Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][CH:31]([CH3:33])[CH3:32])[C:5]=1[O:21][CH3:22]
Reactant: CC(C)CBr
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCC(C)C
Temperature: 80 °C
Yield: 42.5 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (104 mg, 0.75 mmol) and isobutyl bromide (102 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (40 mg, 43%).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[C:26]([CH3:33])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:32]2)=[C:26]([CH3:33])[CH:25]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1cc(Cl)ccc1N=C=S
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(Cl)ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Chloro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-Chloro-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-chloro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:22][S-:23].[Na+]>O1CCCC1>[CH3:22][S:23][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: C[S-]
Reactant: O=C(O)c1c(CBr)c(-c2ccccc2)nc2ccccc12
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 3-(Bromomethyl)-2-phenylquinoline-4-carboxylic acid (650 mg, 1.9 mmol) in tetrahydrofuran (40 mL) was added sodium methanethiolate (400 mg, 5.7 mmol). The mixture was stirred overnight, concentrated, diluted with pH 4 buffer (40 mL) and ethyl acetate (40 mL), and extracted. The organic phase was dried (MgSO4), and concentrated to afford the desired product as a brown oil which was used without purification.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[K+].C(OCC)(=O)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH2:25]([O:24][C:22]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 2.5 h

Procedure:
4-Piperidone hydrochloride hydrate (50.0 g, 325 mmol) and potassium bicarbonate (181.9 g, 1.82 mol) were combined in a two phase mixture of ethyl acetate (750 mL) and water (75 mL). Benzyl chloroformate (49 mL, 343 mmol) was added dropwise to the stirred mixture over 10 minutes. The mixture was stirred 2.5 hours, then it was diluted with water (700 mL) and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated to a light yellow oil (76.75 g, 100%). The material was found to be analytically pure and suitable for further transformation without further workup. Analysis calculated for C13H15NO3 : C, 66.94; H, 6.48; N, 6.00. Found: C, 66.67; H, 6.48; N, 5.90.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Cl:29][Sn]Cl.C(O)C.Cl>O>[ClH:29].[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Sn]Cl
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc([N+](=O)[O-])cc3)nc(=O)c1-2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(N)cc3)nc(=O)c1-2
Yield: 60.6 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-6-(4-nitrophenyl)pyrazolo[3,4-d]pyrimidin-4-one (1.38 g, 3.9 mmol), SnCl2.2H2O (2.64 g, 11.72 mmol), ethanol (24 ml) and water (10 ml) was added concentrated HCl (14.5 ml). The reaction mixture was refluxed for 2 hours, cooled, and the product was collected by filtration and dried in vacuo to afford 0.85 g (67%) of 1-cyclopentyl-3-ethyl-6-(4-aminophenyl)pyrazolo[3,4-d]pyrimidin-4-one hydrochloride 1/3 hydrate, m.p. 279° C. (dec.).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 235.6 %

Procedure:
3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (17.3 g, 66.33 mmol) was suspended in tetrahydrofuran (800 mL) and a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (20 g, 99.5 mmol) in tetrahydrofuran (300 mL) and triphenylphosphine (34.8 g, 132.66 mmol) were added The reaction mixture was cooled to 0° C. and diethyl azodicarboxylate (23.1 g, 132.66 mmol) was added dropwise. After 2 hours at room temperature, the reaction was concentrated under reduced pressure to yield crude tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate as an orange oil (69.44 g). HPLC-RT: 14.29 min., 19%, (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 Å, 5μm, 150×3.9 mm column).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li][CH2:16]CCC.CI>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH3:16])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1cccc(-n2c(C)ccc2C)n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cccc(-n2c(C)ccc2C)n1
Temperature: -30 °C
Yield: 60 %

