Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=O)C1C=CC=CC=1.[Cl:29][C:30]1[CH:45]=[C:34]([C:35](OCC2C=CC=CC=2)=[O:36])[C:33]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:45]=[C:34]2[C:33](=[CH:32][CH:31]=1)[NH:46][C:47](=[O:48])[N:28]([S:25]([C:14]1[CH:13]=[C:12]([NH2:11])[C:17](=[CH:16][CH:15]=1)[C:18]([OH:20])=[O:19])(=[O:26])=[O:27])[C:35]2=[O:36]
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3ccc(Cl)cc3c2=O)ccc1C(=O)O
Yield: 26 %

Procedure:
300 mg (0.74 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 310 mg (0.81 mmol) of benzyl 5-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 75 mg (yield 26%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 7.13-7.20 (2H, m), 7.56 (1H, s), 7.72 (1H, d), 7.82 (1H, s), 7.90 (1H, d), 11.68 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH3:27])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:19]1[CH3:27])[CH3:17]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a stirred suspension of 9.66 g (0.017 mole) of tetrachlorophthalic anhydride and 13.5 g (0.034 mole) of 80 percent active 1-ethyl-2-methylindole in 30 ml of benzene maintained at 0°-5° C. by means of an ice bath, 10.6 g (0.079 mole) of aluminum chloride was added in small increments. The reaction mixture was then maintained at 0° to 5° C. for an additional twenty minutes, allowed to warm to room temperature and stirred overnight. The mixture was transferred to a beaker and triturated successively with hexane, 10 percent hydrochloric acid, and lastly with 5 percent aqueous sodium hydroxide which had been heated to 70° C. The residual oil was filtered, acidified with dilute hydrochloric acid and allowed to stand overnight. On standing, the oil gave way to a solid which was collected by filtration, washed with water and dried to yield 6.8 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =CH3CH2 ; Y1 =H), an off white solid melting at 214°-216° C. Analysis by mass spectrum showed m/e peaks at 443 (M+, Cl=35) and 398 (M+ -COOH).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:13]=[N:14][C:15]([CH:18]3[CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].O>CO.O1CCCC1>[CH:18]1([C:15]2[N:14]=[CH:13][C:12]([N:9]3[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[CH:17][CH:16]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cnn(-c2ccc(C3CC3)nc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ccc(C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of 1-(6-cyclopropylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (910 mg) in methanol (3 ml) and tetrahydrofuran (5 ml) were added 4 N aqueous solution of sodium hydroxide (7 ml) and water (3 ml), and stirred at room temperature overnight. After completion of the reaction, the organic solvent was evaporated in vacuo, then water and diethyl ether were added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. To the obtained residue were added ethyl acetate and n-hexane, the precipitated solid was collected by filtration, washed with ethyl acetate/n-hexane solution, and heat-dried in vacuo at 60° C. to give the titled compound (321 mg) as a pale yellow solid. MS (ESI) m/z: 244 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][P:11](Cl)([CH3:13])=[O:12]>C1COCC1>[CH3:10][P:11]([CH3:13])([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: CP(C)(=O)Cl
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CP(C)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
To a cooled (0° C.) flask containing 34.0 mL (2.0 M in Et2O, 68.4 mmol) of 4-fluorophenylmagnesium bromide, under an atmosphere of N2, was added a solution of dimethylphosphinic chloride (3.50 g, 31.1 mmol) in 84 mL of THF, dropwise via cannulation, over 20 min. The green reaction mixture was stirred at 0° C. for 1 h, then quenched at 0° C. with 30 mL of saturated NH4Cl resulting in the formation of a white precipitate. The mixture was concentrated on a rotary evaporator and partitioned between EtOAc (200 mL) and H2O (200 mL), upon which the layers were separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organics washed with brine, then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 5% MeOH/DCM) to provide 2.08 g of an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ7.83 (m, 2H), 7.35 (td, J=8.9, 1.7 Hz, 2H), 1.66 (s, 3H), 1.61 (s, 3H). 31P NMR (121 MHz, DMSO-d6) δ37.186. 19F NMR (282 MHz, DMSO-d6) δ-105.14.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH:22][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
22 g (75 mmol) of 1,4-dibenzyl-2-aminomethylpiperazine dissolved in 300 ml of toluene are mixed with 100 ml of triethylamine in a ground-necked conical flask. 97 ml (0.1 mol) of isopropyl chloroformate, taken up by syringe, are dissolved in 50 ml of toluene, and are then added dropwise to the above solution. At the end of the addition, the mixture is stirred for 2 hours at room temperature. The solution is diluted with ether, washed with saturated NaHCO3 solution and then with water to obtain a neutral pH. The organic phase is dried (MgSO4), filtered and evaporated to give 28.3 g of 1,4-dibenzyl-2-isopropyloxycarbonylaminomethylpiperazine in the form of a viscous compound. Yield: 99.6%. Rf=0.4 (95/5 v/v CH2Cl2/MeOH).
Reaction SMILES: [CH3:1][C:2]([CH3:40])([CH3:39])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([N:20]4[CH2:24][CH2:23][C:22]([CH2:26][O:27]C(=O)C)([CH3:25])[CH2:21]4)[CH:17]=[CH:18][CH:19]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].C([O-])(=O)C.CO.O>CCN(CC)CC>[OH:27][CH2:26][C:22]1([CH3:25])[CH2:23][CH2:24][N:20]([C:16]2[CH:15]=[C:14]([C:11]3[N:12]=[C:13]4[C:5]([C:3](=[O:4])[C:2]([CH3:39])([CH3:1])[CH3:40])=[CH:6][NH:7][C:8]4=[N:9][CH:10]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:21]1
Reactant: CC(=O)OCC1(C)CCN(c2cccc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)C1
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CC1(CO)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Yield: 15 %

