Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FF.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])I>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CCOCC.[OH-].[Na+]>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:13]([F:16])([F:15])[C:12]([F:18])([F:17])[F:11])=[CH:6][CH:5]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: Sc1ccc(Br)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: FF
Agent: [Cl-]
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)Sc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared using perfluoroalkylation conditions originally described by Popov et. al. J. Fluorine Chem. 1982, 21, 365. To a solution of 4-bromobenzenethiol (500 mg, 2.64 mmol, 1.00 eq) and triethylbenzyl ammonium chloride (60 mg, 0.26 mmol, 0.10 eq) in 10 mL of 1:1 Et2O/NaOH (25% aq) at 0° C. was bubbled 1,1,1,2,2-pentafluoro-2-iodoethane gas for 30 min (>5 eq). During this time a UV lamp was directed at the reaction vessel while the temperature was maintained below 10° C. by intermittent use of an ice bath. The contents were then warmed to room temperature, extracted into Et2O (300 mL), dried (MgSO4), and concentrated under reduced pressure. A portion of this crude material was used in subsequent reactions without further purification (200 mg residue: 120 mg product, 0.39 mmol, 1.2 eq).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O1CCCC1>CO.[C].[Pd]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 107 %

Procedure:
10% Palladium carbon (water content 51.7%, 250 mg) was added to a solution of methyl ester of 2-amino-3-nitrobenzoic acid (980 mg, 5.00 mmol) in methanol (20 ml)-tetrahydrofuran (10 ml) and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hrs. The catalyst was removed by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and the solvent was distilled off under reduced pressure to give methyl ester of 2,3-diaminobenzoic acid (814 mg, 98%) as a yellowish green solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>C[O-].[Na+].CO>[Cl:18][C:15]1[N:14]([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])[C:7]([OH:24])=[C:8]2[C:16]=1[Cl:17]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2CCC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCn1c(Cl)c(Cl)c2c(O)c(C(=O)NCC(=O)O)nc(C#N)c21

Procedure:
7-Cyano-2,3-dichloro-4-hydroxy-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (80 mg, 0.22 mmol) and glycine (324 mg, 4.32 mmol) were suspended in 8.64 mL of 0.5 N sodium methoxide in methanol. The reaction was heated at reflux temperature overnight, cooled, and concentrated. The residue was dissolved in water (15 mL), and the solution was acidified to pH 1-2 with 1 N hydrochloric acid. The title compound (60 mg) was collected by filtration as a light yellow solid. MS: (+) m/z 399.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[C:14](O)([CH3:17])([CH3:16])[CH3:15].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:14]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([CH3:13])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 3-nitro-4-methylbenzoic acid (17.3 g 96 mmol) in dichloromethane (250 ml) and tert-butanol (35.8 g 470 mmol) at 0° C. under nitrogen was added 4-dimethylaminopyridine (6 g 50 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25.8 g 140 mmol) and the solution allowed to come to room temperature over 1 hour. then stirred overnight. The solution was poured into 1:1 ethyl acetate:water (800 ml each) and the organic layer washed with aqueous bicarbonate and saturated aqueous sodium chloride, then dried (MgSO4) and evaporated, to give the product as a clear oil (22.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:22][CH2:23][CH2:24]Cl)[CH2:20]Cl>CN(C=O)C.O>[O:22]1[CH2:23][CH2:24][N:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: NC(=O)c1ccc(N)cc1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 4-aminobenzamide (6.81 g, 50 mmol) in DMF (70 mL) were added NaI (22.48 g, 150 mmol) and K2CO3 (13.82 g, 100 mmol). The mixture was heated to 140° C. and 2,2′-dichlorodiethyl ether (14.30 g, 100 mmol) was added. The reaction mixture was heated at 150° C. for 5 h, and cooled to rt. The mixture was diluted with water (100 mL), stirred for 10 min, and filtered. The filter cake was washed with water and dried to give the title compound as a yellow solid (6.60 g, 64%).
