Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+].Cl>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[CH:16][N+:13]([O-:15])=[O:14]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 34.5 g. (0.208 mole) 3,5-dimethoxybenzaldehyde and 12.68 g. (0.208 mole) nitromethane in 40 ml. methanol was cooled to 0° C. under a nitrogen atmosphere. To this was added dropwise a cold solution of 8.43 g. (0.211 mole) sodium hydroxide in 30 ml. water and stirring continued at 0° C. for 15 minutes after the addition was completed. The mixture was diluted with ice-water and added slowly to a solution of 40 ml. concentrated hydrochloric acid in 60 ml. water. The precipitated product (44 g.) was collected by filtration and recrystallized from methanol to give 28.6 g., M.P. 132° C. J. Org. Chem., 27, 376 (1976) reported M.P. 133.5°-134.5° C.
Reaction SMILES: [Br-:1].[Br-:2].[Br-].C(CC[P+]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[C:28]([CH2:31][CH2:32][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:30])=O.[C:52]([CH2:55][CH2:56][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[O:76]1CCCC1>>[Br:1][CH:56]([C:22]1[CH:23]=[CH:24][C:25]([O:30][CH2:28][CH2:31][CH2:32][Br:2])=[CH:26][CH:27]=1)[C:55](=[O:76])[CH3:52]
Reactant: C1CCOC1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Br-]
Product: CC(=O)C(Br)c1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 1C (865 mg, 3.19 mmol) in anhydrous tetrahydrofuran (30 mL) was slowly added a tetrahydrofuran (10 mL) solution of (2-carboxyethyl)triphenylphosphonium tribromide (1.85 g, 3.19 mmol) at 0° C. The mixture was then stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was washed with additional ethyl acetate. The organic fractions were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel eluting with 10% ethyl acetate/hexanes to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 2.31 (s, 3H), 2.37-2.27 (m, 2H), 3.60 (t, J=6.4 Hz, 2H), 4.11 (t, J=5.8 Hz, 2H), 5.42 (s, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H); MS (DCI/NH3) m/z 366 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.Br[CH:14]([CH2:20][CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:20][CH3:21])[CH3:19]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxy-chromen-2-one (2.0 g) and ethyl 2-bromobutyrate (2 mL) in DMF was added anhydrous potassium carbonate (8.5 g). The resulting reaction mixture was stirred at room temperature for 72 hours, then diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and conc. in vacuo to provide colorless oil, which was purified by column chromatography to give 2-(4-Hydroxy-2-oxo-2H-chromen-3-yl) -butyric acid ethyl ester as a white solid, MS: 275[M−H].
Reaction SMILES: CSC.C([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)C1C=CC=CC=1.O>C(Cl)Cl>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[OH:11])=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: c1ccc(COc2ccccc2Cc2ccc(C3CC3)cc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: Oc1ccccc1Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 79.1 %

Procedure:
In a nitrogen stream, dimethyl sulfide (2.2 mL, 51.7 mmol) and a boron trifluoride-diethyl ether complex (1.1 mL, 8.8 mmol) were added to a solution of 1-benzyloxy-2-(4-cyclo-propylbenzyl)benzene (1.1 g, 3.5 mmol) in methylene chloride (24 mL) under cooling with ice, and the reaction mixture was stirred for 23 hours while gradually raising its temperature to room temperature. Water was added thereto under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:4)] to obtain the title compound (620.7 mg, 79%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[O:27]=[C:28]1[N:32]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[NH:29]1.CCCCCC.C(OCC)(=O)C>CS(C)=O>[O:27]=[C:28]1[N:32]([CH:33]2[CH2:34][CH2:35][N:36]([CH2:11][CH:12]3[O:25][C:16]4=[C:17]5[C:21](=[CH:22][CH:23]=[C:15]4[O:14][CH2:13]3)[NH:20][C:19](=[O:24])[CH2:18]5)[CH2:37][CH2:38]2)[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[NH:29]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CN2CCC(n4c(=O)[nH]c5ccccc54)CC2)CO3)N1
Temperature: 85 °C
Yield: 55.8 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.04 g, 2.77 mmole) and 4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine (2.71 g, 12.5 mmole) were combined in 40 ml of dry DMSO and heated to 85° C. for 4 hours under a nitrogen atmosphere. The reaction was cooled and taken into 400 ml of 1:1 hexane/ethyl acetate. This was washed with 200 ml of water, with 200 ml of saturated brine, dried over MgSO4, filtered and concentrated to yield an oil. This oil was column chromatographed on silica gel using 1% methanol/CH2Cl2 as eluant to give the free base of the title compound as a yellow oil (0.65 g, 53%). This oil was crystallized from ethanol with the addition of a solution of fumaric acid in hot ethanol to give 0.61 g of the (S) enantiomer of the title compound as a light yellow solid fumarate, hemihydrate, m.p. 262°-263.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@@H:12]2[CH3:30])=[O:10])=[CH:4][CH:3]=1.[NH:31]1[CH2:34][CH2:33][CH2:32]1>C(O)(C)C>[ClH:1].[N:31]1([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH2:13][C@@H:12]3[CH3:30])=[O:10])=[CH:4][CH:3]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: Cc1nc(Cl)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Reactant: C1CNC1
Solvent: CC(C)O
Product: Cc1nc(N2CCC2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Product: Cl
Temperature: 120 °C
Yield: 61.9 %

