Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[H-].[Na+]>C1COCC1>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:15]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[N:11]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)c1ccc(-c2csc(NCc3cccs3)n2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2csc(N(CC(=O)OC(C)(C)C)Cc3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a THF solution of [4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amine (80 mg, 0.25 mmol) and tert-butyl bromoacetate (41 μL, 0.28 mmol) was added NaH (15 mg, 60%, 0.38 mmol) and the resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with brine and extracted with ethyl acetate (3×5 mL). Combined ethyl acetate extracts were dried over sodium sulfate, concentrated and purified on silica gel column to afford 2-{thiophen-2-ylmethyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}acetic acid tert-butyl ester (75 mg). LCMS m/z: 430 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[N:3]=1.[H][H]>[Pd].C(O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(Nc2ccc(Sc3ccncc3)c(F)c2)cc(-c2cccc([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(-c2cc(Nc3ccc(Sc4ccncc4)c(F)c3)nc(N)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
A dry flask under argon was charged with 10% palladium on carbon (20 mg). A solution of N-[2-amino-6-(3-nitrophenyl)-4-pyrimidinyl]-N-[3-fluoro-4-(4-pyridinylsulfanyl)phenyl]amine (Example 20, 200 mg, 0.46 mmol) in ethanol (12 mL) and EtOAc (1 mL) was added via syringe through a septa to the palladium on carbon. The flask was then fitted with a hydrogen balloon and stirred at room temperature for 48 h. At this time the palladium was filtered through a pad of Celite®. The filtrate was coated on silica and purified on the MPLC (Biotage) with 2-8% MeOH in CH2Cl2 to afford the desired product as a solid (120 mg, 64%). TLC (6% MeOH in CH2Cl2) Rf0.26; MS (ES) 405 [M+H]+; 1H-NMR (DMSO-d6) δ 5.22 (bs, 2H), 6.45 (s, 1H), 6.49 (bs, 2H) 6.62-6.65 (m, 1H), 6.98 (d, J=6.4 Hz, 2H), 7.02-7.16 (m, 3H), 7.43-7.55 (m, 2H), 8.30-8.35 (m, 3H), 9.75 (bs, 1H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=[CH:16]4)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:32]([O:34][CH3:35])=[O:33].O>O1CCOCC1>[C:23]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:12]=[CH:11][C:7]1[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=1)[CH2:1][N:2]([C:32]([O:34][CH3:35])=[O:33])[CH2:3][CH2:4]3)[CH:22]=[CH:21]2)#[N:24]
Reactant: N#Cc1ccc2cc(C=Cc3ccc4c(c3)CCNC4)ccc2c1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N1CCc2cc(C=Cc3ccc4cc(C#N)ccc4c3)ccc2C1
Reaction time: 16 h

Procedure:
A solution of Example 42J (650 mg, 1.53 mmol) in dioxane (30 mL) at room temperature was treated with 10% K2CO3 (10 mL) and methyl chloroformate (700 mg) and stirred for 16 hours. The mixture was treated with water and extracted with dichloromethane. The combined extracts were washed sequentially with 5% HCl, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([N:19]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:27](=[O:29])[CH3:28])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(NCc3ccccc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccccc1)c1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine prepared in accordance with Example A-303 (0.15 g, 0.00043 mol), DMAP (0.027 g, 0.00022 mol) and acetic anhydride (0.066 g, 0.00066 mol) in 10 mL of THF was added triethylamine (0.053 g, 0.00052 mol). The solution was stirred at room temperature overnight. After the removal of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was triturated with ether to give 0.1 g of product, N-[4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)acetamide, as a white solid (60% yield), mp: 176-178° C.; Anal. Calc'd for C22H18FN5: C, 68.21; H, 4.68; N, 18.08. Found: C, 67.67; H, 4.85; N, 17.79.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[C:14]([NH:16][C:17](SC)=[N:18][CH3:19])#[N:15]>>[C:14]([NH:16][C:17]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:7]1[O:8][C:4]([CH2:3][NH:2][CH3:1])=[CH:5][CH:6]=1)=[N:18][CH3:19])#[N:15]
Reactant: CN=C(NC#N)SC
Reactant: CNCc1ccc(CSCCN)o1
Product: CN=C(NC#N)NCCSCc1ccc(CNC)o1
Yield: 38.6 %

