Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[C:17]([F:29])[CH:16]=2)[CH2:10]1)(C)(C)C.[F:31][CH:32]([F:38])C(OCC)=O>>[F:21][C:19]1[CH:20]=[C:15]([N:11]2[CH2:10][CH:9]([CH2:8][NH:7][C:6](=[O:30])[CH:32]([F:38])[F:31])[O:13][C:12]2=[O:14])[CH:16]=[C:17]([F:29])[C:18]=1[N:22]1[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reactant: CCOC(=O)C(F)F
Product: O=C1C=CN(c2c(F)cc(N3CC(CNC(=O)C(F)F)OC3=O)cc2F)CC1

Procedure:
The compound is prepared from {3-[3,5-difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (402 mg, 0.92 mmol) and ethyl difluoroacetate (360 mg, 2.88 mmol) following the method described in example 9. The crude product is purified by silica gel column chromatography (eluent: EtOAc) to give a white solid. Yield 68 mg (18%). MS (m/z): 402 [M+1]+. 1H NMR (300 MHz, DMSO-d6): 9.16 (br. t, 1H), 7.46–7.38 (m, 3H), 6.24 (dd, J=11.0 and 14.8 Hz, 1H), 4.99 (d, J=7.4 Hz, 1H), 4.85–4.81 (m, 1H), 4.15 (t, J=9.3 Hz, 1H), 3.81–3.74 (m, 3H), 3.52 (t, J=5.5 Hz, 2H), 2.48 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Br[CH2:26][C:27]#[N:28].O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:26][C:27]#[N:28])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.50 g, 1.84 mmol) in dimethyl formamide (50 ml) under nitrogen at room temperature, was added sodium hydrogen carbonate (1.50 g) followed by bromoacetonitrile (1.9 ml). The reaction mixture was stirred at room temperature for 16 h, then poured into water and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (MgSO4), filtered and the solvent was removed in vacuo to leave an oily residue. Trituration with diethyl ether, followed by recrystallisation from an ethyl acetate, petrol (60-80) mixture, gave the title compound as a white solid (0.15 g). Mp 209°-211° C. Found: C, 65.60; H, 3.74; N, 8.75; C17H11N2O2Cl requires C, 65.71; H, 3.57; N, 9.02%. δ (360 MHz, DMSO-d6) 4.59 (2H, s, OCH2CN), 7.31 (1H, dd, J=8.63 Hz, J=2.10 Hz, 6-H), 7.40-7.49 (6H, m, Ph+8-H), 7.83 (1H, d, J=88.63 Hz, 5-H), 12.10 (1H, bs, NH). m/z (CI+), 311, (M+1).
Reaction SMILES: [CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]1=[O:24])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Na+].O.Cl>CO.C(Cl)(Cl)Cl>[CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=2[N:8]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]1=[O:24])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)n(CCC(C)C)c(=O)n2CCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(C)CCn1c(=O)n(CCC(C)C)c2cc(C(=O)O)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
In 7 ml of methanol is dissolved 0.34 g of methyl 1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate. After adding 1.5 ml of 1 mol/L solution of sodium hydroxide, the mixture is stirred at 50° C. for one hour. Water and chloroform are successively added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 0.29 g of 1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid is obtained as a white solid product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](O)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:21])[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])=[CH:8][CH:9]=2)[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1noc(C)c1-c1ccc2c(O)c([N+](=O)[O-])cnc2c1
Product: Cc1noc(C)c1-c1ccc2c(Cl)c([N+](=O)[O-])cnc2c1
Yield: 75 %

Procedure:
A suspension of 7-(3,5-dimethyl-4-isoxazolyl)-3-nitro-4-quinolinol (for a preparation see intermediate 15, 5 g, 17 mmol) in POCl3 (50 ml) was refluxed overnight. After cooling the solvent was evaporated in vacuo. The resulting residue was poured over saturated aqueous Sodium hydrogen carbonate, extracted with DCM, washed with water, dried over Na2SO4. The solvent was evaporated under reduce pressure to give the title compound as a light brown solid (4 g, 75%). 1H NMR (300 MHz, CDCl3, ppm) δ: 9.23 (s, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.67 (dd, J=8.9, 1.5 Hz, 1H), 2.47 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38]>>[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1CBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: Cc1ccccc1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-2-methylbenzene following the procedure of Example 478: MS (ESI) m/z 498.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>>[ClH:9].[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccncc1
Reactant: Fc1ccc(S)cc1
Product: Cl
Product: Fc1ccc(Sc2ccncc2)cc1
Yield: 92.5 %

