Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Temperature: 120 °C
Yield: 44.7 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5 g), 4-nitrothiophenol (4.83 g) and potassium carbonate (7.8 g) in N,N-dimethylformamide (100 ml) was heated at 120° C. for hours with stirring. The reaction mixture was poured into ice-water. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 200 g) and eluted with a mixture of n-hexane and ethyl acetate (3:1). The fractions containing the objective compound were combined and concentrated under reduced pressure give 2-acetylamino-5-(4-nitrophenylthio)thiazole (3.74 g, yield: 50.2%)
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>C1COCC1>[F:16][C:17]1[C:22]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Fc1cnccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccnc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
n-Butyllithium (1.6 M in hexane, 0.920 mL, 10.99 mmol) was added to 2,2,6,6-tetramethylpiperidine (2.024 mL, 11.99 mmol) in THF (50 mL) at −50° C. Following the addition, the mixture was stirred at 0° C. for 20 min and then cooled down to −100° C. 2-Fluoropyrazine (980 mg, 9.99 mmol) in THF (5 mL) was then added dropwisely. After 5 min, tributyltin chloride (3.25 mL, 11.99 mmol) in THF (5 mL) was added dropwisely and stirring was continued for 1 h. The reaction was quenched with a solution of 35% aqueous HCl, ethanol, THF (1:4:5) and allowed to warm to 20° C. The reaction mixture was diluted with sat. aqueous NaHCO3 (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated aqueous NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column eluting with 50% CH2Cl2/hexanes to give 2-fluoro-3-(tributylstannyl)pyrazine (2980 mg, 7.70 mmol, 77% yield) as colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H); 8.02 (s, 1H); 1.46-1.68 (m, 6H); 1.12-1.42 (m, 12H); 0.88 (t, J=7.23 Hz, 9H).
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3.C(=O)([O-])[O-].[Na+].[Na+].[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[SH:42].CN(C=O)C>O>[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][C:2]1[C:3]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3
Reactant: Nc1ccccc1S
Reactant: CCCCC(CC)COc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COc1cc2c3c(cccc3c1Sc1ccccc1N)C(=O)c1ccccc1-2
Temperature: 125 °C
Reaction time: 3 h

Procedure:
A 250 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 27 g of 3-bromo-2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one, 5.0 g sodium carbonate, 8.5 g 2-aminothiophenol and 80 g DMF. The mixture was agitated well, heated to 120-130° C., and held at 120-130° C. for three hours. Sodium carbonate (1.0 g) and 1.2 g 2-aminothiophenol were added and the mixture heated for an additional one hour. The reaction mixture was cooled to 25° C. and 250 g of water were added. The reaction mixture was extracted twice with 200 g chloroform. The organic layers were combined and washed twice with 250 g water. The solvent was removed on a rotary evaporator, then the crude product was passed through a flash silica gel column using methylene chloride as the elutant. The product fractions were collected and the solvent removed using a rotary evaporator. The yield of semi-solid 3-[(2-aminophenyl)thio]-2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one was 27.5 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9].C([O-])(O)=O.[Na+].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>C(Cl)Cl>[OH:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:16](=[O:17])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccccc1NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1N(O)C(=O)Oc1ccccc1
Temperature: -10 °C
Yield: 72 %

Procedure:
A mixture of 350 g (purity about 80%; 2.3 mol; prepared by a similar method to Bamberger et al., Ann. Chem. 316 (1901), 278) of N-(2-methylphenyl)hydroxylamine and 286.8 g (3.4 mol) of NaHCO3 in 700 ml of CH2Cl2 is treated with 447 g (2.85 mol) of phenyl chloroformate with vigorous stirring at about -10° C. The mixture is stirred for about 1 hour at -10° C. and 600 ml of water are then added dropwise, the temperature of the reaction mixture increasing to 5°-10° C. and a vigorous evolution of gas occurring. The aqueous phase is then separated off and extracted once more with CH2Cl2. The combined organic phases are extracted with water, dried over MgSO4 and concentrated. The residue crystallizes and is stirred with cyclohexane. 407 g (72%) of the title compound are obtained as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[NH:17][C:16]=2[CH3:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[C:30]([N:17]1[C:18]2[C:23](=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:15]([CH2:14][CH2:13][N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:16]1[CH3:26])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCC3CC3CCCCC3)c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCC1CC1CCCCC1)c(C)n2C(=O)c1ccccc1