Procedure:
(2S)-1-[(6-Chloro-2-methyl-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 24) (66 mg, 0.14 mmol) was transferred into a microwave vial as a solution in isopropanol (1.4 ml). Azetidine (0.163 ml, 2.42 mmol) was added and the clear solution was heated in the microwave to 120° C. for 18 h with stirring. LCMS analysis showed >80% conversion. The reaction mixture was concentrated to give the crude material as a colourless gum (˜200 mg). This was purified by MDAP to give the free base of the title compound as a brown gum (45 mg).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]1[C:13]([Cl:14])=[N:12][C:11]([C:15]#[N:16])=[C:10]([C:17]#[N:18])[N:9]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([SH:26])[CH:21]=1>ClCCCl>[Cl:14][C:13]1[N:12]=[C:11]([C:15]#[N:16])[C:10]([C:17]#[N:18])=[N:9][C:8]=1[S:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=1
Reactant: Cc1cccc(S)c1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cccc(Sc2nc(C#N)c(C#N)nc2Cl)c1
Reaction time: 0.25 h

Procedure:
Pyridine (2.37 g) was mixed rapidly with a solution of 6.00 g of 2,3-dichloro-5,6-dicyanopyrazine in 240 ml of 1,2-dichloroethane. After 15 minutes the well stirred mixture, protected from moisture, was cooled to -30° and 3.72 g of m-thiocresol was added in one portion. The temperature was maintained at -30° for 0.5 hour and then was allowed to return to ambient over the course of 2 hours. The mixture was then washed with water to remove pyridine hydrochloride, dried over MgSO4, and concentrated on a rotary evaporator to a solid residue. The residue was purified by the technique of dry column chromatography using silica gel adsorbent and 1-chlorobutane as solvent and eluent. The yield of pure product was 6.9 g, mp 117°-119°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](OC(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2)#[N:2].Cl>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2)#[N:2]
Reactant: CC(C)(C)OC(=O)ON1CCC(COc2cc3nccc(Oc4ccc5[nH]ccc5c4)c3cc2C#N)CC1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OCC1CCNCC1
Reaction time: 17 h
Yield: 7.5 %

Procedure:
6-Cyano-4-(1H-indol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline (0.25 g, 0.5015 mmol) was dissolved in ethanol (2 ml) and tetrahydrofuran (2 ml), and then concentrated hydrochloric acid (0.2 ml) was added at room temperature and the mixture was stirred for 17 hours. The solvent was distilled off under reduced pressure, saturated sodium bicarnobate water was added, and then extraction was performed with a tetrahydrofuran and ethyl acetate mixed solvent, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto NH silica gel and purified by column chromatography (ethyl acetate-methanol system) with NH silica gel, and the obtained crystals were suspended in ethanol and diluted with diethyl ether and hexane. The crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (15 mg, 0.0376 mmol, 7.51%).
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:32].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])=[CH:38][CH:37]=1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])=[CH:40][CH:41]=2)[C:24]=1[CH3:32]
Reactant: CCS(=O)(=O)c1ccc(CBr)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)cc1
Reaction time: 1.33 h

Procedure:
BEMP (182 μl, 0.64 mmol) is added to a stirring solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (prepared as described in U.S. Pat. No. 3,320,268, 82 mg, 0.40 mmol) in DMF (2.6 ml). After 80 minutes, 1-bromomethyl-4-ethanesulfonyl-benzene (75 μl, 0.63 mmol) is added and the reaction stirred for 2 hours before partitioning between water and 1:1 EtOAc/diethyl ether. The organic layer is washed with brine then reduced in vacuo. The residue is purified by flash column chromatography (1:1 iso-hexane/EtOAc elution) to furnish [1-(4-ethanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester as a solid.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11]CC)=[O:10])=[O:7]>O1CCOCC1>[Cl:23][C:21]1[CH:22]=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([OH:11])=[O:10])=[CH:14][N:15]2[CH:16]2[CH2:18][CH2:17]2)=[CH:19][C:20]=1[F:24]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.7 %