Procedure:
To 50.0 g of 4-fluorobenzenethiol cooled in an ice bath at 0° was slowly added 44.3 g of 4-chloropyridine. After several minutes, a vigorous reaction ensued with the formation of a white solid. The product was washed with ether and dried to yield 87.2 g (92.8%) of white powder, m.p. 217°-220°. Recrystallization from isopropanol gave white needles, m.p. 224°-226°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[OH:7][CH:8]([CH3:41])[CH2:9][S:10]([C:13]1[CH:14]=[C:15]([C@H:24]2[CH2:28][CH2:27][C@H:26]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[O:25]2)[CH:16]=[C:17]([OH:23])[C:18]=1[O:19][CH2:20][CH2:21][CH3:22])(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:7][CH:8]([CH3:41])[CH2:9][S:10]([C:13]1[CH:14]=[C:15]([C@H:24]2[CH2:28][CH2:27][C@H:26]([C:29]3[CH:30]=[C:31]([O:39][CH3:40])[C:32]([O:37][CH3:38])=[C:33]([O:35][CH3:36])[CH:34]=3)[O:25]2)[CH:16]=[C:17]([O:23][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:18]=1[O:19][CH2:20][CH2:21][CH3:22])(=[O:11])=[O:12]
Reactant: BrCCCCBr
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1,4-Dibromobutane (75 uL, 0.63 mmol) was added to a solution of trans-2-[3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (75 mg, 0.15 mmol) in DMF (0.5 mL) containing potassium carbonate (75 mg, 0.54 mmol). The reaction mixture was heated with stirring under nitrogen at 70° C. for 1.5 h, cooled, and partitioned between ethyl ether and water. The ethereal layer was separated and the aqueous layer was re-extracted twice with ether. The organic extracts were combined, dried, and evaporated to a residue. Purification by preparative TLC (hexane-ethyl acetate; 1:1, v/v) gave the title compound as a colorless viscous oil: Rf 0.5; NMR (CDCl3) δ 1.25 (d, CH2CHOHCH3).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)=[O:16])[CH2:4][O:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[CH:20][CH:19]=2)=[O:16])[CH2:4][O:3]1
Reactant: OB(O)c1cccnc1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccc(I)cc2)[C@H](c2ccccc2)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)OC[C@H](NC(=O)Nc2ccc(-c3cccnc3)cc2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
To a stirred solution of 10 mg (0.0088 mmol) of tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (2.0 mL) was added 100 mg (0.22 mmol) of the product from Example 7. After stirring for 15 min, 27 mg (0.22 mmol) of pyridine-3-boronic acid dissolved in ethanol (0.20 mL) was added followed by 0.22 mL (0.44 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated to 80° C. for 12 h and then cooled to room temperature. The mixture was taken up in 10 mL of dichloromethane and washed with water. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (hexanes/ethyl acetate) to yield 40 mg (45%) of the title compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]>C(OCC)C>[CH3:1][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][S:26]([C:29]([F:32])([F:30])[F:31])(=[O:28])=[O:27])[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
With cooling with ice, potassium carbonate (152 mg, 1.10 mmol) and iodomethane (0.137 mL, 2.20 mmol) were added to a DMF solution (3.0 mL) of methyl 3-hydroxy-5-trifluoromethane-sulfonyloxybenzoate (300 mg, 1.00 mmol), and stirred at room temperature for 17 hours. The reaction mixture was diluted with diethyl ether (30 mL), washed with water and aqueous saturated sodium chloride solution, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=O)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:7]1[NH:8][S:9](=[O:11])(=[O:10])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ccc(Cl)cc2S(=O)(=O)N1
Solvent: Cc1cccc(C)n1
Product: O=S1(=O)NC(Cl)=Nc2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 8.0 g of 7-chloro-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine 1,1-dioxide in 80 g of phosphorus oxychloride is added dropwise 7.4 g of 2,6-lutidine, while the mixture is cooled in an ice bath. After the addition, the mixture is heated under reflux for 12 hours and concentrated under reduced pressure. To the residue is added 400 ml of ice water and the resulting mixture is stirred for 30 minutes. The crystalline precipitate is collected by suction filtration, washed with water and then with 2-propanol, and recrystallized from 2-propanol to afford the desired product, m.p. 242°-244° C.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH2:23][CH2:24][CH3:25]>C(C1C=CC=CC=1)(=O)C.CCOCC>[CH2:22]([O:8][C:7]1[C:4]([O:5][CH3:6])=[CH:3][C:2]([C:1]([OH:14])=[O:13])=[CH:12][C:9]=1[O:10][CH3:11])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCBr
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)c1ccccc1
Product: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Temperature: 135 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
Methyl syringate (10 g, 0.047 mol) and potassium carbonate (8.5 g, 0.061 mol) were stirred in acetophenone (100 mL) at 135° C. Butyl bromide (6.6 mL, 0.061 mol) was added dropwise over 1.5 h and the reaction was stirred over 18 h at 135° C. The reaction was cooled, filtered and the inorganic solids washed with acetone (20 mL). The combined filtrate was concentrated under high vacuum to give a red oil which was redissolved in ether (50 mL) and washed with 2N aqueous NaOH (2×10 mL) and water (3×10 mL). The organic layer was dried using anhydrous NaSO4 and the solvent removed under reduced pressure. The crude product was redissolved in methanol (250 mL) followed by addition of aqueous potassium hydroxide (44%, 20 mL). After heating at reflux for 2 h the reaction mixture was allowed to cool down to room temperature and left to rest over 18 h. The solvent was then concentrated under reduced pressure, the residue reconstituted in water (100 mL) and the resulting aqueous solution washed with ether (3×30 mL). The aqueous layer was acidified to pH=1 with 5N HCl and the precipitated product collected by filtration. The crude product was recrystallised from methanol to give 6.1 g, 51% yield of 4-butyloxy-3,5-dimethoxybenzoic acid as a colourless solid. 1H NMR (CDCl3) δ: 0.98 (t, J=5.1 Hz, 3H), 1.49 (m, 2H), 1.74 (m, 2H), 3.91 (s, 6H), 4.06 (t, J=5 Hz, 2H), 7.37 (s, 2H). MS m/z 255.4 (MH+).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(O)CCC>[S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)([O-:18])(=[O:17])=[O:16].[CH3:9][CH2:10][CH2:11][CH2:12][O:8][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][NH3+:6])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CCCCN1
Reactant: O
Solvent: CCCCO
Product: CCCCOC(=O)CCCC[NH3+]
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 60 °C