Reaction SMILES: [CH2:1]([N:4]([CH2:24][CH2:25][CH3:26])[CH2:5][CH2:6][C:7]([N:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:15][CH:14]=1)[CH2:10][CH:11]=[CH2:12])=O)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:24]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][N:9]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:17][CH:18]=1)[CH2:10][CH:11]=[CH2:12])[CH2:25][CH3:26]
Reactant: C=CCN(C(=O)CCN(CCC)CCC)c1ccc(-n2ccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=CCN(CCCN(CCC)CCC)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 4, react 3-(dipropylamino)-N-[4-(1H-imidazol-yl)phenyl]-N-(2-propenyl)propanamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:21])[S:15][N:14]=2)=[CH:9][CH:8]=1.O.[OH-].[Na+]>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:21])[S:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2nsc(C)c2C(=O)O)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1snc(-c2ccc(O)cc2)c1C(=O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
The solution of boron tribromide in dichloromethane (1.0 M, 12.4 mL) in a 100-mL round bottom flask was cooled to −78° C., followed by the addition of 1.03 g of 3-(4-methoxyphenyl)-5-methylisothiazole-4-carboxylic acid as a solid slowly. The reaction mixture was stirred at −78° C. for 2 hrs. and at room temperature overnight. Water (20 mL) was added slowly, followed by the addition of 20 mL of 1.0 N NaOH and 100 mL of dichloromethane. The two layers were separated with a separatory funnel. The aqueous layer was acidified by the addition of concentrated hydrochloric acid. The product was extracted with ethyl acetate (3×100 mL). Solvent was evaporated in vacuo to give 0.935 g of 3-(4-hydroxyphenyl)-5-methylisothiazole-4-carboxylic acid (96%, theoretical yield 0.972 g). LCMS (method B) RT 2.28 min., MH+236. 1H NMR (500 MHz, CD3OD) δ 7.42 (d, J=8.5Hz, 2H), 6.80 (d, J=8.5Hz, 2H), 2.70 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.Cl[CH2:32][CH:33]=[CH:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=1>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([CH2:32][CH:33]=[CH:34][C:35]3[CH:36]=[C:37]([O:45][CH3:46])[C:38]([O:43][CH3:44])=[C:39]([O:41][CH3:42])[CH:40]=3)[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Reactant: COc1cc(C=CCCl)cc(OC)c1OC
Solvent: CN(C)C=O
Product: COc1cc(C=CCN2CCC3C(=C4C(=CC(C(C)CCCc5ccc(F)cc5)=CC4(O)O)OC3(C)C)C2)cc(OC)c1OC

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and 1-(3-chloropropenyl)3,4,5-trimethoxybenzene (0.5 mole) were reacted in dimethylformamide as described in Example 7 to give the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1)=[C:37]=[O:38]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:37]([NH:36][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=3)=[O:38])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C=Nc1cccc(O)c1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3cccc(O)c3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-(3-hydroxyphenyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (40 mg, 0.13 mmol) and 3-isocyanatophenol (40.4 mg, 0.15 mmol) according to General Procedure G to give 20 mg (34.4%) of white solid. Anal. Calcd. for C25H31N5O2 m/z 433.2, found: 434.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (s, 1H), 8.66 (m, 1H), 8.52 (s, 1H), 8.41 (m, 1H), 7.41 (d, J=8.9 Hz, 2H), 6.97 (m, 4H), 6.66 (d, J=9.3 Hz, 2H), 6.34 (m, 2H), 3.79 (m, 1H), 3.56 (m, 3H), 3.26 (m, 2H), 3.00 (m, 1H), 2.11 (m, 2H), 1.92 (m, 1H), 1.78 (m, 1H), 1.62 (m, 1H), 1.49 (m, 1H), 1.32 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:24]([O:28][C:29](=[O:41])[NH:30][C@H:31]1[CH2:40][CH2:39][C:34]2[N:35]=[C:36]([NH2:38])[S:37][C:33]=2[CH2:32]1)([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[C:24]([O:28][C:29](=[O:41])[NH:30][C@H:31]1[CH2:40][CH2:39][C:34]2[N:35]=[C:36]([NH:38][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][N:12]4[CH:13]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=5)[CH:10]=[N:11]4)[CH:16]=3)[S:37][C:33]=2[CH2:32]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)O)c3)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(N)sc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)cn4)c3)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Dissolve 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoic acid (0.25 g, 0.82 mmol) and ((S)-2-amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.22 g, 0.82 mmol) and TBTU (0.40 g, 1.24 mmol) and N,N-diisopropylethylamine (0.40 ml, 2.47 mmol) into 1.5 mL dry DMF and stir overnight at room temperature under Ar. Pour the reaction into H2O, giving a precipitate. Filter the solid, wash with H2O, and dry. Extract the filtrate 3 times with EtOAc and washed 4 times with H2O, 3 times with aq. NH4Cl and once with aq.Na2CO3. Dry the organic phase and concentrate to give an oil. Both crops are combined and purified via prep plate chromatography eluting with 3% MeOH/CH2Cl2 to give 0.42 g, 92% yield as a clear hard resin of ((S)-2-{3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].[C:18]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[C:31]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][NH:4][C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=3[N+:15]([O-:17])=[O:16])[CH2:29][CH2:30]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 9 parts of N-(2-chloroethyl)-2-nitro-4-(trifluoromethyl)benzenamine, 7.65 parts of 1-(diphenylmethyl)piperazine, 7.9 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol. The product is filtered off and dried, yielding 4-(diphenylmethyl)-N-[2-nitro-4-(trifluoromethyl)phenyl]-1-piperazineethanamine; mp. 152.1° C.