Procedure:
A mixture of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.0 g) and N-cyano-N'-methylcarbamimido-thioic acid, methyl ester (1.25 g) was heated on a steam bath for 6.5 hr. Vacuum was applied at regular intervals to remove methanethiol. The crude product was purified by column chromatography Rf 0.65 (silica/methanol:ammonia 79:1) to give N-cyano-N'-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine (1.05 g) m.p. 81°-85°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][N:7]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=C(NCCc1ccccc1)c1ccc(F)c(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(C2=NCCc3ccccc32)cc1F
Temperature: 25 °C

Procedure:
To a 250-mL round-bottomed flask, 3,4-difluoro-N-phenethylbenzamide (1.97 g, 7.54 mmol) and phosphorus pentoxide (3.25 g, 22.9 mmol) were suspended into 40 mL of toluene. Phosphorus oxychloride (3.51 mL, 37.7 mmol) was added and the mixture was refluxed for overnight. The mixture was cooled to RT. The supernatant contained only the starting material and was removed. Ice water (75 mL) was added to the residue in the flask and stirred to break up the solid into powder. EtOAc was added and the pH was adjusted to ˜12 with 3N aqueous potassium hydroxide. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow viscous oil. The crude product was purified by silica gel chromatography (20-70% EtOAc in hexanes) to afford the title compound as a clear oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.17-7.52 (m, 7H) 3.78-3.92 (m, 2H) 2.73-2.89 (m, 2H)
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].S(O)(O)(=O)=O.[NH2:17]O>O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:17]=1
Reactant: NO
Reactant: CC(C)(C)C(=O)CC#N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Reaction time: 0.05 h
Yield: 124.7 %

Procedure:
To a suspension of pivaloylacetonitrile (1.252 g) and 86% potassium hydroxide (0.717 g) in water (20 ml) is added hydroxylamine sulfate (0.903 g) at 25° C. and the mixture is stirred for 3 minutes. pH 8.30. The reaction mixture is treated as in Example 2 to give 3-amino-5-t-butylisoxazole (1.204 g). Yield, 85.9%. Purity, 95.8%.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[CH:28]=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:31].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[CH:28]=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:31])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Sc1cccc2nccn12
Reactant: O=c1cc2n(c(=O)n1CCCCCl)CCCS2(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc2n(c(=O)n1CCCCSc1cccc3nccn13)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.053 g (2.2 mmol) of 60% oily sodium hydride in 15 ml of N,N-dimethylformamide, 0.33 g (2.2 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 0.61 g (2.0 mmol) of 7-(4-chlorobutyl)-1,1-dioxo-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.33 g (2.2 mmol) of sodium iodide were added, followed by stirring at 100° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by recrystallization (solvent, chloroform/diethyl ether) to yield 0.442 g (52.6%, light green powder) of the desired product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([F:11])[C:7]([O:9][CH3:10])=[O:8].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C@@H:2]2[CH2:6][CH2:5][CH2:4][C@:3]2([F:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@@]1(F)CCC[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl (1R,2R)-2-amino-1-fluorocyclopentanecarboxylate (0.47 g, 2.4 mmol, 1 eq) in CH2Cl2 (10 mL) was added 4-benzyloxy-benzenesulfonyl chloride followed by saturated sodium bicarbonate (10 mL). The reaction was stirred overnight, and then taken up in ethyl acetate. The organics were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified using silica chromatography eluting with 30% ethyl acetate/hexanes to afford methyl (1R,2R)-2-({[4-(benzyloxy)phenyl]sulfonyl}amino)-1-fluorocyclopentanecarboxylate as an off white solid (0.575 g, 60%). MS: 408.1 (M+H)+.
Reaction SMILES: ClCC1N=NC=CC=1.C(N)CN.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][CH2:21][CH2:22][NH2:23])[N:14]=1.[CH3:24][N:25]=[C:26]=[S:27]>>[CH3:24][NH:25][C:26]([NH:23][CH2:22][CH2:21][NH:20][CH2:19][C:15]1[N:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[S:27]
Reactant: CN=C=S
Reactant: NCCNCc1cccnn1
Agent: ClCc1cccnn1
Solvent: NCCN
Product: CNC(=S)NCCNCc1cccnn1