Procedure:
3.44 g of 80% sodium hydride are added in portions, with cooling in ice and stirring, to a solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-cyclopropylaminoacrylate (6) in 100 ml of anhydrous dioxane. The mixture is then stirred at room temperature for 30 minutes and under reflux for 2 hours and the dioxane is removed in vacuo. The residue (40.3 g) is suspended in 150 ml of water, 6.65 g of potassium hydroxide are added and the mixture is refluxed for 1.5 h. The warm solution is filtered and washed with H2O. The solution is then acidified to pH 1 to 2 with half-concentrated hydrochloric acid, cooling in ice, the precipitate is filtered off with suction, washed with water and dried in vacuo at 100° C. In this manner, 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid VII, of melting point 234°-237° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](/[C:10](/[C:17]2[CH:18]=[CH:19][C:20]([NH:23]C(=O)OC(C)(C)C)=[N:21][CH:22]=2)=[CH:11]/[CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:9])=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOCC>[NH2:23][C:20]1[N:21]=[CH:22][C:17](/[C:10](=[CH:11]\[CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:8]([NH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)=[O:9])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Cl)s2)cn1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Cl)s2)cn1
Reaction time: 2 h

Procedure:
A stirred solution of (E)-tert-butyl {5-[1-(5-chlorothiazol-2-ylcarbamoyl)-2-cyclopentylvinyl]pyridin-2-yl}carbamate (Preparation 18, 212 mg, 473 μmol) in CH2Cl2 (5 mL) was treated with TFA (5 mL, 65.1 mmol). After 2 h, the mixture was evaporated to dryness, then EtOAc (60 mL) was added. The EtOAc solution was washed with H2O-saturated aqueous NaHCO3 (1:1, 20 mL) and brine (20 mL), before being dried (MgSO4). Filtration and solvent evaporation gave a residue that was dissolved in a minimal amount of Et2O. IH was added to the Et2O solution to precipitate a solid, which was collected and dried to furnish the title compound: RTA=3.07 min; m/z (ES+)=349.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]([O:12]C(=O)C)(=O)[CH3:10].C([O-])(=O)C.[Na+].N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:33]Cl>>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:8][Cl:33])=[CH:2][CH:1]=1)(=[O:12])[CH3:10]
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Reactant: ClCl
Agent: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Product: CC(=O)Oc1ccc(CCl)cc1
Temperature: 150 °C

Procedure:
A mixture of p-cresol (108 g., 1.0 mole) and acetic anhydride (16.6 ml., 18.0 g., 0.18 mole) was heated at 130° C. while acetic anhydride (87 ml., 94 g., 0.92 mole) was added over a 30 minute period (a gentle exotherm slowly brought the mixture to reflux). This solution was further heated at reflux (150° C.) for one hour and then acetic acid was distilled off until the pot temperature reached 195° C. Heating of the mixture containing p-cresol acetate was discontinued and acetic anhydride (99 ml., 1.0 mole) was added. The mixture was cooled to 50° C. and anhydrous sodium acetate (131 g., 1.6 mole) was added followed by 3.0 g. of azobisisobutyronitrile (AIBN). After heating to 70° C. chlorine (49 g., 0.69 mole) was added through a gas dispersion tube below the surface of the liquid over a period of 1-2 hours while maintaining the temperature between 70°-75° C. The reaction was mildly exothermic and required some cooling. Upon completion of the chlorine addition, the p-acetoxybenzyl chloride thus obtained was converted to p-acetoxybenzyl acetate by refluxing (150° C.) the reaction mixture for 4 hours. The reaction mixture is cooled to 60°-65° C. and 10 ml. water is added to destroy remaining acetic anhydride. The temperature is controlled at 70°-75° C. while four 10 ml. portions of water are added at 30-minute intervals. The mixture is then cooled to 35° C. and drowned into 300 ml. water. After all salts are dissolved the layers are allowed to separate and the aqueous layer is discarded. Toluene (200 ml.) is added to the organic phase and the resulting solution is washed three times with water. The toluene solution then was distilled to give the following fraction.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[CH2:11][OH:12])[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C(OCC)(=O)C>[CH2:15]([O:12][CH2:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:4][CH2:3][CH2:2][O:1]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCCCC12OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(COCC2CCCCC23OCCO3)cc1
Reaction time: 1 h