Procedure:
Into a flask equipped with magnetic stirrer, thermometer, nitrogen inlet tube, and Dean-Stark trap were placed 25.0 parts of valerolactam (5-pentanelactam), 47.8 parts of para-toluenesulfonic acid monohydrate and 74.7 parts of butanol. The aforesaid mixture was placed under nitrogen atmosphere, heated to reflux to azeotropically remove any water present, and maintained at reflux until a constant acid value was attained. (The acid value was determined by the procedure described in Example I, above.) The reaction mixture was allowed to cool to 60° C. followed by the addition of 146.9 parts of methanol. The mixture was stirred and filtered to yield the [(4-butoxycarbonyl)butyl]ammonium tosylate. The aforesaid latent acid catalyst had a solids content of 30 percent in methanol and butanol.
Reaction SMILES: [C:1]([S:5][S:6][CH2:7][CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].CCN(C(C)C)C(C)C.[C:26](OC([O-])=O)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C(Cl)Cl>[C:29]([O:28][C:26]([N:9]([CH2:8][CH2:7][S:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CC(C)(C)SSCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CN(CCSSC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.6 %

Procedure:
2-(tert-Butyldisulfanyl)ethanamine (Compound 6c-A, 0.21 g, 1.26 mmol) and ethyl 2-bromoacetate (0.23 g, 1.39 mmol) were dissolved in DCM (6.0 ml), DIPEA (1.10 ml, 6.31 mmol) was added, and the mixture was stirred at room temperature for 17 hours. tert-Butyl dicarbonate (358 mg, 1.64 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was then directly purified by column chromatography (hexane:ethyl acetate=4:1) to afford the title compound (334.8 mg, 75%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:9][N:8]=1.CN([CH:26]=[O:27])C.[BH4-].[Na+]>C1COCC1.CO>[Si:16]([O:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:26][OH:27])=[N:8][CH:9]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BuLi (14.6 ml of a 1.6 M solution in hexanes, 23 mmol) was added to a stirred solution of 2-bromo-5-[2-(tert-butyldimethylsilyloxy)ethyl]pyridine (4.92 g, 15.6 mmol) in THF (100 ml) at −78° C. The resulting pale yellow solution was stirred for 1 h and then DMF (3.6 ml, 46.6 mmol) was added in one portion. The reaction mixture was warmed to room temperature and stirred for 90 min. MeOH (70 ml) was added, followed by NaBH4 (589 mg, 15.6 mmol) and stirring was continued for a further 1 h. The reaction was quenched by cautious addition of NH4Cl (sat. 100 ml) and the organics extracted with EtOAc (3×100 ml). The combined extracts were then washed with H2O (70 ml) and brine (70 ml), dried (MgSO4) and concentrated under reduced pressure. The material was used crude without further purification.
Reaction SMILES: COC([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:54][CH2:53]C1>C1(C)C=CC=CC=1.Cl>[F:25][C:26]([F:28])([F:27])[C:53]([C:13]1([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:15][CH:16]=[C:11]([C:7]2[CH:6]=[CH:5][CH:10]=[CH:9][CH:8]=2)[CH2:12]1)=[O:54]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1cccc(-c2cccc(OCc3ccccc3)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: Cc1ccccc1
Product: O=C(C(F)(F)F)C1(OCc2ccccc2)C=CC=C(c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 940.2 %

