Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH3:11][C:5]1[CH:6]=[CH:7][C:8]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:9][CH:10]=1
Reactant: O=S(=O)=O
Reactant: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 50 °C
Reaction time: 22 h
Yield: 28 %

Procedure:
Sulfur trioxide (0.6 g, 7.5 mmol, stabilized, 99% from Aldrich, Milwaukee, Wis.) was weighed into a 100-ml round-bottom flask in the dry box Toluene (50 g) was added to the sulfur trioxide via syringe under an inert atmosphere. The solution was stirred at 50° C. for 22 hours under a nitrogen atmosphere before it was cooled to room temperature. A dark colored oil formed at the bottom of the solution. The toluene and oil layer was extracted with three 10-cc portions of distilled water. The analysis by HPLC showed 28% yield of p-TSA and 5.5% o-TSA (ratio p/o -5.1) for a total yield of 33.5%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[N:12]=[C:11]([C:26]([C:28]([F:30])([F:31])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])[CH2:10]1
Reactant: OC(C1=NN(c2ccc(N3CCNCC3)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
5-(2-Chloro-phenyl)-1-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 428, cyclopropanesulfonyl chloride (6.0 uL, 0.06 mmol), and triethylamine (25.0 uL, 0.18 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:7]([O])[C:6]([CH3:10])([CH3:9])[CH2:5][CH2:4][CH2:3]1.[C:12]([O:16]N=O)(C)([CH3:14])[CH3:13].N[C:20]1[CH:25]=CC=C[CH:21]=1>N1C=CC=CC=1.[Cu]>[O:16]([N:7]1[C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1([CH3:10])[CH3:9])[C:12]1[CH:14]=[CH:25][CH:20]=[CH:21][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)ON=O
Reactant: CC1(C)CCCC(C)(C)N1[O]
Agent: [Cu]
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 86.4 %

Procedure:
The procedure of Example 5 is repeated using 1.95 g (12.5 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl, 3.09 g (30.0 mmol) of tert-butylnitrite and 758 mg (˜0.25mmol) of copper polyoxometallate (K7PCuW11O39•H2O) in 100 mL of pyridine and 2.32 g (25 mmol) of aniline in 5 mL of pyridine. The crude is purified by vacuum flash chromatography (heptane) to give 2.52 g of a colorless oil in 82.8% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9].[S:10]([O-])([O-:12])=[O:11].[Na+:14].[Na+]>CCO.O>[Na+:14].[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:10]([O-:12])=[O:11])#[N:9]
Reactant: O=S([O-])[O-]
Reactant: N#CCCCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCCCCCCS(=O)[O-]
Yield: 36 %

Procedure:
In a three necked flask, fitted with a water condenser, a mechanical stirrer and a dropping funnel was placed a solution of 1-bromo-6-cyanohexane (8.04 g, 42.3 mmol) in 75 mL of 95% EtOH was prepared. The mixture was heated to reflux and to it was slowly added a solution of sodium sulfite (8.00 g, 63.5 mmol) in 50 mL of H2O over a period of 30 min. The mixture was heated for 2 h and then concentrated under reduced pressure. The residue was dissolved in 95% EtOH (200 ml), heated to boiling and filtered. The filtrate was concentrated and cooled in an ice bath. The precipitate was collectedby filtration and dried to give 3.00 g of a white solid. The mother liquor on further concentration, produced another batch of 2.2 g of the product.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:29][CH2:30][S:31][CH3:32])[N:5]([C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11](=[CH:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:6].O.[OH-].[Li+].CO>C1COCC1.O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([N:5]([CH3:6])[C@H:4]([C:3]([OH:33])=[O:2])[CH2:29][CH2:30][S:31][CH3:32])=[O:28])=[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:10]=2)[CH:17]=1
Reactant: COC(=O)[C@H](CCSC)N(C)C(=O)C1=C(c2ccccc2)CC(=CNc2cccnc2)C=C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CSCC[C@@H](C(=O)O)N(C)C(=O)c1ccc(CNc2cccnc2)cc1-c1ccccc1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a 0° C. solution in THF (3.0 mL) of [4-(3-Pyridylaminomethylene)-2-phenylbenzoyl-]N-methylmethionine methyl ester (135 mg, 0.29 mmol), prepared as in Example 158, was added a solution of lithium hydroxide hydrate (20 mg, 0.49 mmol) in water (1 mL). Methanol (1 mL) and water (0.5 mL) were then added to obtain a clear solution. The reaction mixture was stirred for 1.5 hours and then the cold bath was removed and stirring was continued for 2.5 hours. The reaction mixture was partitioned between water which was taken to pH 4 with HCl and ethyl acetate. The aqueous phase was extracted three times with chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in acetonitrile-methanol. The solution was diluted with water, frozen, and lyophilized to give [4-(3-pyridylaminomethyl)-2-phenylbenzoyl]-N-methylmethionine (120 mg) as a white powder. 1H NMR (300 MHz, D3COD) δ 7.93 (d, 1H), 7.78 (dd, 1H), 7.50 (d, 1H), 7.38 (m, 7H), 7.20 (m, 1H), 7.12 (m, 1H), 5.20 and 4.55 (both m, total 1H), 4.45 (s, 2H), 2.70 and 2.45 (both br s, total 3H), 2.24 and 2.10 (both m, total 2H), 2.00 (br s, 3H), 1.80 and 1.68 (both m, 2H); MS (DCI-NH3) m/e 450 (M+H)+. Anal calcd for C25H27N3O3S.0.65 HCl: C, 63.45; H, 5.89; N, 8.88. Found: C, 63.51; H, 5.54; N, 8.53.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[Br:17]Br>P(OC)(OC)(OC)=O.O>[CH3:1][C:2]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: CCOP(=O)(Cc1ccccc1C)OCC
Reactant: BrBr
Solvent: COP(=O)(OC)OC
Solvent: O
Product: CCOP(=O)(Cc1ccc(Br)cc1C)OCC