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-6-ylmethanol (2.3 g, 13.3 mmol) in THF (20 mL) and cooled in an ice bath, was treated with a NaH (0.48 g, 20.0 mmol). The reaction mixture was stirred for 1 hour and then benzyl bromide (2.4 mL, 20 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at rt for 5 hours and then diluted with ethyl acetate (100 mL). The organic layer was washed with water, brine and dried over sodium sulfate and concentarted. Purification by silica chromatography using hexane-Et2O 20% linear gradient afforded the title compound as pale yellow solid. MS m/z 263.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([O:12][CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([F:30])[C:16]=1[O:31][CH3:32].[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:10]=[C:9]3[C:5]([N:6]([CH3:11])[CH:7]=[N:8]3)=[C:4]([O:12][CH3:13])[N:3]=2)=[C:17]([F:30])[C:16]=1[O:31][CH3:32]
Reactant: COc1nc(Cl)nc2ncn(C)c12
Reactant: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1c(Cl)ccc(-c2nc(OC)c3c(ncn3C)n2)c1F
Reaction time: 2 h
Yield: 67 %

Procedure:
2-Chloro-6-methoxy-7-methyl-7H-purine (1.2 g, 6.0 mmol, see Monatshefte fuer Chemie (1985), 116(3), 341-51 for preparation), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.1 g, 8.6 mmol), Pd(PPh3)2Cl2 (300 mg, 0.42 mmol) and cesium fluoride (1.6 g, 11 mmol) were combined in 10 mL dry, deaerated acetonitrile and heated to reflux. After 2 h, the mixture was cooled and mixed with ethyl acetate and water. The organic phase was washed with water, brine, dried and evaporated under vacuum. The residue was purified by flash chromatography on silica gel with 20% ethyl acetaete/hexane to give the title compound (1.3 g, 67% yield: mp 191-192° C.: 1H NMR (CDCl3) δ 8.0 (s, 1H), 7.90 (dd, 1H), 7.22 (dd, 1H), 4.22 (s, 3H), 4.08 (s, 3H), 4.02 (s, 3H).
Reaction SMILES: C([S-])C.[Na+].CN(C=O)C.[Cl:10][C:11]1[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:12]=1[C:19]1[N:23]([CH3:24])[C:22]([C:25]2([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:21][N:20]=1>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:19]1[N:23]([CH3:24])[C:22]([C:25]2([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:21][N:20]=1
Reactant: COc1ccc(-c2nnc(C3(c4cccs4)CCCC3)n2C)c(Cl)c1
Agent: CC[S-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(O)cc2Cl)nnc1C1(c2cccs2)CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 10.4 %

Procedure:
Sodium ethanethiolate was added to a DMF (10 ml) solution of 3-(2-chloro-4-methoxyphenyl)-4-methyl-5-[1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazole (300 mg), followed by stirring at 100° C. for 2 hours. After the reaction solution and chloroform were added to distilled water, the organic layer was separated. Furthermore, the organic layer washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=97:3) and then the resulting solid was recrystallized from isopropanol to obtain 30 mg of 3-chloro-4-{4-methyl-5-[1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazol-3-yl}phenol (colorless solid).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH2:8]([Br:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Br-:15].[CH2:8]([N+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc[n+](Cc2ccccc2)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 4-picoline (9.3 g, 0.1 mol) in toluene (200 mL), benzyl bromide (34.2 g, 0.2 mol) was added dropwise at room temperature. After the addition, the mixture was heated to reflux for 5 hrs. The mixture was cooled to room temperature. The precipitate formed was collected by filtration, washed with toluene and dried under vacuum to give Compound 1 as white solid (21.4 g, 81%). It was used without further purification. The structure of Compound 1 is given below:
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:13]1[S:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]#[C:24][CH:25]([CH3:27])[CH3:26])=[O:19])=[CH:16][N:17]=1)(=O)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:13]2[S:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]#[C:24][CH:25]([CH3:27])[CH3:26])=[O:19])=[CH:16][N:17]=2)[CH2:3]1
Reactant: CCS(=O)(=O)c1ncc(C(=O)NCCC#CC(C)C)s1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C#CCCNC(=O)c1cnc(OCC2CO2)s1
Temperature: -5 °C

Procedure:
In this preparation 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for 10 minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfonyl-5-(5-methylhex-3-ynylaminocarbonyl)thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained at 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording an oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]propane.