Procedure:
Reaction of 3-[2-(2-cyclohexylmethylpyrrolidino)ethyl]-5-methoxy-2-methylindole with a mineral oil dispersion of sodium hydride in DMF and reaction of the resulting sodium salt with benzoyl chloride affords 1-benzoyl-3-[2-(2-cyclohexylmethylpyrrolidino)ethyl]-5-methoxy-2-methylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.C(OC([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Clc1ccc2c(c1)CCC2N1CCNCC1

Procedure:
The title compound was prepared in two steps by a standard reductive amination starting with 5-chloro-1-indanone and piperazine carboxylic acid tert -butyl ester followed by removal of the t-Boc group with HCl in 30% overall yield.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16]CC)=[O:15].[OH-].[Na+].C(O)(=O)C>O1CCOCC1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cccc(N2CCc3ccncc3C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(N2CCc3ccncc3C2)c1
Temperature: 70 °C

Procedure:
A mixture of ethyl 3-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)benzoate (51 mg, 0.18 mmol) and 0.5 mL 1.0 M NaOH in 2.0 mL dioxane was heated at 70° C. for 2.3 hours. The pH of the reaction was adjusted to pH 5 using glacial acetic acid. The mixture was evaporated and then chased with MeOH to give a yellow solid film. An impure lot from a previous reaction was combined, and this material triturated with EtOAc. The remaining solid was dissolved in MeOH, and then Bio-rad AG1-X8 basic resin (hydroxide form) was added. The mixture was filtered and the resin rinsed with MeOH and CH2Cl2. The product was eluted from the resin using 10% formic acid in MeOH. The solvent was evaporated, chased with MeOH and EtOAc to give the title compound (used as is for the next step) as a yellow solid (49 mg). 1H NMR (CD3OD) δ: 8.42 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.68-7.70 (m, 1H), 7.48-7.51 (m, 1H), 7.33-7.39 (m, 1H), 7.30 (dd, J=2.5, 1.3 Hz, 1H), 7.26 (d, J=4.7 Hz, 1H), 4.48 (s, 2H), 3.64 (t, J=5.9 Hz, 2H), 3.04 (t, J=5.6 Hz, 2H).
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30]1([C:36]([CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)([OH:40])[CH2:37][CH2:38]Cl)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)CCC.O>[C:30]1([C:36]([CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)([OH:40])[CH2:37][CH2:38][NH:23][CH2:22][CH2:21][NH:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OC(CCCl)(c1ccccc1)C1CCCCC1
Reactant: NCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: OC(CCNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)C1CCCCC1
Yield: 61.7 %

