Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].COS([O-])(=O)=O.CN(C)[C:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N+:11]=1[CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=1.O>C(O)C.C(OCC)C>[CH2:30]([O:29][C:27]([C:26](=[C:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[CH3:17])[C:23]1[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: CN(C)C1=[N+](C)CCCCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(=C1CCCCCN1C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add (drop by drop at 90° in a stream of nitrogen to let the alcohol escape) a solution of 4.6 g of sodium in 100 ml of ethyl alcohol to a mixture of 53.2 g of the title compound of Example 1 and 29.8 g of ethyl 4-chlorophenylacetate. Stir it for a further 4 hours at 90° and then cool it to ambient temperature. Mix the cooled reaction mixture with 100 ml of water and 100 ml of diethyl ether, collect the organic phase and dry the latter over sodium sulfate. Concentrate the dried organic phase and then distil off any excess ethyl 4-chlorophenylacetate under a high vacuum to obtain a crude yield [15.5 g (34% of theory)] of the title compound as yellow oil.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH2:10](Br)[C:11]#[CH:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH2:12][CH:11]=[CH2:10]
Reactant: C#CCBr
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
To a well stirred solution of guaiacol (10.0 g, 80.55 mmol) and propargyl bromide (11.5 g, 96.66 mmol) in DMF (100 mL) was added anhydrous K2CO3 (22.0 g, 161.2 mmol) and the mixture was stirred at room temperature for 3-4 hours. The mixture was then filtered to remove inorganic material. Filtrate was concentrated under vacuo and diluted with water (250 mL). It was then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave the product (13.0 g) as brown oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:21]([CH2:22][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:20][C:19]3[C:18]([CH3:29])([CH3:28])[CH2:17][CH2:16][C:15]([CH3:31])([CH3:30])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:28][C:18]1([CH3:29])[CH2:17][CH2:16][C:15]([CH3:30])([CH3:31])[C:14]2[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=3)[C:21]([CH2:22][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:20][C:19]1=2
Reactant: COC(=O)c1ccc(C=Cc2cc3c(cc2Cn2cccn2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(Cn3cccn3)c(/C=C/c3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 27.6 g (64.4 mmol) of methyl-4-[2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate and 97 mL (193 mmol) of 2 N sodium hydroxide in 300 mL of ethyl alcohol was heated at reflux. After 1 hour, the reaction mixture was cooled to room temperature and diluted with 900 mL of water. The reaction mixture was acidified with 2 N HCl and the product was isolated by filtration, washed with water and pentane and dried to give 25.9 g (97%) of 4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid (m.p.=246.5-248° C.) 6.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:33]1([O:32][C:30](=[O:31])[NH:1][C:2]2[CH:22]=[C:21]([C:23]3[N:27]=[C:26]([CH3:28])[O:25][N:24]=3)[CH:20]=[CH:19][C:3]=2[CH2:4][NH:5][C:6](=[O:18])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NC(=O)Oc2ccccc2)cc(OC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
A suspension of compound 1g (100 mg, 0.26 mmol), phenyl chloroformate (0.033 mL, 0.26 mmol) and potassium carbonate (72 mg, 0.52 mmol) in DCE (2 mL) was stirred at rt overnight. Additional phenyl chloroformate (0.015 mL, 0.13 mmol) was added and the reaction was stirred at rt for 24 h. The reaction was concentrated on a rotary evaporator and the residue purified by silica gel chromotagraphy (ethyl acetate) to afford compound 19a (157 mg, 100%).