Procedure:
A solution of 29 (0.1 g, 0.314 mmol) in anhydrous toluene (5 mL) was cooled to −78° C., under nitrogen, and trifluoromethyltrimethylsilane (62.5 mg, 0.44 mmol) was added. The mixture was stirred for 15 min at −78° C., then a 1M anhydrous solution of tetrabutylammonium fluoride in THF (0.026 ml, 0.026 mmol) was added and the resultant mixture was gradually warmed to room temperature. After stirring for 12 h at room temperature, the reaction mixture was diluted with 4N HCl solution (2 mL) and stirred for an additional 2 h period. The organic layer was separated and the aqueous layer was extracted with diethyl ether (20 mL). The combined organic layer was washed with aqueous saturated NaHCO3 solution (5 mL) and brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (25% diethyl ether-hexane) and the fraction that contains the product 30 and its hydrate form (2:1 ratio by 1H NMR) was concentrated and dried in high vacuum (in the presence of P2O5) to give pure compound 30 (0.0876 g, 76% yield) as a viscous liquid.
Reaction SMILES: [OH:1][P:2]([CH2:14][C:15]([N:17]1[CH:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:20][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:18]1)=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:3].CN(C)C=O.[C:43]([O:49][CH2:50]Cl)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:45][C:44]([CH3:47])([CH3:46])[C:43](=[O:48])[O:49][CH2:50][O:3][P:2]([CH2:14][C:15]([N:17]1[CH:21]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:20][C:19]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:18]1)=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:1]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(OCc1ccccc1)C1CC(c2ccccc2)=NN1C(=O)CP(=O)(O)CCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1N=C(c2ccccc2)CC1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 4.0 g. of the benzyl ester product from part (c) dissolved in 40 ml. of dry dimethylformamide under argon is treated at ambient temperature with 1.5 g. of chloromethyl pivalate and 1.8 g. of triethylamine. After stirring overnight, the solution is diluted with ethyl acetate and washed with 10% potassium dihydrogen sulfate, water, and saturated brine. The organic solution is dried (MgSO4) and concentrated in vacuo to give the crude product. Flash chromatography on silica gel and elution with ethyl acetate/dichloromethane (1:1) gives homogeneous (+)-4,5-dihydro-1-[[[(2,2-dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, phenylmethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[CH2:4][C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([F:15])=[N:10][C:11]=2[NH2:14])[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:34][CH2:35][CH2:36][C:37]#[CH:38])(=O)=O>CN(C=O)C>[F:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([CH2:4][C:3]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:2]=3[Cl:1])[N:6]2[CH2:38][CH2:37][CH2:36][C:35]#[CH:34])=[C:11]([NH2:14])[N:10]=1
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(Cl)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)c(OC)cc2Cl)nc2c(N)nc(F)nc21

Procedure:
A solution of 8-(2-chloro-4,5-dimethoxy-benzyl)-2-fluoroadenine (22 mg, 0.065 mmol), Cs2CO3 (21 mg, 0.065 mmol), pent-4-ynyl tosylate (20 mg, 17.3 L, 0.085 mmol) in anhydrous DMF (170 L) was stirred at 50° C. for 2 h. Following solvent removal, the product (14 mg, 53.8%) was collected through silica gel column purification (CHCl3:EtOAc:hexanes:i-PrOH at 20:10:20:1). 1H NMR (400 MHz, CDCl3) 6.91 (s, 1H), 6.67 (s, 1H), 6.01 (bs, 2H), 4.31 (s, 2H), 4.14 (t, J=7.5 Hz, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 2.24-2.20 (m, 2H), 2.01-1.99 (m, 1H), 1.97-1.88 (m, 2H); 13C NMR (100 MHz, CDCl3) 1596, 157.9, 156.3, 152.3, 148.9, 146.0, 124.9, 112.7, 82.3, 69.9, 56.3, 56.2, 42.2, 31.2, 28.1, 15.9; MS m/z 404.1 (M+H)+. HPLC: (a) 95.1% (65% water-35% acetonitrile); (b) 96.7% (35% to 45% acetonitrile).