Procedure:
Reacting 3-chloromethylpyridazine with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(3-pyridazinylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b), then chromatographing gives N-methyl-N'-[2-(3-pyridazinylmethylamino)ethyl]thiourea. This intermediate is reacted with lead cyanamide by the procedure of Example 3(b) to give N-cyano-N'-methyl-N"-[2-(3-pyridazinylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2-(3-pyridazinylmethylamino)ethyl]guanidine dihydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]([O:15][CH3:16])=[O:14])=[S:10])=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:22]([O:21][C:17](=[O:20])[CH2:18][CH2:19][S:10][C:9](=[N:11][NH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: COC(=O)NNC(=S)Cc1ccc(C)cc1
Reactant: C=CC(=O)OCC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCSC(Cc1ccc(C)cc1)=NNC(=O)OC

Procedure:
A mixture of 30 g of 2-[2-(4-methylphenyl)-1-thioxoethyl]hydrazinecarboxylic acid, methyl ester, 25 g of ethyl acrylate, 500 μl of triethylamine and 250 ml of benzene was heated at reflux for 24 hours, cooled and concentrated in vacuo. The resulting oil was purified by dry column chromatography on silica gel, eluting with dichloromethane. The desired fractions were collected and evaporated, giving [1-[(3-ethoxy-3-oxopropyl)thio]-2-(4-methylphenyl)ethylidene]hydrazinecarboxylic acid, methyl ester as an oil.
Reaction SMILES: C(Cl)(Cl)Cl.Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:8].[C:19]1([CH:25]2[CH2:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:32][C:27]1[CH2:26][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:30][C:29](=[O:31])[C:28]=1[CH2:6][C:7](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccccc2)CC(O)=C1CC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
To a chloroform solution (2 mL) of 2-bromo-3′-trifluoromethylacetophenone (534.1 mg, 2 mmol) and 5-phenyl-1,3-cyclohexanedione (376.5 mg, 2 mmol) was added potassium carbonate (276.4 mg, 2 mmol) and stirred under suspension at room temperature over night. The reaction liquid was added with ethyl acetate (5 mL), to filter off undissolved substance, followed by concentration of thus obtained organic layer under reduced pressure and purification of concentrated residue using silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain a crude product, which was further purified by suspension (hexane 1 ml/ethyl acetate about 0.2 ml) to obtain an objective compound (257.8 mg, 35.0%).
Reaction SMILES: C([O:3][C:4](=O)[C@:5]([O:11][CH2:12][C:13]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([Br:35])[N:29]=1)([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.CO.[NH3:39]>>[Br:35][C:30]1[N:29]=[C:28]([C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:9])([F:8])[F:7])[C:4]([NH2:39])=[O:3])[C:33]([F:34])=[CH:32][CH:31]=1
Reactant: CCOC(=O)[C@@](C)(OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1nc(Br)ccc1F)C(F)(F)F
Reactant: N
Solvent: CO
Product: CC(CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1nc(Br)ccc1F
Yield: 73 %

Procedure:
A solution of (R)-2-[2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (720 mg, 1.195 mmol) in NH3 7N in methanol (19 ml, 133 mmol) was stirred at 50° C. for 2 days in a sealed 25 ml microwave vial. The solvent was removed in vacuo and the residue (987 mg) was chromatographed over silica gel (cyclohexane/ethyl acetate) affording the title compound as a mixture of two diastereoisomers (500 mg, 73% yield). TLC (cyclohexane/ethyl acetate 1:1) Rf=0.30; LC-MS RtH5=1.05 min (ES+ 573, 575).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:26])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:14]=1)[C:9](O)=[O:10].[CH2:27]([O:29][C:30](=[O:39])[CH2:31][S:32][C:33]1[S:37][C:36]([NH2:38])=[N:35][CH:34]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:39])[CH2:31][S:32][C:33]1[S:37][C:36]([NH:38][C:9](=[O:10])[C:8]2[CH:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:26])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:35][CH:34]=1)[CH3:28]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(C(F)(F)F)cc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-((S)-2-methoxy-1-methyl-ethoxy)-5-(4-trifluoromethyl-phenoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [CH:1]([N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3([CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][CH2:17]3)[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)n1ncc2c1-c1ccccc1OC21CCNCC1
Yield: 101.8 %