Procedure:
To a solution of the product from Example 2a (6.82 g, 36.6 mmol) in 75 mL of dry THF cooled to 40° C. under a N2 atmosphere was added dropwise n-BuLi as a 2.5M solution in hexanes (16 mL, 40 mmol). The resulting solution was stirred at low temperature for thirty minutes then treated with CH3I (2.4 mL, 38.6 mmol). On completion of the addition the mixture was allowed to warm to −30° C. and after 20 min to room temperature. The reaction was subsequently quenched by pouring into brine solution, the product isolated by extraction with EtOAc. Dried over MgSO4, filtered and concentration under vacuum. Purified by silica gel column chromatography eluting with EtOAc/hexane gave the title compound (4.42 g, 60%).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][NH2:13].CO>C(Cl)(Cl)Cl.Cl>[CH2:1]([NH:8][C:9](=[O:10])[N:12]([CH3:11])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNN
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(N)C(=O)NCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of Benzyl isocyanate (1.85 mL, 15.0 mmol) in 7.5 mL of CHCl3 was treated with methyl hydrazine (795 μL, 15.0 mmol) at 0° C. and stirred at the same temperature for 2 h. The resulting mixture was dissolved in 1N HCl (200 mL) and the solution was washed with CHCl3 (50 mL×3). The aqueous phase was adjusted to pH 12 with 2 M NaOHaq and then extracted with CHCl3 (100 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from hexane-CHCl3 to afford (1.7 g, 9.5 mmol, 63%) as a colorless crystal. Rf=0.44 (CHCl3:MeOH=9:1); 1H NMR (400 MHz, DMSO-d6) δ 7.28-7.19 (5H, m), 4.47 (2H, s), 4.20 (2H, d, J=6.3 Hz), 2.96 (3H, s); 13C NMR (99.5 MHz, DMSO-d6) δ 159.3, 141.1, 128.1, 127.1, 126.5, 43.1, 37.8; LC/MS [ESI+] (m/z) 180.3 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[C:23](=O)([O-])[O-:24].[K+].[K+].C(OCC)(=O)C>C(O)=O>[CH:23]([NH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)=[O:24]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(CN)nc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(CNC=O)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a stirred solution of methyl 3-(6-(aminomethyl)pyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.24 g, 0.80 mmol) in formic acid (3 mL) was added potassium carbonate (0.2 g) portionwise. The reaction mixture was stirred at 90° C. overnight under argon and then concentrated. The residue was made basic with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were dried (Na2SO4) and concentrated. Silica gel flash chromatography (20-100% ethyl acetate in hexanes) gave methyl 3-(6-(formamidomethyl)pyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.19 g, 0.58 mmol, 73% yield) as a solid. MS found: (M+H)+=327.35.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[CH3:22].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>CCOC(C)=O>[CH2:21]([O:23][C:24](=[O:37])[C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:32][CH2:33][N:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=4)=[CH:14][N:15]=3)[CH2:35][CH2:36]2)=[CH:29][CH:30]=1)[CH3:22]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Cl)nc2)c1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester was prepared from N-(3-tert-butyl-phenyl)-6-chloro-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. The product was isolated after silica gel column chromatography with 20-50% EtOAc in hexanes gradient. HRMS m/z calcd for C29H34N4O3 [M+H]+: 487.2704. Found: 487.2701.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:31])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[N:17]([CH3:31])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.84 ppm (d, 1H), 7.37 ppm (d, 1H), 6.38 ppm (s, 1H), 5.25 ppm (m, 1H), 3.57 ppm (d, 3H), 1,36 ppm (d, 6H),
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:42])=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH:23]=2)[CH:21]=1.CCN(CC)CC>C(Cl)Cl>[CH3:41][C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:24]2[CH:23]=[C:22]([C:20]3[C:19]([F:42])=[CH:18][CH:17]=[C:16]([CH2:15][NH:14][S:2]([C:5]4[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=4)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH:21]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31]1)=[O:36])([CH3:39])[CH3:40]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNS(=O)(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of 3-(chlorosulfonyl)benzoic acid (0.0331 g, 0.15 mmol) in DCM (1.5 mL) was added 1,1-dimethylethyl 4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.060 g, 0.15 mmol), and Et3N (0.0211 mL, 0.15 mmol). The resulting mixture was stirred at room temperature for 1 h before it was concentrated and purified using a Gilson HPLC to afford the title compound 0.0374 g (43%). LC-MS m/z 584 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:18][C:19]([S@@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)/[CH:5]=[N:24]/[S@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1c(F)ccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C/c1c(F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a stirred suspension of 3-chloro-2,6-difluorobenzaldehyde (0.615 g, 3.48 mmol) and Cs2CO3 (1.702 g, 5.23 mmol) in DCM (20 mL) was added a solution of (S)-2-methylpropane-2-sulfinamide (0.422 g, 3.48 mmol) in DCM (20 mL) dropwise for 10 min. The solution was then stirred at rt overnight. After overnight stirring, the reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product (0.98 g, 100%) as yellow oil. MS (ESI) m/z: 282.0 (M+H)+.
Reaction SMILES: CS([CH:5]([OH:20])[C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=O)=O.[C:21]([O-])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+].O>CN(C=O)C>[C:21]([CH:5]([OH:20])[C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])c1ccccc1
Reactant: Cc1cn([C@H]2C=C[C@@H](C(O)S(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C=C[C@@H](C(O)C(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of 5'-mesyl-d4T (6, 0.4 g) in 6 ml of DMF was added powdered sodium benzoate (0.24 g). The reaction was stirred at 100° C. for 6 hours. After cooling, water (30 ml) was added. The resulting precipitate was filtered, washed with 2×5 ml water and dried to give 5'-benzoly-d4T (7'), 0.04 g (91%).
Reaction SMILES: Cl.[N+:2]([O-:11])([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:3].C(N(CC)CC)C.[C:19](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:20][C@@H:21]1[CH2:25][O:24][C@@H:23]2[C@H:26]([OH:29])[CH2:27][O:28][C@H:22]12>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N+:2]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:19]([O:20][C@@H:21]2[CH2:25][O:24][C@@H:23]3[C@H:26]([OH:29])[CH2:27][O:28][C@H:22]23)=[O:30])[CH2:7][CH2:6]1)([O-:11])=[O:3]
Reactant: O=[N+]([O-])OC1CCNCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)N1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of piperidin-4-yl nitrate hydrochloride (0.620 g, 3.40 mmol), triethylamine (0.567 ml, 4.07 mmol) and 4-dimethylaminopyridine (0.083 g, 0.680 mmol) in DCM (23 ml), (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-nitrophenyl carbonate (1.06 g, 3.40 mmol) was added; the mixture was stirred at room temperature for 18 hrs. Then the mixture was diluted with DCM and washed with a 5% solution of sodium dihydrogen phosphate (2×30 ml) and brine (1×30 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 30 to 100%), affording the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[OH-].[K+].C1C(=O)N([Br:27])C(=O)C1.O>CN(C=O)C>[Br:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH:10]=2)[NH:14][N:13]=1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(Br)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of 5-(2,6-difluoro-phenyl)-1H-indazole (1 g, 4.35 mmol) in DMF (13 ml) were added KOH (488 mg, 8.7 mmol) and NBS (1.15 g, 6.48 mmol) at RT. The reaction mixture was stirred for 2 h at RT. Water was added to the reaction mixture and extracted with EtOAc (2×20 ml). Combined organic layers were washed with brine and dried over Na2SO4. The organic layer was concentrated and purified by column using silica (100-200 mesh) and 0-15 EtOAc-hexane to provide 3-bromo-5-(2,6-difluoro-phenyl)-1H-indazole (600 mg, 45% yield). MS (ESI, pos. ion) m/z: 306.9 (M−1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Br:14][C:15]1[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[C:18]([Br:27])[C:16]=1[NH2:17]>C(#N)C>[CH3:1][C:2]1[S:3][C:4]([C:11]([NH:17][C:16]2[C:18]([Br:27])=[CH:19][C:20]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:21][C:15]=2[Br:14])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: Nc1c(Br)cc(OC(F)(F)F)cc1Br
Reactant: Cc1nc(C(F)(F)F)c(C(=O)Cl)s1
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)c(C(=O)Nc2c(Br)cc(OC(F)(F)F)cc2Br)s1
Yield: 98.9 %