Reaction SMILES: [Cl:1][C:2]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1)=[O:3].C=O.Cl.[CH:16](Cl)(Cl)[Cl:17]>[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]([O:4][C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[C:10]=1[CH2:16][Cl:17])=[O:3]
Reactant: ClC(Cl)Cl
Reactant: Cc1cc(C)cc(OC(=O)Cl)c1
Agent: C=O
Agent: Cl
Agent: [Cl-]
Product: Cc1cc(C)c(CCl)c(OC(=O)Cl)c1
Temperature: 0 °C

Procedure:
Into a stirred mixture of 37 parts of 3,5-xylenyl chloroformate, 78 parts of paraformaldehyde, 10 parts of powdered anhydrous zinc chloride, and 150 parts of chloroform at 20-30 degrees, was passed hydrogen chloride gas over 101/2 hours. The paraformaldehyde slowly dissolved. Then the reaction mixture was agitated briefly with ice water, after which the organic layer was decanted, dried over magnesium sulfate, filtered, and solvent was evaporated off. The residual liquid was distilled to obtain 17 parts of chloromethyl-3,5-dimethylphenyl chloroformate, boiling point 80° - 85° (0.005 millimeter), in which the position of the chloromethyl group is indicated to be mostly para by NMR analysis.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[BH4-].[Na+].O>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cnc2ccccc2c1
Yield: 89 %

Procedure:
3-Quinolinecarbaldehyde (2.00 g, 12.7 mmol) was dissolved in 25 mL of methanol. To this solution was added sodium borohydride (0.24 g, 6.4 mmol) in small portions over a period of 20 minutes. Then 2 mL of water were added and the mixture was evaporated. The residue was dissolved in ethyl acetate (75 mL) and washed with water (3×75 mL), dried (MgSO4) and evaporated, providing 1.8 g of quinolin-3-yl-methanol in 90% yield; 1H NMR (DMSO-d6) δ 4.89 (s, 2H), 7.53 (t, J=7.1 Hz, 1H), 7.64-7.71 (m, 1H), 7.77 (d, J=8.2 Hz, 1H), 8.04-8.12 (m, 2H), 8.83 (d, J=2.0 Hz, 1H).
Reaction SMILES: [O:1]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[CH:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[O:19])=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: O=C(O)c1ccc2c(c1)CCC2Oc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc3c(c2)CCC3Oc2ccccc2)c(O)n1
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a solution of 1-phenoxy-2,3-dihydro-1H-indene-5-carboxylic acid (100 mg, 0.39 mmol) in dichloromethane (50 mL) were added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) and triethylamine (71 mg, 0.7 mmol). And then the mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (61 mg, 0.4 mmol) was added. The mixture was stirred at room temperature for 12 hours. The resultant mixture was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-phenoxy-2,3-dihydro-1H-indene-5-carboxamide (Compound I-45) (35 mg, 23%) as white solid. LRMS (M+H+) m/z: calcd 388.18. found 388. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.41-7.29 (m, 3H), 7.05-6.93 (m, 3H), 5.89-5.86 (m, 2H), 4.30 (d, J=4.8 Hz, 2H), 3.10-2.84 (m, 2H), 2.64-2.56 (m, 1H), 2.16 (s, 3H), 2.11 (s, 3H), 2.09-1.98 (m, 1H).