Procedure:
To a mixture of N-tritylethylenediamin (3.66 g) and sodium carbonate (9.2 g) in n-butanol (20 ml), a solution of 1-phenyl-1-cyclohexyl-3-chloro-1-propanol (3 g) in butanol (10 ml) was added. The mixture was refluxed overnight, then cooled, diluted with water and extracted with ethyl acetate. The solvent was dried and evaporated. The residue was purified by column chromatography (methylene chloride, methanol, ammonia 99:1:0.1) to afford 3.8 g of 1-phenyl-1-cyclohexyl-3-(2-tritylaminoethyl)amino-1-propanol. M.p. 198° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:30])CC.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])([F:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(Cl)cc1C1(O)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C1(F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-piperidin-4-ol (4b, 17 g, 0.05 mol) in dry dichloromethane (70 mL) was added dropwise DAST (10 g, 0.061 mol) at −78° C. under N2 atmosphere. The mixture was stirred at this temperature for 1 h and then warmed to room temperature slowly. NaHCO3 (sat., aq., 200 mL) was carefully added dropwise to quench the reaction. The separated aqueous was extracted with dichloromethane (150 mL×3), the combined extracts was washed with water and brine, dried over Na2SO4, concentrated to dryness. The residue was titrated with petroleum ether and the precipitated solid was filtered and washed with petroleum ether to afford 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-4-fluoro-piperidine 4c as white powder.
Reaction SMILES: [CH:1]([N:4]([CH:9]1[CH:14]=[C:13]([CH3:15])[CH2:12][CH2:11][CH:10]1[C:16]#[N:17])[C:5](OC)=[O:6])([CH3:3])[CH3:2].[OH-:18].[Na+].OO>C(O)C>[CH:1]([N:4]1[CH:9]2[CH:10]([CH2:11][CH2:12][C:13]([CH3:15])=[CH:14]2)[C:16](=[O:18])[NH:17][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)N(C(C)C)C1C=C(C)CCC1C#N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CC1=CC2C(CC1)C(=O)NC(=O)N2C(C)C

Procedure:
To a solution of 100 g 2-(N-isopropyl-N-carbomethoxyamino)-4-methyl-3-cyclohexene-nitrile in 700 ml 95% ethanol are added 90 ml of concentrated aqueous sodium hydroxide. To this mixture are added dropwise within 4 hours under stirring and at an internal temperature of 40° 600 ml 40% hydrogen peroxide. Stirring is continued over night at room temperature. The reaction mixture is concentrated in vacuo and the residue treated with water and toluene. The water layer is extracted twice with toluene and the combined toluene extracts are washed with water and evaporated in vacuo to give the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:21])[CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[C:22]([O:26][C:27](=[O:32])[CH:28](Br)[CH2:29][CH3:30])([CH3:25])([CH3:24])[CH3:23].O>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCCC>[CH2:3]([O:21][CH:28]([CH2:29][CH3:30])[C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:32])[CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCO
Reactant: CCC(Br)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCOC(CC)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 60.4 %

Procedure:
An aqueous solution of sodium hydroxide (50% (w/w), 6 mL) was added portionwise to a mixture of (3Z,6Z,9Z,12Z,15Z)-octadeca-3,6,9,12,15-pentaen-1-ol (1.66 g, 6.37 mmol), tert-butyl-2-bromobutyrat (2.86 g, 12.8 mmol) and tetrabutylammonium bisulfate (0.65 g, 1.91 mmol) in toluene (12 ml). The reaction mixture was vigorously stirred under N2-atmosphere and warmed to 50° C. The reaction mixture was stirred at 50° C. for a total of 25 hrs. Additional tert-butyl-2-bromobutyrat (1.43 g, 6.41 mmol) and (1.42 g, 6.38 mmol) was added after 1½ hrs and 3 hrs respectively. The mixture was cooled to room temperature and added water (30 mL) and heptane (50 mL), the resulting two phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure. Flash chromatography on silica gel (30 g) eluting with heptane-heptane/EtOAc (99:1) yielded 1.55 g of the title compound as a liquid. 1H NMR (300 MHz, CDCl3) δ 0.96 (t, 3H), 0.97 (t, 3H), 1.48 (s, 9H), 1.64-1.86 (m, 2H), 2.03-2.12 (m, 2H), 2.39 (dd, J=12.1, 6.7 Hz, 2H), 2.79-2.86 (m, 8H), 3.29-3.37 (m, 1H), 3.57-3.66 (m, 2H), 5.27-5.49 (m, 10H).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:7][C:8]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:15][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:16][CH:17]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc(Oc2ccc(F)cc2F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
Ethanesulfonyl chloride (9.4 mL, 99 mmol) was added dropwise over 5 min to a dark gray solution of 4-(2,4-difluorophenoxy)aniline (20.0 g, 90 mmol) and 4-dimethylaminopyridine (16.6 g, 136 mmol) in methylene chloride (180 mL) at room temperature under nitrogen, after which the mixture was stirred at room temperature for 26 h. The mixture was washed with saturated aqueous sodium bicarbonate solution (200 mL), brine (100 mL), dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford the crude product as an amber oil. This residue was triturated with diethyl ether (300 mL) and filtered to provide an amber solid. This material was further purified by flash column chromatography on silica gel, eluting with ethyl acetate/chloroform (1:9), to provide the title compound as an off-white powder: 1H NMR (300 MHz, DMSO-d6) 9.69 (s, 1H), 7.52-7.44 (m, 1H), 7.28-7.09 (m, 2H), 7.20 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 3.03 (q, J=7.6 Hz, 2H), 2.50 (t, J=1.6 Hz, 3H).
Reaction SMILES: [H-].[Na+].C(O[CH2:7][C@@:8]1([CH2:22][O:21][C@H:20]([CH2:23][O:24][C:25](=O)[CH3:26])[C@@H:15](OC(=O)C)[C@@H:10]1OC(=O)C)O)(=O)C.[F:28][C:29]1[CH:34]=CC(O)=[CH:31][CH:30]=1.[NH4+].[Cl-]>CN(C=O)C>[C:8]([C@H:22]1[O:21][C@H:20]([CH2:23][O:24][C:25]2[CH:26]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:15][CH2:10]1)#[CH:7]
Reactant: Oc1ccc(F)cc1
Reactant: CC(=O)OC[C@H]1OC[C@@](O)(COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C#C[C@@H]1CC[C@@H](COc2ccc(F)cc2)O1
Temperature: 80 °C
Yield: 59 %