Procedure:
2-Methyl-4-trifluoromethyl-5-chlorocarbonyl thiazole 6.47 g and 2,6-dibromo-4-trifluoromethoxy aniline 8.91 g were added in acetonitrile 16.8 ml, and they were heated to reflux for 6.5 hours. Solvent was removed from the reaction mixture by distillation under a reduced pressure, and then ethyl acetate 420 ml and water 300 ml were added and they were agitated. After standing calmly, the ethyl acetate layer was collected, and washed with water, saturated sodium bicarbonate solution, and water (300 ml each) in succession. Then, after drying over anhydrous sodium sulfate, solvent was removed by distillation under a reduced pressure, to obtain thifluzamide 13.9 g.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[O:13][CH2:14][O:15][CH3:16].[Li]CCCC.[I:22]I>C1COCC1.CC(OC)(C)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[C:4]([I:22])[C:3]=1[O:13][CH2:14][O:15][CH3:16]
Reactant: II
Reactant: COCOc1cc2c(c(F)c1F)OCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COCOc1c(F)c(F)c2c(c1I)CCCO2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
16.6 g (72.1 mmol) of 7,8-difluoro-6-methoxymethoxychroman are initially introduced in 350 ml of THF, and 54.3 ml (86.5 mmol) of n-BuLi (15% soln. in hexane) are added dropwise at −78° C. When the addition is complete, the mixture is stirred at this temperature for 30 min and subsequently at 20° C. for 1 h. The solution is re-cooled to −78° C., and a solution of 22.0 g (86.5 mol) of iodine in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 1.5 h and subsequently diluted with MTBE. The solution is washed with water and sat. sodium chloride soln. and dried using sodium sulfate. The crude product remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=2:1), giving 7,8-difluoro-5-iodo-6-methoxymethoxychroman as a brownish oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.Cl[CH2:22][C:23]([NH:25][CH3:26])=[O:24]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:22][C:23]([NH:25][CH3:26])=[O:24])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: CNC(=O)CCl
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CNC(=O)CN1CCC2=C(C1)c1c(O)cc(C(C)C)cc1OC2(C)C

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-8-isopropyl-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N-methylacetamide according to the method of Example 1; m.p. 178-190°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=[CH:12][C:11]=2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:8])=[CH:5][CH:4]=1.[OH:32]O>C(Cl)Cl>[C:25]([O:24][C:23]([NH:22][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[CH:17]=[CH:18][N+:19]([O-:32])=[CH:20][CH:21]=2)=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccncc3)ccc2NC(=O)OC(C)(C)C)cc1
Reactant: OO
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3cc[n+]([O-])cc3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A solution of compound 461 (0.55 g, 1.31 mmol) and ReO3Me (33 mg, 0.13 mmol) in DCM (10 mL) was stirred 5 min, 35% H2O2 (0.14 mL, 1.53 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with water, and AcOEt was added. The white precipitate was filtered and washed with AcOEt and MeOH (5 mL) to afford the title compound 462 (350 mg, 61%) as a white solid.