Procedure:
1-{2-[3-(3-Hydroxymethyl-3-methyl-pyrrolidin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared following a similar procedure but using acetic acid 1-{3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-3-methyl-pyrrolidin-3-ylmethyl ester as starting material. In this reaction, the acetate was hydrolysed at the same time of the second step of the SEM hydrolysis by heated at reflux the hydrolysis intermediate in a 8/1/1 mixture of MeOH, H2O, and Et3N over the weekend. The product was obtained in 15% yield after SiO2 chromatography (hexanes/EtOAc 0-30% EtOAc).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C@@H:27]([C:28](O)=[O:29])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:28]([C@H:27]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]1[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:29]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a solution of oxalyl dichloride (1.14 g, 9 mmol) in dichloromethane (30 mL) was added dimethyl sulfoxide (1.4 g, 18 mmol) at −78° C. After stirring at −78° C. for 20 min, to the mixture was added a solution of (R)-tert-butyl3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (2), 1.32 g, 5 mmol) in dichloromethane (30 mL) and stirred at −78° C. for 30 to 45 min. Then triethylamine (36 mmol) was added and the reaction mixture was warmed up to rt over 2 h. Saturated sodium carbonate solution was added and extracted with dichloromethane. The solvent was removed and the crude mixture was purified by silica gel Flash chromatography to give the title compound: 1.2 g (90% yield). 1H NMR (CDCl3, 500 MHz) δ 1.48 (9H, d, J=35 Hz), 3.06-3.62 (2H, m), 4.45-4.81 (3H, m), 7.09-7.19 (4H, m), 9.48 (1H, d, J=25 Hz).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH2:27]1[C:30]2([CH2:35][NH:34][CH2:33][CH2:32][O:31]2)[CH2:29][N:28]1[CH2:36][CH2:37][C:38]1[CH:39]=[C:40]([CH2:44][CH2:45][OH:46])[CH:41]=[CH:42][CH:43]=1.[CH:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[OH:46][CH2:45][CH2:44][C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[CH2:37][CH2:36][N:28]1[CH2:29][C:30]2([CH2:35][N:34]([C:55]([C:53]3[N:54]=[C:50]([CH:47]([CH3:49])[CH3:48])[S:51][CH:52]=3)=[O:56])[CH2:33][CH2:32][O:31]2)[CH2:27]1
Reactant: OCCc1cccc(CCN2CC3(CNCCO3)C2)c1
Reactant: CC(C)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCO)c4)C3)C2)cs1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
HATU (0.792 g) was added in one portion to a stirred solution at 0° C. of 2-(3-(2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethyl)phenyl)ethanol 2HCl (0.56 g) (example 176 step e), 2-isopropylthiazole-4-carboxylic acid (0.275 g) and triethylamine (1.117 ml) in DMF (7 mL). The mixture was stirred at 20° C. for 3 hours and then partitioned between ethyl acetate and brine, the organic layer was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, 5% methanol in ethyl acetate with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.475 g
Reaction SMILES: C([O:4][CH2:5][C:6]1[S:7][CH2:8][C:9]([CH2:12][Cl:13])(O)[N:10]=1)(=O)C.C(OCC)C>Cl.C(O)(C)C>[ClH:13].[Cl:13][CH2:12][C:9]1[N:10]=[C:6]([CH2:5][OH:4])[S:7][CH:8]=1
Reactant: CC(=O)OCC1=NC(O)(CCl)CS1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: OCc1nc(CCl)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
7.48 g of 2-acetoxymethyl-4-chloromethyl-4-hydroxythiazoline, prepared according to either Example 3 or 4, was suspended in 20 ml of 5N hydrogen chloride in isopropanol and heated to reflux for 45 minutes. The suspension was cooled in an ice bath and 30 ml of diethyl ether added dropwise over 30 minutes. The slurry was stirred a further 30 minutes at 0° C. and the precipitate filtered, washed with ether and dried under vacuum. 4-chloromethyl-2-hydroxymethylthiazole hydrochloride, 6.22 g (93% yield) was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:39])([F:38])[C:5]1[CH:6]=[C:7]([CH2:15][NH:16][C:17](=[O:37])[CH2:18][C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)=[O:20])[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].C(OOC(=O)C1C=CC=CC=1)(=[O:47])C1C=CC=CC=1>CN(C)C=O>[F:3][C:4]([F:38])([F:39])[C:5]1[CH:6]=[C:7]([CH2:15][NH:16][C:17](=[O:37])[CH:18]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:24]=2)=[O:20])[OH:47])[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(CC(=O)NCc1ccc(C(F)(F)F)c(C(F)(F)F)c1)NCc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(F)(F)F)c(C(F)(F)F)c1)C(O)C(=O)NCc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 0.515 g of sodium hydride (57% in mineral oil) in 10 ml of dry dimethylformamide, under a nitrogen atmosphere, add dropwise a solution of 6.0 g N,N'-bis-[3,4-bis-(trifluoromethyl)phenyl]methylmalonamide dissolved in 35 ml of dry dimethylformamide. Upon cessation of gas evolution, cool the resulting orange solution to about 0°-5° C. and add dropwise a solution of 2.8 g dibenzoyl peroxide in 30 ml of dry dimethylformamide. Stir the resulting white suspension for 16 hours at room temperature under a nitrogen atmosphere, quench with aqueous sodium bisulfite and extract with ether. Wash the ether extract with water, dry over sodium sulfate and remove the ether in vacuo. Chromatograph the residue on 200 g of acidic alumina and elute with hexane/methylene chloride (3:2) to separate the product from unreacted starting material. Recrystallize this material from 1:2 benzene/hexane to give the title compound [Rf =0.55 (tlc-silica gel, 7:1 chloroform/hexane].
Reaction SMILES: CI.[C:3]([O:7][C:8](=[O:32])[NH:9][C:10]1[CH:11]=[N:12][C:13]([CH:16]2[NH:29][C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[N:26]=4)[N:21]=[CH:20][C:19]=3[O:18][CH2:17]2)=[CH:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:3]([O:7][C:8](=[O:32])[NH:9][C:10]1[CH:11]=[N:12][C:13]([CH:16]2[N:29]([CH3:33])[C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[N:26]=4)[N:21]=[CH:20][C:19]=3[O:18][CH2:17]2)=[CH:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2ncc3c(c2n1)NC(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2ncc3c(c2n1)N(C)C(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 123.6 %