Procedure:
Benzyl 1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.1 g, 2.6 mmol) was stirred in methanol (14.4 mL) with Pd/C (140.3 mg, 0.1318 mmol) under a balloon of hydrogen for 16 h. The reaction was filtered through a syringe filter and the solvent evaporated to give 1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (750 mg, 100%). ESI-MS m/z calc. 283.2. found 284.3 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: BrC1C2OCCNC=2C=C(C)C=1.[Br:13][C:14]1[C:24]2[O:23][CH2:22][CH2:21][CH2:20][NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([S:31]([N:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:13])[C:24]=3[O:23][CH2:22][CH2:21][CH2:20]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Brc1cccc2c1OCCCN2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cc1cc(Br)c2c(c1)NCCO2
Product: O=S(=O)(c1ccccc1)N1CCCOc2c(Br)cccc21

Procedure:
In another variation of the above procedure, 8-bromo-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine was replaced with 4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (obtained by reduction of 4-bromo-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one, which in turn was prepared by reaction of 2-amino-6-bromophenol with 3-chloropropionyl chloride as described by Combs et al.; J. Med. Chem.; 33; 380-386 1990). Reaction of 4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene with benzenesulfonyl chloride yielded 9-benzenesulfonyl-4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as a white solid, MS: M+=336. Method A: Synthesis of 4-(4-chloro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine
Reaction SMILES: [H-].[Na+].O1C[CH2:6][CH2:5][CH2:4]1.[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][N:21]=2)=[CH:16][CH:15]=1.C(Br)CC>O>[CH2:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][N:21]=2)=[CH:18][CH:19]=1)[CH2:5][CH3:6]
Reactant: C1CCOC1
Reactant: CCOc1cnc(-c2ccc(CCCCCO)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCBr
Product: CCCOCCCCCc1ccc(-c2ncc(OCC)cn2)cc1
Reaction time: 5 h

Procedure:
A mixture of 1.2 g of sodium hydride (60-65 wt. %) and 150 ml of tetrahydrofuran was treated with 8.5 g of 2-[4-(5-hydroxy-1-pentyl)phenyl]-5-(ethoxy)pyrimidine while gassing with nitrogen, stirred for 5 hours, treated with 4 g of propyl bromide and subsequently stirred at room temperature overnight. The reaction mixture was treated with 500 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 500 ml of concentrated sodium chloride solution each time, dried over magnesium sulfate, filtered and subsequently concentrated. Chromato- graphy of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) and recrystallization from ethyl alcohol gave 7.5 g of pure 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-(ethoxy)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH3:27])[C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:28]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH3:27])[C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:4][CH:3]=1
Reactant: OO
Reactant: Cc1cc(OCCCCSc2ccc(Cl)cc2)cc2c1NC(=O)OC2(C)C
Product: Cc1cc(OCCCCS(=O)c2ccc(Cl)cc2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-chloro-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C@H:12]([NH:14][C:15]1[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=[C:31](Br)[N:32]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH3:13].[CH2:34]([NH2:36])[CH3:35]>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C@H:12]([NH:14][C:15]1[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=[C:31]([NH:36][CH2:34][CH3:35])[N:32]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH3:13]
Reactant: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Br)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCN
Solvent: C1COCCO1
Product: CCNc1nc(N[C@H](C)CSc2nc3ccccc3s2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The title compound was prepared according to general method B by reaction of N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-bromoadenosine (Example 7) (0.24 g, 0.35 mmol) with 70% w/w aqueous ethylamine (0.23 g) in dioxan (10 ml) in a sealed vessel at 100° C. to provide the desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-(ethylamino)adenosine as a foam (following column chromatography), 1H NMR (DMSO-d6) δ1.04 (3H, br t, --NCH2CH3), 1.42 (3H, d, --CHCH3), 3.20 (3H, br m, --NCH2CH3), 3.55-3.80 (4H, m, H-5'a and H-5'b and --CH2 --), 3.95 (1H, q, H-4'), 4.15 (1H, q, H-3'), 5.16, 5.41 (2H, 2d, 2'- and 3'-OH), 5.79 (1H, d, H-1'), 6.22 (1H, t, --NHCH2CH3), 7.43, 7.54 (2H, 2 t, Ar--H), 7.98 (1H, s, H-8). HPLC retention time 17.0 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)Cl>[Br:17][CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
To a solution of 1-[4-(4-bromophenyl)phenyl]ethanone (5 g, 18.17 mmol) in CH2Cl2 (40 mL) is added bromine (983 μL, 19 mmol). The resulting mixture is stirred for 48 hours at room temperature. The mixture is diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate and concentrated. The crude solid is triturated with ether to give 2-bromo-1-[4-(4-bromophenyl)phenyl]ethanone (5.7 g, 88.6%) as a white solid.