Procedure:
To a stirred suspension of NaH (0.57 g, 23.86 mmol) in DMF (5 mL), a solution of (2S,5S)-5-ethynyl-2-(p-toluene sulfonyloxymethyl)-tetrahydrofuran 17 (3.34 g, 11.92 mmol) in DMF (5 mL) was added, followed by the addition of 4fluoro phenol (1.74 g, 15.5 mmol) in DMF (5 mL) and heating at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and treated with NH4Cl solution (20 mL). It was extracted with ether (3×40 mL) and organic layer was washed with water (2×25 ML), brine (25 mL) and dried (Na2SO4). Evaporation of solvent and purification of residue by column chromatography (Si-gel, 2% EtOAc-hexane) afforded (2S,5S)-5-ethynyl-2-(4-fluorophenoxymethyl)-tetrahydrofuran 18 (1.55 g) in 59.6% yield as a colorless liquid, whose spectral data was comparable with the reported reference values. [α]D−15.07(c 1.26, CHCl3); 1HNMR (CDCl3, 200 MHz): δ2.0-2.35 (m, 4H, H-3,4′), 2.45 (d, 1H, J 2.2 Hz, H-7), 3.95 (dd, 1H, J 4.5, 9.0 Hz, H-1), 4.12 (dd, 1H, J 4.54, 9.0 Hz, H-1a), 4.35 (quin, 1H, H-2), 4.65 (m, 1H, H-5), 6.85-7.05 (m, 4H, Ar—H); 13CNMR (CDCl3, 50 MHz): δ28.24, 33.1, 68.45, 72.9, 79.9, 83.8, 71.28, 115.43, 115.52, 115.68, 115.89, 154.91, 159.66; MS: m/z 220 (M+); HRMS: Calculated for C13H13O2 (M+): 220.089958; Observed; 220.089905.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C1(C)C=CC=CC=1>[OH:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][CH2:13][CH:15]2[O:17][CH2:16]2)[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)CC(OCC2CO2)CC(C)(C)N1O

Procedure:
A vigorously stirred two phase solution of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, epichlorohydrin, tetrabutylammonium bromide in 50% aqueous sodium hydroxide and toluene is reacted together. The organic phase is dried over anhydrous magnesium sulfate and concentrated to yield the title compound as a low melting red solid after column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>C(Cl)Cl.O>[CH3:21][CH:20]([CH3:22])[CH2:19][O:18][C:16](=[O:17])[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1cccc(F)c1
Reaction time: 2.5 h