Procedure:
Methyl iodide (10.5 μL, 0.17 mmol, 1.0 eq) is added at room temperature to a stirred solution of [6-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester (70 mg, 0.17 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by cesium carbonate (55 mg, 0.17 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [6-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester as an orange viscous oil (89 mg, 75% yield) that is directly engaged in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19]OS(OC)(=O)=O.[OH-].[Na+].O1CCOCC1>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH3:19])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1c(OCc2ccccc2)ccc(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C=O)ccc(OCc2ccccc2)c1C
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 4-benzyloxy-2-hydroxy-3-methyl-benzaldehyde (1.57 g, 6.49 mmol), dimethylsulfate (1.04 ml, 10.9 mmol), NaOH (1.02 g, 25.5 mmol), 1,4-dioxane (20 mL) and water (10 mL) was stirred at 90° C. for 6 h. The reaction mixture was cooled to RT, water (100 mL) was added, extracted with EtOAc (150 mL). The extract was washed with brine (100 mL), dried over Na2SO4 and evaporated. The residue was purified on SiO2 (25 g) column, hexane to toluene. Yield 1.20 g (4.68 mmol, 72%), white solid. 1H NMR (300 MHz, DMSO): δ 10.11 (s, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.49-7.32 (m, 5H), 7.05 (d, J=8.9 Hz, 1H), 5.24 (s, 2H), 3.81 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [C]=O.[H][H].[CH3:5][CH:6]([CH2:9][OH:10])[CH2:7][OH:8].[CH:11]([CH:13]=[CH2:14])=O>O1CCCC1>[CH:13]([CH:14]1[O:10][CH2:9][CH:6]([CH3:5])[CH2:7][O:8]1)=[CH2:11]
Reactant: [H][H]
Reactant: CC(CO)CO
Reactant: C=CC=O
Agent: [C]=O
Solvent: C1CCOC1
Product: C=CC1OCC(C)CO1