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].[CH3:11][S:12][C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]2[C:21]=1[C:20](=[O:22])[CH2:19][CH2:18]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:23][C:16]1[CH:15]=[CH:14][C:13]([S:12][CH3:11])=[C:21]2[C:17]=1[CH2:18][CH2:19][C:20]2=[O:22])([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCSP(=O)(Cl)OCC
Reactant: CSc1ccc(O)c2c1C(=O)CC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCSP(=O)(OCC)Oc1ccc(SC)c2c1CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-methylthio-4-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-ethyl S-propyl O-(7-methylthioindan-1-on-4-yl) thiophosphate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccc(Cl)c(Cl)c2)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[ClH:30]>C(OCC)(=O)C>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[ClH:30]
Reactant: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC
Reaction time: 0.5 h

Procedure:
3.24 g of BOC-Met-Leu-Gly-OMe are dissolved in 13 ml of 3.8 N hydrogen chloride in ethyl acetate and allowed to stand for 30 minutes at 20° C. On adding 100 ml of petroleum ether the tripeptide ester hydrochloride is precipitated as a sticky mass, and the supernatant solution is decanted off. On triturating with 100 ml of peroxide-free ether at 0° C. a finely powdered product is obtained which is filtered off and dried to constant weight over potassium hydroxide at room temperature in a desiccator. The compound is chromatographically pure but amorphous and strongly hygroscopic. It shows the following Rf-values on silica gel: Rf 43 C = 0.48; Rf (toluene-acetone 1:1) = 0.35.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[NH2:13].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>CC(N(C)C)=O>[Cl:14][C:15]1[N:20]=[C:19]([NH:13][C:5]2[C:6]3[O:10][CH2:9][O:8][C:7]=3[CH:11]=[CH:12][C:4]=2[Cl:3])[CH:18]=[CH:17][N:16]=1
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Clc1nccc(Nc2c(Cl)ccc3c2OCO3)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (13.4 g, 60% dispersion in mineral oil) was added portionwise to (5-chloro-1,3-benzodioxol-4-yl)amine (11.5 g, prepared as described in WO2001094341) in DMA (100 ml) at 0° C. 2,4-Dichloropyrimidine (10 g) was added and the reaction warmed to room temperature and stirred overnight. The reaction was quenched cautiously with water, the solution filtered and concentrated and the residue dissolved in DCM, washed with water and brine, dried and concentrated to give 2-chloro-N-(5-chlorobenzo[d][1,3]dioxol-4-yl)pyrimidin-4-amine as a dark brown oil that was used without further purification (16 g, 85%); NMR Spectrum (300 MHz, DMSO) 6.10 (s, 2H), 6.58 (d, 1H), 6.94 (d, 1H), 7.05 (d, 1H), 8.15 (d, 1H), 9.76 (s, 1H); Mass Spectrum M+ 284.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21].O.[NH2:30][NH2:31].O>CN(C=O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: CC(C(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccc1)c1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-(2-phenylpropionyl)-1,8-naphthyridin-2(1H)-one (370 mg, 1.0 mmol) produced in Synthesis Example 8 in DMF (8 mL) was added hydrazine monohydrate (purity of 80%, 160 μL), and the mixture was stirred at 100 to 110° C. for 3 hours. To the reaction solution was added water. The resulting precipitate was separated by filtration, washed with water, and dried to give 5-phenyl-3-(1-phenylethyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (306 mg, yield 84%).
Reaction SMILES: [CH2:1]([N:5]1[C:12]([NH2:13])=[CH:11][C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[N:14]([O-])=[O:15].[Na+].C(O)(=O)C>O>[CH2:1]([N:5]1[C:12]([NH2:13])=[C:11]([N:14]=[O:15])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=N[O-]
Reactant: CCCCn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Yield: 84.8 %

Procedure:
91.5 g (0.5 mole) of 1-butyl-6-aminouracil are suspended in 1 liter of water in a reactor equipped with a magnetic stirrer. A solution of 38 g of sodium nitrite in 250 ml of water is added to the suspension. 65 ml of acetic acid are then run in dropwise with stirring, after which the mixture is stirred for 18 hours at ambient temperature. After cooling in an ice bath, the precipitate is filtered, giving 90 g of violet-coloured crystals.