Procedure:
10 g (42 mmol) of diethyl 2-methylbenzylphosphonate were dissolved in 60 ml of trimethyl phosphate and the solution was introduced into a flask protected from light and moisture. 16 g (0.05 mol) of Br2 were added dropwise, while stirring. The mixture was stirred at 90° C. for 15 hours and, after cooling, was diluted with 100 ml of water and extracted three times with 100 ml of n-hexane each time. The organic phase wa dried, concentrated and distilled.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:9][C:10]([Cl:17])([Cl:16])[CH2:11][O:12][C:13](Cl)=[O:14].[CH3:18][C:19]1[NH:20][C:21](=[O:25])[CH2:22][S:23][CH:24]=1>>[CH3:18][C:19]1[NH:20][C:21](=[O:25])[CH2:22][S:23][C:24]=1[CH:7]1[CH:6]=[CH:5][N:4]([C:13]([O:12][CH2:11][C:10]([Cl:17])([Cl:16])[Cl:9])=[O:14])[CH:3]=[C:2]1[C:1]#[N:8]
Reactant: CC1=CSCC(=O)N1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N#Cc1cccnc1
Product: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2C#N)SCC(=O)N1
Yield: 25 %

Procedure:
A mixture of nicotinonitrile (1.62 g), 2,2,2-trichloroethylchloroformate (2.13 ml) and 5-methyl-2H-1,4-thiazin-3(4H)-one (1.0 g) was treated in the same manner as described in Example 4 (i) to give the titled compound (0.8 g, yield 25%) as pale yellow crystals. Chloroform-methanol (=20:1) was used as a developing eluant.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH:30]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:29][CH2:28]3)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:38][N:36]([CH2:35][CH:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([O:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)=[CH:40][CH:39]=3)[CH:26]=2)[CH2:31]1)[CH3:37]
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
p-Anisoyl chloride (0.20 ml) was added dropwise to pyridine solution (6 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (300 mg) under ice-cooling, which was stirred at room temperature for 30 minutes. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: ethyl acetate), and recrystallized (THF-IPE) to give the titled compound (300 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3ccccc3F)cc2)no1
Temperature: 90 °C
Yield: 83.8 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-fluorophenol (16 μL, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-fluoro-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 84%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.93 (d, J=8.2 Hz, 2H), 7.60 (d, J=7.2 Hz, 3H), 7.17-7.29 (m, 2H), 7.11 (t, J=7.7 Hz, 1H), 6.87-7.01 (m, 1H), 5.25 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)=[O:46])=[CH:40][CH:39]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (20 μL, 0.14 mmol) followed by 4-fluorophenyl isocyanate (14.6 μL, 0.13 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 26 mg (40%) of the desired N-(4-fluorophenyl)-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]urea product as a yellow oil, which was greater than 95% pure by reverse phase HPLC analysis. HRMS calcd. for C25H22F8N3O3:564.1533 [M+H]+, found: 564.1566. 1H NMR (CDCl3) δ 3.7 (m, 2H), 4.1 (m, 1H), 4.7 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.9-7.4 (m, 1H), 7.5 (s, 1H), 7.8 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:41])[CH:12]=[C:13]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=1)[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:44]1>C(Cl)Cl.CC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:41])[C:12]([OH:44])=[C:13]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:32]=1)[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OO1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)cc2)oc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=c1c(O)c(-c2ccc(OCc3ccccc3)cc2)oc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution containing 1.00 g (1.85 mmol) of 3 in 30 mL of CH2Cl2 at 0° C. was added 30 mL of a 0.9-0.11 M solution of DMDO in acetone. The reaction mixture was stirred at 0° C. overnight under N2.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:21](O)[CH2:20]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li][N:55]=[N+:56]=[N-:57].CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:27]([O:26][CH2:25][C@H:23]1[O:24][C@@H:19]([N:14]2[C:15]3[N:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:11]=3[N:12]=[CH:13]2)[CH2:20][C@@H:21]1[N:55]=[N+:56]=[N-:57])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@@H](O)[C@@H](COC(=O)c2ccccc2)O1)c1ccccc1
