Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C[N:33]1CCOCC1.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH2:33])=[O:5]
Reactant: CN1CCOCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 30 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.076 mL, 0.696 mmol), ammonia (0.5M in dioxane, 0.278 mL, 0.139 mmol), and HATU (39.7 mg, 0.104 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.4 min) to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10 mg, 0.021 mmol, 30.4% yield): LCMS=431.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.36 Hz), 7.65-7.80 (4 H, m), 7.52-7.65 (3 H, m), 5.11 (1 H, s). HPLC Peak RT=7.9 min (Analytical Method C).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:17]([O:26][CH3:27])[CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:17]([O:26][CH3:27])[CH:16]=2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Cc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1OC

Procedure:
3.41 g of methyl 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxyphenylacetate was dissolved in 50 ml of toluene. After adding 3.5 g of p-toluenesulfonic acid monohydrate, the mixture was heated under reflux for 1 hour and 45 minutes. After adding water and triethylamine, the reaction mixture was extracted with dichloromethane and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 3.6 g of a pale yellow oily substance was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])/[CH:3]=[CH:4]/[C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[C:6]=1[CH3:13].[NH2:16][C:17]1[C:18](=[O:30])[N:19]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:20]([CH3:23])[C:21]=1[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:24]1([N:19]2[C:18](=[O:30])[C:17]([NH:16][C:10]([C:7]3[C:6]([CH3:13])=[C:5](/[CH:4]=[CH:3]/[C:2]([CH3:1])([CH3:15])[CH3:14])[O:9][N:8]=3)=[O:12])=[C:21]([CH3:22])[N:20]2[CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)noc1/C=C/C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1/C=C/C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(E)-5-(3,3-Dimethylbut-1-en-1-yl)-4-methylisoxazole-3-carboxylic acid (102 mg, 0.487 mmol) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (112 mg, 0.536 mmol) in DMF (2 mL) were treated with DIPEA (0.341 mL, 1.950 mmol) and HATU (222 mg, 0.585 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was treated with water and extracted with EtOAc. The combined organic extracts were washed with 0.5 M LiCl (aq), dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]([O:29][CH3:30])=[C:9]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:14]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]([O:29][CH3:30])=[C:9]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:37][CH3:36])[N:22]=3)[CH:14]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(NC(=O)c2ccc(C)c(Oc3ccnc(Cl)n3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1nccc(Oc2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)ccc2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 200 mg N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-(2-chloro-pyrimidin-4-yloxy)-4-methyl-benzamide and 2 ml of a 2 M methylamine solution in tetrahydrofuran is stirred overnight at ambient temperature in a closed microwave glass container. For working up the reaction mixture is diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried on magnesium sulphate and evaporated down. The crude product is chromatographed on a silica gel column with ethyl acetate/cyclohexane (50:50→100:0) as eluant.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH2:1]([NH:11][C:20](=[O:21])[CH:19]=[C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN
Reactant: O=C(Cl)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred solution of 5.89 g. of decylamine in 25 ml. of tetrahydrofuran was added a solution of 4.89 g. of 3-phenyl-3-(4-nitrophenyl)propenoyl chloride in 25 ml. of tetrahydrofuran, dropwise, during 20 minutes, at ice-bath temperature. The solvent was removed by evaporation in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated, and the ethyl acetate layer was washed with water, dried using sodium sulfate, and then evaporated in vacuo. This afforded 5.6 g. of the title compound, m.p. 91°-93° C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[C:12](Cl)=[N:11][C:10]([C:14]#[N:15])=[C:9]([C:16]#[N:17])[N:8]=1.O.Cl>O1CCCC1>[C:1]([NH:5][C:12]1[C:7]([Cl:6])=[N:8][C:9]([C:16]#[N:17])=[C:10]([C:14]#[N:15])[N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: CC(C)(C)N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc(C#N)c(C#N)nc1Cl
Reaction time: 0.5 h