Procedure:
To a mixture of 3-fluoroaniline (I, 29.058 g, 261.5 mmol) in methylene chloride (116 ml) is added a mixture of potassium carbonate (27.26 g, 197.3 mmol, 0.75 eq) in water (116 ml) at 20-25°. The mixture is warmed to 32°, and isobutyl chloroformate (38.5 g, 282 mmol, 1.08 eq) is added over 13 min while maintaining 30-35° with mild cooling. The mixture is stirred at 30-35° for 2.5 hr until the reaction is complete to give 2-methylpropyl-(3-fluorophenyl)carbamate as determined by GC [GC method A, <0.1 area % 3-fluoroaniline; RT (3-fluoroaniline)=3.97 min, RT=14.2 min]. Aqueous ammonia (29.3 wt %, 4.20 ml, 65.0 mmol, 0.25 eq) is added and the mixture stirred at 30-35° for 15 min. The mixture is cooled to 20-25° and the pH adjusted from 8.7 to 1.9 with hydrochloric acid (37 wt %, 6.36 g, 64.5 mmol, 0.25 eq). The phases are separated and the aqueous washed with methylene chloride (58 ml). The combined organics are washed with water (118 ml) and the water wash back extracted with methylene chloride (58 ml). [In a prior experiment crystallization at this point from heptane at −30° gave 2-methylpropyl-(3-fluorophenyl)carbamate analytically pure in 98.1% yield.]. Dibromantin (57.37 g;, 200.6 mmol, 0.767 eq) and water (174 ml) are added to the combined organics and the mixture stirred at 40° for 12 hr until complete as measured by HPLC (<0.1 2-methylpropyl-(3-fluorophenyl)carbamate). The mixture is cooled to 20-25° and clarified on a “C” frit by vacuum filtration. The phases are separated and the organic (lower) phase added to a mixture of sodium sulfite (33.06 g, 262.3 mmol, 1.00 eq) in water (220 ml) with good agitation. The phases are separated and the organic phase washed with water (150 ml). Serial back-extracted the clarified solids and all aqueous with a single portion of methylene chloride (150 ml). Added heptane (520 ml) to the combined organic phases and concentrated under reduced pressure. Heptane (240 ml) is added, the mixture cooled to −30°, the precipitate is collected by vacuum filtration, washed with cold heptane (150 ml) and dried in a nitrogen stream to give the title compound; mp=79-82°; TLC Rf=0.41 (ethyl acetate/hexanes, 5/95); HPLC (method A) rt=6.75 min; NMR (CDCl3, 400 MHz) d 7.41, 6.96, 6.87, 3.96, 1.97 and 0.96; CMR (CDCl3, 75 MHz) d 159.2, 153.4, 139.0, 133.3, 115.1, 107.1, 102.0, 71.8, 27.9 and 19.0; MS (CI, NH3) m/Z (relative intensity) 310 (9.3), 309 (100), 308 (6.1), 307 (100), 292 (11), 291 (18), 290 (7.5) and 289 (19)
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl.O1CCOCC1>C(O)C>[CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([Cl:19])[CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(SCc2ccccc2)n2nccc2n1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1cccc(Nc2cc(SCc3ccccc3)n3nccc3n2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To the reaction flask, 7-(benzylthio)-5-chloropyrazolo[1,5-a]pyrimidine (3.45 g, 12.5 mmol) was added along with 3-chloroaniline (3.3 mL, 31.3 mmol), 4N HCl in dioxane (3.1 mL, 12.5 mmol), and ethanol (42 mL). The reaction was stirred at reflux for 12 hours then cool to room temperature. Excess solvent was removed under vacuum and the residue was diluted with water. The mixture was made basic with 3N NaOH, filtered and washed with water. The product, 7-(benzylthio)-N-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine, was collected as a solid in 90% yield after drying under vacuum overnight. LCMS (M+1=376)