Reactant: [Li]N=[N+]=[N-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N6 -Benzoyl-9-(5-O-benzoyl-2-deoxy-β-D-threo-pentofuranosyl)adenine (7.0 g, 15.3 mmol), triphenylphosphine (6.0 g, 22.9 mmol), and LiN3 (2.8 g, 56.4 mmol) were dissolved in DMF (100 mL). To this stirring mixture was added diethylazodicarboxylate (3.6 mL, 22.9 mmol) in one portion, the reaction was stirred for 2.5 h at RT, and the reaction was quenched with H2O (10 mL). The solvents were removed in vacuo, the residual oil was redissolved in EtOAc (300 mL) and extracted with H2O (2×200 mL) and saturated. aq. NaCl (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residual oil was purified on SiO2 (2-5% MeOH/CH2Cl2) to afford 5'-O-Benzoyl-N2 -benzoyl-3'-azido-2',3'-dideoxyadenosine, 1a, as an amber foam, which was taken on directly to hydrogenation.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[S:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[B:25](OC)([O:28]C)[O:26]C.Cl>C1COCC1.CCCCCC>[C:1]1([C:7]2[C:12]3[S:13][C:14]4[C:19]([B:25]([OH:28])[OH:26])=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COB(OC)OC
Reactant: c1ccc(-c2cccc3c2sc2ccccc23)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc2c1sc1c(-c3ccccc3)cccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3.5 g (13.4 mmol) 4-phenyldibenzothiophene was dissolved in ˜30 mL anhydrous THF in a three necked 250 mL flask and cooled down to −78° C. To the mixture, 17 mL (27 mmol) 1.6 M BuLi in hexane was added and stirred for 30 minutes. The cooling batch was removed and let reaction kept stirring for overnight. The reaction mixture was cooled down again to −78° C. and 4.5 mL (40 mmol) trimethyl borate was added and stirred at room temperature for 4 hours. ˜100 1 M HCl was added and kept stirring for 1 hour. The mixture was extracted by ethyl acetate and the organic extracts were combined. The solvent was evaporated to dryness. The solid was added with ˜100 mL 20% ethyl acetate in hexane was stinrred for few hours and then filtered. The filtered solid washed by hexane few times. ˜2.5
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[C:26]([Cl:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O.C(OCC)(=O)C>[ClH:34].[C:26]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:8][CH2:9]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CN2CCN(C(=O)c3ccccc3)CC2)cc(OC)c1OC
Product: Cl

Procedure:
To a mixture of 1-(3,4,5-trimethoxybenzyl)piperazine (0.5 g), potassium carbonate (3 g), ethyl acetate (30 ml) and water (20 ml) is added dropwise benzoyl chloride (1 ml) at room temperature with stirring. The mixture is stirred for one hour. Ethyl acetate (100 ml) and water (100 ml) are added to the mixture, followed by extraction. The ethyl acetate layer is separated, washed with water, dried, and concentrated under reduced pressure. The residue is dissolved in ethyl ether (200 ml). To the mixture is added hydrogen chloride - ethyl acetate (1N) (4 ml). Resultant precipitates are recrystallized from ethanol - ethyl ether to afford 1-benzoyl-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.5 g) as colorless powdery crystals, m.p. 220°-225° C. (decomp.).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[C:9]([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[N:14]S(C(C)(C)C)=[O:16])[CH:10]=[CH:11][CH:12]=1.[O:29]1[CH2:33][CH2:32]CC1>>[C:33]([OH:29])(=[O:16])[CH3:32].[Br:6][C:7]1[CH:8]=[C:9]([C:13]2([CH:1]3[CH2:3][CH2:2]3)[C:21]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]([NH2:28])=[N:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1ccccc1C#N
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Product: CC(=O)O
Product: NC1=NC(c2cccc(Br)c2)(C2CC2)c2ccccc21
Temperature: 30 °C
Reaction time: 2.5 h
Yield: 11 %

