COC(=O)CCCC(=O)CBr
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Ethyl 4-acetylbutyrate was dissolved in MeOH (0.5M) and cooled to 0° C. Bromine (1.0 eq) was added dropwise and the mixture was stirred at room temperature for 18 hrs. The solvent was removed in vacuo and the residue was dissolved in ether, washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatograpy (7% EtOAc/Hexanes). EI-MS m/z 224 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([C:33]([O:35]C)=[O:34])=[O:32])=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:37].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([C:33]([OH:35])=[O:34])=[O:32])=[CH:21][CH:20]=2)[C:7]([C:16]([NH2:17])=[O:37])=[C:8]([CH:10]([OH:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1

Procedure:
335 mg of 2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]imidazole-5-carbonitrile [prepared as described in step (a) above] were subjected to hydrolysis using 7 ml of a 1N aqueous solution of sodium hydroxide in the same manner as described in Example 10(b), to give 256 mg of the title compound as a crystalline powder, melting at 192°-194° C. (with decomposition).