Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12C(=O)CC[C@H:15]1[C@H:14]1[C@@H:5](C3C(CC1)=CC(O)=C(OC)C=3)[CH2:4][CH2:3]2.[C:23]([O-:26])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:26][CH2:23][C:2]1[CH:15]=[CH:14][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:14][CH:15]=1
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 379.6 %

Procedure:
The 2-Methoxy estrone (0.521 g, 0.00173 mol) was dissolved in anhydrous DMF under nitrogen atmosphere, added K2CO3 (0.718 g, 0.00225 mol) and stirred at r.t. for approximately 40 h. The crude mixture was diluted with EtOAc, washed with water and brine. The organics were dried (MgSO4) and concentrated. The crude product was pre-absorbed onto silica gel, purified using Flash Master-2 system to give the benzylated compound 32 (0.651 g, 96%) as a chalky white solid: TLC (Rt, 0.4, EtOAc:Hexane, 3:7); 1H NMR (270 MHz, CDCl3) δ 0.90 (s, 3H, 18-CH3 diastereomeric methyl signals), 1.24-1.27 (t, J=3.4 Hz, 3H, CH2—CH3), 1.24-1.29 (t, J=7.1 Hz, 3H, CH2—CH3), 1.39-2.44 (broad m, 12H), 2.44-2.54 (dd, J=18.8 and 8.6 Hz, 1H), 2.77-2.83 (m, 2H), 3.84-3.87 (s, 3H, OMe), 5.0 (s, 2H, PhCH2), 6.6 (s, 1H, aromatic), 6.77 (s, 1H, aromatic), 3.87-3.84 (s, 3H, OMe), 4.10-4.16 (q, J=7.0 Hz, 2H, CH3—CH2—O), 5.09 (s, 2H, CH2-phenyl), 6.61 (s, 1H, 4-CH), 6.82 (s, 1H, aromatic 1-CH), 7.41-7.43 (m, 5H).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].C(Cl)Cl>CO.[Fe]>[CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(I)c2oc(C3CC3)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(I)c2oc(C3CC3)cc2c1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a solution of the title compound from Step 1 (2.0 g, 6.0 mmol) and Fe (1.0 g, 18 mmol) in MeOH (80 mL) was added sat. NH4Cl solution (10 mL). The reaction mixture was refluxed for 1 h. The mixture was cooled to room temperature and poured into 400 mL of DCM. The resulting mixture was filtered and the filtrate was washed with water (100 mL) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (1.5 g, 83% yield) as red oil that was used for the next step directly. 1H NMR (CDCl3, 400 MHz): δ 6.87 (d, J=2.4 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.19 (s, 1H), 3.45 (br, 2H), 1.97-1.90 (m, 1H), 0.95-0.85 (m, 4H). LCMS: 300 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 12.8 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (100 mg, 0.26 mmol) was reacted with 3-methoxy phenyl boronic acid (48 mg, 0.32 mmol) to give the title compound (15 mg, 10%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[N:24][OH:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)c2ncc(C(F)(F)F)cc2Cl)cc1Br
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2ncc(C(F)(F)F)cc2Cl)cc1Br
Yield: 97.7 %

Procedure:
A solution of (3-bromo-4-methoxyphenyl)[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methanone (8.90 g, 22.5 mmol) and hydroxylamine hydrochloride (3.92 g, 56.3 mmol) in pyridine (60 mL) was stirred 2 h at 50° C. then overnight at room temperature. After removal of the solvent in vacuo, addition of water (50 mL) and extraction with ethyl acetate (3×40 mL), the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel to afford 1-(3-bromo-4-methoxyphenyl)-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-hydroxymethanimine [9.00 g, yield 88%; HPLC/MS: m/z=410 (M+H); log P(HCOOH)=3.37].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:18]I>CN(C)C=O.O.[Cl-].[Na+].O>[CH3:18][O:3][C:4]1([CH3:17])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CI
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% dispersion on mineral oil) (198 mg, 4.95 mmol) was added portionwise to tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (21) (710 mg, 3.30 mmol) in N,N-dimethylformamide (12 mL) at ambient temperature over a period of 30 seconds under an air atmosphere. The resulting suspension was stirred at 25° C. for 20 minutes. Methyl iodide (0.411 mL, 6.60 mmol) was then and the resulting suspension was stirred at 25° C. for 18 hours. The reaction mixture was diluted with water (150 mL) and saturated brine (25 mL), then washed sequentially with dichloromethane (3×100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, which was used directly in the next stage.
Reaction SMILES: [CH:1]1([N:7]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:32]=[CH:31][C:20]([CH2:21][NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[CH:1]1([N:7]([CH2:33][CH:34]2[CH2:35][CH2:36]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:31][CH:32]=3)=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
A solution of tert-butyl N-{4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]benzyl}glycinate (Example 73; 60 mg; 0.12 mmol) in DCM (5 ml) was treated with trifluoroacetic acid (200 μl; 2.61 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The solvents were removed to give the title compound as a yellow oil in 77% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:21])[C:13]([CH3:15])=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.4 %