Procedure:
Cyclopropylmagnesium bromide (7.20 mL, 3.60 mmol, 0.5 M in tetrahydrofuran) was added drop wise to N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide (Scheme #5, N) (1.00 g, 2.57 mmol) in dry tetrahydrofuran (10 mL) at room temperature under argon atmosphere. The reaction was heated to 30° C. and stirred for 2.5 h, then cooled to 0° C. The reaction was quenched with methanol (5 mL) and extracted twice with ethyl acetate. The organic phases were pooled, washed (saturated aqueous ammonium chloride and water), dried over magnesium sulfate and concentrated. Column chromatography using gradient solution from dichloromethane to dichloromethane:3.5 M ammonia in methanol 97:3 followed by preparative HPLC (Column: Gemini C8; Mobile phase: 35% acetonitrile in 0.1 M ammonium acetate/water; Flow: 1 mL/min) afforded 0.108 g (11% yield) of the title compound: 1H NMR (DMSO-d6) δ 7.72-7.69 (m, 1 H), 7.62-7.57 (m, 3 H), 7.40-7.35 (m, 3 H), 7.25 (t, J=7.78 Hz, 1 H), 1.89 (s, 3 H), 1.86-1.81 (m, 1 H), 0.46-0.35 (m, 2 H), 0.21-0.13 (m, 1 H), −0.09-−0.02 (m, 1 H); MS (ES) m/z 327, 329 [M+1]+.
Reaction SMILES: C[Al](C)C.[CH:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]([S:12]([NH:15][C:16]2[S:20][CH:19]=[CH:18][N:17]=2)(=[O:14])=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@H:31]1[CH2:35][CH2:34][O:33][C:32]1=[O:36].Cl>CCCCCC.ClCCl.C(OC(=O)C)C>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@@H:31]([CH2:35][CH2:34][OH:33])[C:32]([NH:11][C:10]1[CH:5]=[CH:6][C:7]([S:12](=[O:14])(=[O:13])[NH:15][C:16]2[S:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:9]=1)=[O:36]
Reactant: O=C1OCC[C@@H]1N1CCc2c(Cl)cccc21
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)[C@H](CCO)N1CCc2c(Cl)cccc21
Temperature: 25 °C
Yield: 79.9 %

Procedure:
Prepared using general procedure 58. Under an N2 atmosphere at RT, 2M-trimethyl aluminum in hexane (9.13 mL) was added dropwise to a stirring solution of sulfathiazole (4.6 g, 18.27 mmol) in dichloromethane (100 mL) in 30 minutes. Upon completion of addition, the mixture was stirred at RT for an hour. Added (s)-3-(4-chloroindolin-1-yl)dihydrofuran-2(3H)-one (3.56 g, 14.97 mmol) in dichloromethane (20 mL) to above solution over 30 minutes. The mixture was stirred for 16 hrs at RT. The reaction mixture was diluted with 500 mL of ethylacetate were added. The aqueous phase was acidified to pH 2 with an (IN) aqueous HCl solution. The ethyl acetate layer was washed with (IN) aqueous HCl (3×200 mL) till LCMS showed disappearance of sulfathiazole. The organic layer was dried over MgSO4, filtered, concentrated. Purification via silica gel chromatography using 2-10% methanol in dichloromethane gave the amide as a white solid (5.9 g, 80% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=493.2; tR=1.46 min. 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 7.74 (s, 4H), 7.24 (d, J=4.6 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 6.81 (d, J=4.5 Hz, 1H), 6.56-6.54 (m, 2H), 4.71 (t, J=4.8 Hz, 1H), 4.43-4.39 (m, 1H), 3.79 (q, J=9.3 Hz, 1H), 3.64-3.58 (m, 2H), 3.51-3.48 (m, 1H), 3.17 (d, J=5.2 Hz, 1H), 3.00-2.89 (m, 1H), 1.93 (dd, J=6.0, 13.5 Hz, 1H), 1.88 (s, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1.ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCOC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(OCCCc1nnn[nH]1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
Heat a solution of 3-cyanopropyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.24 g; 1.0 equiv; 0.64 mmoles), azidotrimethylsilane (0.85 mL; 10 equiv; 6.38 mmoles) and dibutyloxostannane (0.040 g; 0.25 equiv; 0.16 mmoles) in toluene (5 mL) to 100° C. for 24 hours, then cool to ambient temperature and concentrate. Purify the crude material by reverse phase chromatography to afford impure product. Dissolve the impure product in 50 mL dichloromethane and wash with saturated sodium bicarbonate, and further extract the aqueous layer 2× dichloromethane. Dry the combined organic extracts over sodium sulfate, filter, and concentrate to afford 3-(1H-tetrazol-5-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.110 g; 41%) as a yellow solid: MS (m/z): 421 (M+1).