Procedure:
A process for producing tetrahydrofuran which comprises (1) continuously feeding and reacting 2-methyl-1,3-propanediol and acrolein to form 2-vinyl-5-methyl-1,3-dioxane in a condensation reaction zone; (2) continuously withdrawing the 2-vinyl-5-methyl-1,3-dioxane from said condensation reaction zone and continuously feeding the 2-vinyl-5-methyl-1,3-dioxane into a hydroformylation reaction zone to produce a mixture of 2-(5-methyl-1',3'-dioxane)propionaldehyde and 3-(5'-methyl-1',3'-dioxane)propionaldehyde in the presence of a hydroformylation catalyst at a temperature between about 25° and 200° C and a pressure between about 15 and 300 psi; (3) continuously withdrawing the propionaldehyde mixture and catalyst from the hydroformylation reaction zone; (4) continuously separating and recycling the hydroformylation catalyst to the hydroformylation reaction zone; (5) continuously feeding and contacting the propionaldehyde mixture with hydrogen in a hydrogenation zone in the presence of a hydrogenation catalyst at a temperature between about 180° and 225° C and a pressure between about 100 and 1000 psi in an aqueous medium maintained at a pH between about 0.2 and 3 with a water-soluble acid to produce a product mixture of tetrahydrofuran and 2-methyl-1,3-propanediol; (6) continuously recovering the tetrahydrofuran and 2-methyl-1,3-propanediol as separate components; and (7) continuously recycling the 2-methyl-1,3-propanediol to the first step condensation reaction zone.
Reaction SMILES: C([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]2[S:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:27]=2)[CH:9]=1)(=O)C(C)(C)C.[OH-].[Na+].O.Cl>CO.C1COCC1>[C:28]([C:25]1[S:24][C:23]([C:10]2[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][C:11]=2[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[N:27][N:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)C(C)(C)C)cc2-c2nnc(C(C)(C)C)s2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(C)(C)C)s2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73 %

Procedure:
To a solution of 2-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl pivalate (191 mg) in methanol (2.0 mL) and THF (2.0 mL) was added 1N aqueous sodium hydroxide solution (1.3 mL), and the mixture was stirred at room temperature for 40 min. Water and hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (113 mg) as a white amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH:31]1[CH2:34][CH2:33][CH2:32]1.O>CN(C=O)C>[CH:31]1([CH2:30][N:16]2[CH2:15][CH2:14][CH:13]([N:12]3[C:11]4[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=4[N:9]=[C:8]3[N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:18][CH2:17]2)[CH2:34][CH2:33][CH2:32]1
Reactant: BrCC1CCC1
Reactant: CN1CCN(c2nc3ccccc3n2C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2nc3ccccc3n2C2CCN(CC3CCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.4 %

Procedure:
A mixture of 2-(4-methylpiperazinyl)-1-(4-piperidinyl)-1H-benzimidazole (300 mg, 1 mmol), K2CO3 (165.9 mg, 1.2 mmol), and (bromomethyl)cyclobutane (178.8 mg, 1.2 mmol) in DMF (4 ml) was stirred at room temperature for 17 h. Then K2CO3 (110 mg, 0.8 mmol), and (bromomethyl)cyclobutane (119 mg, 0.8 mmol) were added to the reaction mixture. After 16 h stirring, the reaction mixture was poured into water and extracted with CH2Cl2. The extracts combined were dried (MgSO4), filtered, and concentrated in vacuo to give 369 mg of oil which was purified by preparative TLC (1 mm thick plate, CH2Cl2/MeOH:10/12 developped) to afford 147.6 mg (40%) of title compound as light brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=C1CCCCCC1
Agent: Cl
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C2=CCCCCC2)c(O)c(C(C)(C)C)c1
Reaction time: 22 h
Yield: 9 %

Procedure:
A mixture consisting of 82.5 g (0.40 mol) of 2,4-di-tert-butylphenol and 22.5 g (0.20 mol) of cycloheptanone is melted together and is then saturated, with stirring, with hydrochloric acid gas at 35-40° C. After 22 hours, the reaction mixture is again saturated with hydrochloric acid gas and then stirred for 17 hours. Subsequently, the reaction mixture is diluted with hexane and washed with water and sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system hexane/ethyl acetate=99:1 and the pure fractions are crystallised from ethanol, giving 5.4 g (9%) of 2,4-di-tert-butyl-6-cyclohepten-1-yl-phenol, m.p. 78-80° C. (compound (105), Table 1).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH:1]1([C:7]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(O)C1CC=CCC1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)C1CC=CCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(±)-3-Cyclohexene-1-carboxylic acid (50 g) was dissolved in N,N-dimethylformamide (550 ml), and triethylamine (170 ml) and benzyl bromide (61 ml) were added under ice cooling to stir the mixture at room temperature for 12 hours. Water was added, extraction was conducted with ethyl acetate, and the resultant organic layer was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound (70.8 g).