Procedure:
t-Butylamine, 7.3 g (.1 mole), in 50 ml of dry tetrahydrofuran was added dropwise under nitrogen to a solution of 10 g (0.05 mole) of 2,3-dichloro-5,6-dicyanopyrazine in 100 ml of tetrahydrofuran. The rate of addition was controlled so that the reactants did not exotherm to greater than 35° C. When the addition was complete, the reactants were stirred an additional half hour and then poured into 1 l. of water. After adjusting the pH to 1-2 with 10% HCl, the precipitated product was filtered and washed thoroughly with water. Crude product after drying was twice recrystallized from 1-chlorobutane to give light yellow crystals having a mp of 169°-173° C.
Reaction SMILES: [OH-].[Br:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:10]I>CS(C)=O>[Br:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CI
Reactant: Oc1cccnc1Br
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cccnc1Br
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
5.93 g (90.0 mmol) of 85% powdered potassum [sic] hydroxide are suspended in 30 ml of DMSO and heated to 50° C. under argon as the inert gas. 2.54 g (14.6 mmol) of 2-bromo-3-hydroxypyridine dissolved in 10 ml of DMSO are added dropwise to this suspension. This solution is stirred for another 10 minutes, after which 12.3 g (5.30 ml, 33.1 mmol) of methyl iodide are added dropwise over a period of 2 minutes. The addition takes place at such a rate that the reaction temperature is always between 50°-55° C. The reaction [sic] is then stirred at this temperature for another 10 minutes. The finished reaction solution is finally poured onto 100 ml of ground ice. The crude product obtained is recrystallized from ether/petroleum ether (4:1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]3[C:21]=2/[CH:22]=[CH:23]/[O:24]CC)=[CH:5][CH:4]=1)#[N:2]>C1COCC1.O.[Hg](OC(C)=O)OC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]3[C:21]=2[CH2:22][CH:23]=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCO/C=C/c1c(-c2ccc(C#N)cc2)nc2cccc(C(=O)OC)n12
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(CC=O)n12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A stirred solution of (A4) in a mixture of THF/H2O 9:1 (0.2 M) was treated with Hg(OAc)2 (1.5 eq.). After the reaction mixture was stirred at 50° C. for 3 h, freshly prepared sat. aq. KI was added and stirring was continued at RT for 10 min. Then, the reaction mixture was extracted with EtOAc, washed with sat. aq. Na2S2O4 and dried (Na2SO4). Evaporation of the solvent gave methyl 2-(4-cyanophenyl)-3-(2-oxoethyl)imidazo[1,2-a]pyridine-5-carboxylate which was used in the next step without further purification. MS (ES+) C18H13N3O3 requires: 319, found: 320 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(CC#N)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C#N)C(=O)C(F)(F)F)cc1OC
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl trifluoroacetate (1.7 mL, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-4,4,4-trifluoro-3-oxobutanenitrile as a brown oil (0.8 g, 3.4 mmol, 30% yield), MS (EI) for C12H10F3NO3: 274 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][C:27]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1.[CH2:36]=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH:14]([CH2:36][N:30]1[CH2:29][CH2:28][C:27]([OH:33])([CH2:26][C:25]3[CH:24]=[CH:23][C:22]([CH3:21])=[CH:35][CH:34]=3)[CH2:32][CH2:31]1)[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2cc(OCc3ccccc3)ccc21
Reactant: C=O
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(CC2(O)CCN(CC3CCc4cc(OCc5ccccc5)ccc4C3=O)CC2)cc1
Yield: 57.1 %

Procedure:
6-Benzyloxy-1-tetralone (1.26 g, 5 mmol), 4-(4-methyl-benzyl)-piperidin-4-ol hydrochloride (1.20 g, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMF (10 ml) were heated at 70° C. for 17 hr. The crude mixture was partitioned between distilled H2O (150 ml), 25% NH4OH (2 ml) and EtOAc (100 ml). The aqueous phase was further extracted with EtOAc (100 ml) and the combined organic extracts washed twice with satd NaCl solution (100 ml), dried Na2SO4 filtered and evaporated to afford an orange oil. Chromatography over SiO2 (Merck 230-400 mesh) eluting with EtOAc-Et3N (19:1) afforded (RS)-6-benzyloxy-2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-ylmethyl]-3,4-dihydro-2H-naphthalen-1-one as an amber oil (1.34 g, 2.85 ml, 57%), MS m/e=470.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:26][C:27]1[C:35]([Br:36])=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=1)[N:6]2[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[Br:36][C:35]1[C:27]([S:26][C:5]2[N:6]([CH2:11][CH2:12][CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:7]3[C:3]([N:4]=2)=[C:2]([NH2:1])[N:10]=[CH:9][N:8]=3)=[CH:28][C:29]2[O:33][CH2:32][O:31][C:30]=2[CH:34]=1.[F:37][C:38]([F:43])([F:42])[C:39]([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCC1CCNCC1
Product: O=C([O-])C(F)(F)F
Reaction time: 8.5 h