Reaction SMILES: C1COCC1.O.[OH:7][C@@H:8]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:20]2[C@@H:14]([O:15][CH2:16][C@@H:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19]2)[CH2:13][C@H:12]1[O:30]C1CCCCO1>C(O)(=O)C>[OH:30][C@@H:12]1[CH2:13][C@@H:14]2[O:15][CH2:16][C@@H:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19][C@@H:20]2[C@H:11]1/[CH:10]=[CH:9]/[C@@H:8]([OH:7])[CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2OC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2OC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
THF (400 μL) and water (400 μL) were added to an acetic acid solution (800 μL) of the compound (151 mg, 0.259 mmol) produced in Example 15, followed by stirring at 60° C. for 3 hours and 30 minutes. The reaction solution was concentrated under reduced pressure, and purified with a column apparatus (Hiflash-SI, Size S, ethyl acetate:hexane=1:1→ethyl acetate) manufactured by Yamazen Corporation to obtain a titled compound (74 mg) having the following physical property values. TLC: Rf 0.28 (dichloromethane:methanol=20:1); 1H-NMR (300 MHz, CDCl3): δ 0.90-1.19, 1.22, 1.36-1.83, 1.84-1.96, 2.03-2.18, 2.23, 2.41-2.53, 2.57, 2.84-2.97, 3.64-3.80, 3.83-3.91, 3.92-4.09, 4.44-4.59, 4.88-5.09, 5.53-5.77, 6.83-7.04, 7.14-7.35.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:35].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[O:35])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 6 (146 mg, 0.313 mmol) in DCM (10 mL) was added TFA (72 μL, 0.939 mmol) followed by a solution of m-CPBA (59 mg, 0.344 mmol) in DCM (2 mL). The resulting mixture was stirred for 1 h at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 15-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH affording 206 as a colorless foam (130 mg, 86%). LCMS: RT 2.47 min [M+H]+ 483.1. 1H NMR (DMSO, 400 MHz): δ 8.59 (1H, d, J=2.27 Hz), 7.93 (1H, s), 7.53 (1H, dd, J=8.53, 2.29 Hz), 7.25 (1H, d, J=8.53 Hz), 5.71-5.58 (1H, m), 4.62-4.50 (4H, m), 2.8-2.75 (2H, m), 2.74-2.58 (2H, m), 2.26 (3H, s), 2.13-2.03 (2H, m), 1.78 (1H, bd, J=12.31 Hz), 1.61 (1H, bd, J=12.24 Hz), 1.50-1.33 (7H, m), 0.90 (6H, d, J=6.54 Hz)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]2[N:12]([N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:23](OCC)=[O:24].[Cl-].[NH4+].[BH4-].[Na+]>O1CCCC1.CO>[Si:1]([O:8][CH2:9][C:10]1[C:11]2[N:12]([N:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=2)[C:13]([CH2:23][OH:24])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cccn2nc(C(F)(F)F)cc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)n2nc(C(F)(F)F)cc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In an argon atmosphere, a 2.67 mol/L n-butyl lithium-hexane solution (14.0 mL) was added dropwise to a solution of the compound of Example 91 (12.4 g) in tetrahydrofuran (200 mL) at −78° C. The mixture was stirred at −78° C. for 30 min. Subsequently, the mixture was added dropwise to a solution of ethyl formate (9.06 mL) in tetrahydrofuran (100 mL) at −78° C. The mixture was then allowed to gradually warm to room temperature. A saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The extract was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give yellow crystals. This product was dissolved in methanol (200 mL). While the solution was kept at 0° C., sodium borohydride (1.56 g) was added and the mixture was stirred at 0° C. for 1 hour. Subsequently, a saturated aqueous ammonium chloride solution was added. The mixture was concentrated and extracted with ethyl acetate (700 mL).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH2:11][CH:12]([S:67][S:68][CH:69]([CH3:71])[CH3:70])[CH2:13][C@@H:14]([NH:59]C(OC(C)(C)C)=O)[C:15]([O:17][C@H:18]1[C@@H:22]([OH:23])[C@H:21]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[NH2:33])[O:20][C@H:19]1[CH2:34][O:35][P:36]([O:39][C@H:40]1[CH2:44][C@H:43]([N:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[N:47][C:46]2=[O:52])[O:42][C@@H:41]1[CH2:53][O:54][P:55]([OH:58])([OH:57])=[O:56])([OH:38])=[O:37])=[O:16])=[N+:9]=[N-:10]>ClCCl>[NH2:59][C@H:14]([CH2:13][CH:12]([S:67][S:68][CH:69]([CH3:71])[CH3:70])[CH2:11][N:8]=[N+:9]=[N-:10])[C:15]([O:17][C@H:18]1[C@@H:22]([OH:23])[C@H:21]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[NH2:33])[O:20][C@H:19]1[CH2:34][O:35][P:36]([O:39][C@H:40]1[CH2:44][C@H:43]([N:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[N:47][C:46]2=[O:52])[O:42][C@@H:41]1[CH2:53][O:54][P:55]([OH:58])([OH:57])=[O:56])([OH:38])=[O:37])=[O:16]