Reaction SMILES: [Na+:1].[Na+].[P:3]([O:7][CH2:8][C@@:9]1([N:24]=[N+:25]=[N-:26])[O:13][C@@H:12]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH2:11][C@@H:10]1[OH:23])([O-:6])([O-:5])=[O:4]>O>[Na+:1].[Na+:1].[Na+:1].[P:3]([O:7][CH2:8][C@@:9]1([N:24]=[N+:25]=[N-:26])[O:13][C@@H:12]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH2:11][C@@H:10]1[OH:23])([O:5][P:3]([O-:6])([O-:5])=[O:4])(=[O:6])[O-:4]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@](COP(=O)([O-])[O-])(N=[N+]=[N-])O2)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: O
Product: Cc1cn([C@H]2C[C@H](O)[C@](COP(=O)([O-])OP(=O)([O-])[O-])(N=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.3 %

Procedure:
A solution of the compound of 4'-azidothymidine 5'-monophosphate disodium salt (55 mg, 0.14 mM) in H2O (5 mL) is applied onto a short column of Dowex 50 (H+) resin (8 mL) and eluted with H2O. After concentrating the eluent to 5 mL, tributylamine (32 μL) and pyridine (5 mL) was added and the mixture evaporated in vacuo. The residue was co-evaporated with pyridine then with dimethylformamide. To a solution of the residue in dimethylformamide (1 mL) was added a solution of carbonyldiimidazole (0.11 g, 0.66 mM) in dimethylformamide (1.5 mL). After 20 hours at room temperature, methanol (0.04 mL, 1.0 mM) was added. Thirty minutes later a solution of tributylammonium pyrophosphate (0.675 mM) in dimethylformamide (7 mL) was added and mixture was vigorously stirred for 20 hours at room temperature. After filtration, the solution was diluted with an equal volume of methanol and evaporated to a sirup. The sirup was dissolved in water (10 mL) and applied onto a 3×23 cm column of DEAE Sephadex (carbonate form) which was eluted with a linear gradient consisting of 2 L of water and 2 L of 0.5M triethylammonium bicarbonate (pH 7). The 4'-azidothymidine 5'-diphosphate was eluted pure followed by the 4'-azidothymidine 5-'triphosphate. After evaporation of solvent and repeated co-evaporation with water, each product was dissolved in a small amount of methanol. The addition of a 0.45M solution of sodium perchlorate in acetone then precipitated the sodium salts. Filtering off the precipitates and drying in vacuo gave 4'-azidothymidine 5'-diphosphate trisodium salt (12 mg) and 4'-azidothymidine 5'-triphosphate tetrasodium salt (54 mg, mp 204° C., decomposition).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].P([O-])([O-])([O-])=O>C1COCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCCCC=COC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: OCCCC=COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A solution of 105 (900 mg, 3 mmol) in THF (20 mL) was treated with Bu4NF (1 M in THF, 3 mL, 3 mmol, 1 equiv) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and at 25° C. for 2 h. Phosphate buffer (100 mL, pH 7) was added and the mixture was extracted with EtOAc-hexane (2:1, 3×30 mL). The combined organic phase was dried (Na2SO4) and the solvent removed under vacuum. Chromatography (SiO2, 4×25 cm, 30% EtOAc-hexane containing 2% Et3N) afforded 106 (445 mg, 557 mg theoretical, 80%) as a colorless oil as a mixture of E- and Z-olefin isomers (50:50). Careful rechromatography of this material (SiO2, 4×25 cm, 10-30% EtOAc-hexane containing 2% Et3N gradient elution) enabled the partial separation of the two isomers.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCCC[C@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@@H]2CCCC[C@H]2c2ccccc2)cc1F
Yield: 99.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1R,2S)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (53.6 mg, 0.0891 mmol) prepared in Example 75a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (40.2 mg, 99%) as a colorless solid.