Procedure:
To a solution of tert-Butyl 4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}ethyl)piperidine-1-carboxylate (0.030 g) in DCM (10 mL) was added trifluoroacetic acid (5 mL) at room temperature and stirring was continued at rt for 1-16 h. The solvent and the excess trifluoroacetic acid was evaporated to dryness. The oily residue was co-evaporated with toluene (3×5 mL) to afford title product as a trifluoroacetate salt. 1H NMR (DMSO-d6) δ 8.21 (s, 1H), 7.40 (s, 1H), 6.85 (s, 1H), 6.10 (s, 2H), 4.19 (t, J=7.6 Hz, 2H), 3.25-3.20 (m, 2H), 2.80-2.75 (m, 2H), 1.88-1.85 (m, 2H), 1.68-1.62 (m, 2H), 1.50-1.42 (M, 1H), 1.30-1.24 (m, 2H); LC-MS [M+H]+ 477.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:19]([OH:20])=[N:18][C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[CH:9]=1.[OH:21]OS([O-])=O.[K+].[OH2:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:19]([OH:20])=[N:18][C:11]2[N:12]=[C:13]([S:16]([CH3:17])(=[O:21])=[O:27])[N:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: O=S([O-])OO
Reactant: O
Reactant: CSc1ncc2cc(-c3ccccc3Cl)c(O)nc2n1
Agent: [K+]
Product: CS(=O)(=O)c1ncc2cc(-c3ccccc3Cl)c(O)nc2n1
Reaction time: 5 h
Yield: 83 %

Procedure:
To a solution of 6-(2-chlorophenyl)-2-methylthio-pyrido[2,3-d]pyrimidin-7-ol (25.2 g, 82.9 mmol) was added a slurry of Oxone™ (105 g, 171 mmol) in 200 mL of water. The reaction mixture was stirred for 5 hours, filtered and concentrated in vacuo. The resulting slurry was filtered and the collected solids were successively washed with water four times and dried to give 23.2 g (83%) of 6-(2-chlorophenyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-Ol as a light-yellow solid. Mass spec. MH+=336, mp=215.1-221.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH2:24]([O:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:28])[C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:20]([F:23])([F:22])[F:21])[C:9]=3[CH:17]=2)[CH:34]=1)[CH3:25]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Product: CCOC(=O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (7.5 g) was reacted with 3-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A. The title compound was obtained as a white solid (72% yield). m.p.=174° C., LCMS: m/z=475.95 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.40 (t, 3H), 3.48 (m, 2H), 3.69 (m, 2H), 4.32 (q, 2H), 4.63 (s, 2H), 5.51 (bs, 1H), 6.52 (s, 1H), 7.35 (m, 1H), 7.42 (m, 1H), 7.48 (s, 1H), 7.54 (m, 1H), 7.65 (d, 1H), 7.70 (s, 1H), 7.90 (d, 1H), 8.03 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[F:31][C:22]1[CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][C:16]1[N:17]=[CH:18][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(COc3ccc(S(C)(=O)=O)cc3F)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(OCc2ncn(C3CCNCC3)n2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[3-(2-fluoro-4-methanesulfonyl-phenoxymethyl)-[1,2,4]triazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (see Example 1, 0.249 g, 2.74 mmol) in methanol (10 mL) was treated with 10 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 30 minutes and the solvent was removed in vacuo to afford the desired product as an HCl salt which was used without further purification.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[C:4]([S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH:23]O>CO>[OH:1][NH:2][C:3](=[O:22])[C:4]([S:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:23])([CH3:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OO
Reactant: COc1ccc(SC(C)(Cc2ccccc2)C(=O)NO)cc1
Solvent: CO
Product: COc1ccc(S(=O)C(C)(Cc2ccccc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide (400 mg, 1.26 mmol) (prepared in Example 1) was dissolved in methanol (100 ml) and 30% H2O2 (10 ml) was added. The reaction mixture was stirred for 48 hours at room temperature at which time it was cooled to 0° C. and quenched with saturated Na2SO3 (20 ml) solution. The reaction mixture became cloudy. It was stirred for 4 hours before it was concentrated in a room temperature water bath, diluted with water, extracted with CHCl3 and washed with H2O.The organic layer was dried over MgSO4, filtered and concentrated The tide compound was isolated by silica gel column chromatography, eluting with 75% ethylacetate:hexane. Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M+H)+; lH NMR (300 Mz, CDC13): d 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:17]>CO>[NH2:17][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCCOCn1cc(I)c2c(Cl)ncnc21
Reactant: N
Solvent: CO
Product: Nc1ncnc2c1c(I)cn2COCCO
Temperature: 130 °C