Reactant: CC(C)SSC(CN=[N+]=[N-])C[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)SSC(CN=[N+]=[N-])C[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(isopropyldisulfanyl)pentanoate (Compound 46) (27.7 mg, 28 μmol) in dichloromethane (0.4 mL), and the mixture was stirred for 35 minutes at room temperature. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-azido-4-(isopropyldisulfanyl)pentanoate (Orn(N3) (4-SSiPr)-pdCpA) (Compound 47) (21.5 mg, 86%).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[CH2:17][CH3:18].C[O:20][B:21](OC)[O:22]C.Cl>C1COCC1>[CH2:17]([C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=1[B:21]([OH:22])[OH:20])[CH3:18]
Reactant: COB(OC)OC
Reactant: CCc1ccc(C(F)(F)F)cc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(C(F)(F)F)cc1B(O)O
Reaction time: 0.5 h

Procedure:
i-Propylmagnesium chloride (2M sol. in THF, 5.81 mL, 11.6 mmol) was added drop wise to a cooled (−30° C.) solution of 2-iodo-1-ethyl-4-(trifluoromethyl)benzene (3.48 g, 11.6 mmol) in dry THF (30 mL) and the reaction mixture was stirred at the same temperature for 30 min, under argon. After this time, trimethylborate (2.6 mL, 23.2 mmol) was added drop wise and the reaction mixture was stirred at the same temperature for 1.5 h. HCl (1 M, 10 mL) was added and the reaction mixture extracted with EtOAc (3×40 mL). The combined organic layers were dried over sodium sulfate and the solvent was evaporated to obtain the title compound as a white solid, crystallized from hexane (2.46 g, 97%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[Cl-].[NH4+].[OH-].[NH4+].[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CCOC(C)=O>[C:17]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1)#[N:18]
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 2-chloro-3-trifluoromethylpyridine (36.2 g, 0.2 moles) in DMF (350 mL) at room temperature. Add water (3.5 mL) and zinc cyanide (14 g, 0.12 moles) to the reaction mixture and degas with nitrogen for 15 minutes. Add catalyst Pd2(dba)3 (5.5 g, 3 mol %) and ligand DPPF (6.5 g, 6 mol %) to the mixture and then heat at 120° C. with stirring for 1 hour. Cool the reaction mixture in an ice bath and then add saturated ammonium chloride (200 mL), 28% ammonium hydroxide (50 mL) and water (50 mL). Stir the resulting reaction mixture in the ice bath for 1 hour and then dilute it EtOAc (300 mL). Separate the organic layer, extract the aqueous layer with EtOAc (3×300 mL), wash the combined organic layers with brine (2×200 mL) and dry (MgSO4). Filter the dried extract and concentrate under vacuum to afford crude product as dark brown oil. Purify the crude product by vacuum distillation to afford pure product as colorless oil.
Reaction SMILES: [CH2:1]([NH:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].B.C1COCC1.Cl.[OH-].[Na+]>>[CH2:16]([NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCNC(=O)CCCCCCCCCCCCC
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 108.1 %

Procedure:
N-myristyl myristamide (0.90 g; 2.1 mmole) was treated with borane THF (5 mL of 1 M solution, 5.0 mmole) and reacted at reflux for 3 hrs. The reaction mixture was carefully neutralized with 3N HCl aqueous solution and stirred at 50° C. for 20 min., the back neutralized with 2N NaOH aqueous solution. The mixture was concentrated, then partitioned between CH2Cl2 and saturated NaHCO3 aqueous solution, dried and concentrated, affording 0.93 g of product. NMR (CDCl3): δ 2.59 (t, 2H, J=7.2 Hz), 1.40-1.55 (m, 2H), 1.15-1.40 (m, 22H), 0.88 (t, 3H, J=6.8 Hz).