Procedure:
In dry N,N-dimethylformamide (8 ml) was dissolved 400 mg (1.3 mmol) of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methyl-1H-imidazole (5a), followed by addition of 80 mg (2.0 mmol) of sodium hydride under ice-cooling. After 5 minutes, 245 mg (1.73 mmol) of methyl iodide was added. After 30 minutes, the reaction mixture was poured in ice-water and extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:2) and recrystallized from n-hexane to provide 313 mg (yield 75%) of 5-(3,5-dichlorophenylthio)-1,2-dimethyl-4-isopropyl-1H-imidazole (Compound I-1). mp 95 to 96° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[O:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[N:16][CH:17]=3)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]4)[CH:5]=[N:6][CH:7]=2)[CH2:24][CH2:25]1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(O)c3)cnc21
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(OCC4CCOCC4)c3)cnc21
Yield: 50.2 %

Procedure:
To a solution of 6-(5-hydroxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (25 mg, 0.092 mmol) in DMA (1 mL) is added 4-(bromomethyl)tetrahydropyran (20 mg, 0.11 mmol) and cesium carbonate (36 mg, 0.11 mmol). The resultant mixture is stirred at 70° C. for 16 h. Water is added and the mixture is extracted with EtOAc. The organic layers are combined, washed with brine and dried (Na2SO4). The solvent is evaporated and the crude product is purified by silica gel column eluting (0-10% MeOH in DCM) to afford the title compound (17 mg).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9].S(=O)(=O)(O)O>[Zn].C1C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:13][CH:12]=1)([OH:10])[CH3:9])[CH3:7]
Reactant: CC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Reactant: CCOC(=O)CBr
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1

Procedure:
A mixture of 20 g. of ethyl bromoacetate, 26.5 g. of 4-acetyl-3',4'-dichlorobiphenyl and 8 lg. of zinc foil is added to 100 ml. of benzene and the mixture is stirred and heated under reflux for one hour. It is cooled and dilute sulfuric acid is added to decompose the alcoholate obtained. The organic phase is separated off and, after the customary work up, 3-(3',4'-dichloro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester is obtained.
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:5]=1[F:32])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:5]=1[F:32]
Reactant: [H][H]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (21.04 g, 46.09 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 2 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (19.46 g, 98.1% yield). 1H NMR (400 MHz, CDCl3): δ 9.07 (s, 1H), 7.77 (s, 1H), 7.06 (m, 4H), 6.95 (m, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.68 (s, 2H), 3.85 (s, 5H), 3.81 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[C@@H:10]2[CH3:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[S:33])[C@@H:10]2[CH3:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2C)CC1
Solvent: c1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@@H]2C)CC1
Yield: 167.6 %

Procedure:
(3R,4S)-4-(1-Ethoxycarbonylcyclopropyl)-3-methyl-1-[(S)-1-phenylethyl]-2-pyrrolidone (1.85 g, 5.87 mmol) was dissolved in benzene (100 ml), and the solution was mixed with Lawesson's reagent (1.31 g, 3.24 mmol) and heated under reflux for 20 minutes. After completing the reaction, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography (silica gel, 160 ml; ethyl acetate:hexane=1:4), to thereby obtain 1.80 g (92%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([CH2:2][CH2:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:6])[CH3:5])[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Product: CC(O)(CCn1ccnc1)c1ccccc1-c1ccccc1

Procedure:
A mixture of 2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol and 1.36 g of imidazole is heated at 140° for 3 hours. After cooling and working up in the customary manner, 1-(1-imidazolyl)-3-p-biphenylyl-butan-3-ol is obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:23])[NH:6]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[C:35]=[O:36]>C1COCC1>[F:44][C:43]([F:45])([F:46])[C:39]1[CH:38]=[C:37]([NH:34][C:35]([N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([O:11][C:12]4[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:15]=[CH:14][N:13]=4)=[CH:9][CH:8]=3)[CH:4]=[C:5]2[CH3:23])=[O:36])[CH:42]=[CH:41][CH:40]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc2c(F)c(Oc3cc(CS(C)(=O)=O)ncn3)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(F)c(Oc3cc(CS(C)(=O)=O)ncn3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: -78 °C