Procedure:
4-Chloro-5-iodo-7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d]-pyrimidine (9b, 0.3 g) was covered with methanol saturated with ammonia (25 mL) and the reaction mixture was heated at 130° C. in a sealed vessel for 10 hours. The solvent was concentrated in vacuo to give a semi-solid mass which was recrystallized from methanol to afford 12, 0.20 g (71.4%), mp 169°-170° C. 1H NMR (DMSO-d6): δ8.7 (s, 1, C2--H), 8.3 (s, 1, C6--H), 5.7 (s, 2, N7--CH2) 4.6 (t, 1, exchangeable with D2O, OH): UVδmax nm (ε×104): (pH 7) 210 (2.0), 280 (0.9); (pH 1) 230 (1.8), 279 (0.9); (pH 11) 228 (0.9), 278 (0.9 ). Anal. Calcd. for C9H11N4O2I; C, 32.43; H, 3.30; N, 16.81. Found: C, 32.49; H, 3.58; N, 16.70.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([NH:32][CH2:33][C:34](O)=[O:35])=O)(C)(C)C.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([Cl:55])(=O)=O)(C)C>N1C=CC=CC=1>[ClH:55].[CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:24][C:34](=[O:35])[CH2:33][NH2:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COCc3ccccc3)O2)cc1F
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: c1ccncc1
Product: Cl
Product: NCC(=O)O[C@H]1C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1COCc1ccccc1

Procedure:
To a solution of 1.00 g of 5'-O-benzyl-2'-deoxy-5-fluorouridine in 30 ml of anhydrous pyridine were added 0.78 g of N-(t-butoxycarbonyl)glycine and 1.80 g of 2,4,6-triisopropylbenzenesulfonyl chloride, and the mixture was subjected to reaction at room temperature overnight.
Reaction SMILES: BrCC1C=C2C(=CC=1)C1=N[O:11][C:12](C3C([C:18]([F:21])([F:20])[F:19])=C(C4C=CC=CC=4)ON=3)=C1CC2.N1CC[O:34]CC1CO.C(N(CC)CC)C.CN([CH:49]=[O:50])C>C(OCC)(=O)C>[OH:34][C:49]([C:18]([F:21])([F:20])[F:19])=[O:50].[CH3:12][OH:11]
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(CBr)ccc2-3)noc1-c1ccccc1
Reactant: CN(C)C=O
Reactant: OCC1COCCN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CO
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (6C, 0.025 g, 0.053 mmol), morpholin-3-ylmethanol (6.16 mg, 0.053 mmol) and triethylamine (7.33 mL, 0.053 mmol) in DMF (3.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (3×1.0 mL). The ethyl acetate extract was concentrated, and the residue was chromatographed using reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 Nm) to give 4-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)morpholino-3-yl)methanol TFA [0.013 g, 0.500 mmol, 50%] as a viscous tan film. The product had an HPLC ret. time=4.02 min. (condition B). LC/MS M+1=512.1. 1H NMR (400 MHz, CD3OD) δ ppm 7.97-8.14 (1H, m), 7.78 (2H, d, J=7.48 Hz), 7.44-7.73 (5H, m), 4.20 (2H, br. s.), 3.76 (6H, br. s.), and 2.96-3.25 (7H, m).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([CH2:25][S:26][CH3:27])[CH:24]=1)[NH:21][CH:20]=[CH:19]2.FC(F)(F)C(O)=O.[Cl-].[NH4+]>ClCCl>[CH:1]1([C:4]2([C:19]3[C:18]4[C:22](=[C:23]([CH2:25][S:26][CH3:27])[CH:24]=[C:16]([F:15])[CH:17]=4)[NH:21][CH:20]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Reactant: OC1(C2CC2)CCc2cc(F)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
633 mg (2.47 mmol) of the compound from Example 76A with a purity of 75% and 530 mg (2.71 mmol) of the compound from Example 11A were introduced into 12 ml of dichloromethane at 0° C., 0.23 ml (2.96 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 0° C. for 4 h. It was diluted with dichloromethane and added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 570 mg (63% of theory) of the title compound.