Procedure:
4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-1H-indole (250 mg, 0.745 mmol) in THF (10 mL) is cooled to −78° C. and a 1 M solution of LiHMDS in THF (1.86 mL, 1.86 mmol) is added. After 12 min 1-isocyanato-3-(trifluoromethyl)-benzene (0.12 mL, 0.895 mmol) is added and the reaction is allowed to stir at −78° C. After 1 h the reaction is quenched with saturated aqueous NH4Cl and then extracted with (3×100 mL) EtOAc, The organic phases are combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified FCC (0-3% MeOH/DCM) to provide 4-fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 523.1 (M+1); 1H NMR (400 MHz, DMSO-d6) ppm 10.99 (s, 1H), 8.77 (d, J=1.01 Hz, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.66 (s, 1H), 7.53 (d, J=9.35 Hz, 2H), 7.36 (d, J=1.01 Hz, 1H), 7.20 (d, J=7.33 Hz, 1H), 6.64 (s, 1H), 4.73 (s, 2H), 3.13 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[K+].COS(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:29])[N:7]([C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2N(C)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
±(1S*,2R*,4R*)-[4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester, from Example (55d) (389 mg) was dissolved in THF (3 ml) and cooled to −78° C. prior to the slow addition of a solution of 0.5M KHMDS in THF (2.65 ml). After 20 min, Me2SO4 (0.15 ml) was added. The reaction was warmed to rt and stirred for 2 h before the solution was quenched with sat. NH4Cl. This was extracted twice with EtOAc. The combined organic layer was dried, filtered, and concentrated. Flash chromatography of the resulting residue gave ±(1S*,2R*,4R*)-[4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester (207 mg): 1H NMR (CDCl3, δppm, 300 mHz) 1.39 (s, 9H), 1.55-1.93 (m, 4H), 2.00 (m, 1H), 2.52 (s, 3H), 2.65 (m, 1H), 2.80 (s, 3H), 3.00 (m, 2H), 3.81 (m, 3H), 7.34 (d, 2H) 7.80 (d, 2H).
Reaction SMILES: ClC1C(Cl)=CC(NC2C3C(=CC(OCCOCC[O:29][S:30]([CH3:33])(=O)=[O:31])=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1.[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][OH:75])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:76])[CH:37]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][S:30]([CH3:33])(=[O:31])=[O:29])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:76])[CH:37]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCO
Reactant: CS(=O)(=O)OCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCCOCCOCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]

Procedure:
Compound 32c was prepared as described hereinabove for Compound 32a, using Compound 29c (0.067 gram, 0.1 mmol), methanesulfonyl chloride (0.036 gram, 0.32 mmol) and triethylamine (0.053 gram, 0.53 mmol) in dichloromethane (6.7 ml), yielding 0.02 gram of the product (26% yield).
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([NH2:7])[C@@H:5]([CH2:8][O:9]C(=O)C2C=CC=CC=2)[O:4][C@H:3]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].[CH3:26][O:27][C:28]1[CH:47]=[CH:46][C:31]([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[F:1][C@@H:2]1[C@H:6]([NH:7][C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:47][CH:46]=2)[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: N[C@H]1[C@@H](F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(N[C@H]2[C@@H](F)[C@H](n3ccc(=O)[nH]c3=O)O[C@@H]2CO)(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
2'-fluoro-3'-(4-methoxytrityl)amino-2',3'-dideoxyuridine (compound 12, FIG. 2) was prepared as follows: To 1.0 g (2.9 mmol) of 11 in 50 mL anhydrous pyridine was added 1.0 g (3.2 mmol) 4-methoxytrityl chloride. The mixture was stirred overnight, 5 mL saturated aqueous NaHCO3 was added, and the mixture concentrated in vacuo to an oil. The oil was dissolved in 125 mL ethyl acetate, which was washed with water (3×100 mL) and reconcentrated in vacuo to 2.05 g of foam.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:9]([CH2:8][C:7]1[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=1[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCNCc1ccccc1OC(C)(C)C
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN(CCCCCCBr)Cc1ccccc1OC(C)(C)C
Reaction time: 48 h
Yield: 64 %

Procedure:
Compound 14 (3.56 g, 14.6 mmol), 1,6-dibromohexane (35.3 g, 146 mmol) and K2CO3 (2 g, 14.6 mmol) were added to 50 mL CH3CN, and the solution was stirred for 48 h. The solvent was evaporated to dryness and the residue was dissolved in a minimum amount of CH2Cl2 followed by purification via silica gel chromatographed, eluting with a 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2 yield the desired product as a pale yellow oil (64%). 1H NMR (CDCl3) δ 7.354 (dd, 1H, Ar), 7.121 (ddd, 1H, Ar), 7.013 (d, 1H, Ar), 6.986 (t, 1H, Ar), 3.569 (s, 2H, —CH2), 3.351 (t, 2H, —CH2—), 3.145 (d, 2H, —CH2—), 2.507 (t, 2H, —CH2—), 2.399 (t, 2H, —CH2—), 1.805 (p, 2H, —CH2—),1.447 (p, 2H, —CH2—), 1.409 (s, 9H, —C(CH3)3), 1.372 (s, 9H, —C(CH3)3), 1.362 (p, 2H, —CH2—), 1.254 (p, 2H, —CH2—). Mass Spec.=485.48 (M+H)+.
Reaction SMILES: C(N(CC)[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH:12]=[O:13])C.CCCCCC.C(OCC)(=[O:25])C>Cl.O>[OH:25][CH:12]1[C:6]2[C:5](=[CH:10][CH:9]=[C:8]([CH3:11])[CH:7]=2)[C:4](=[O:14])[O:13]1
Reactant: CCOC(C)=O
Reactant: CCN(CC)C(=O)c1ccc(C)cc1C=O
Agent: Cl
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)C(O)OC2=O
Temperature: 25 °C

Procedure:
N,N-diethyl-2-formyl-4-methyl-benzamide (7.98 g, 36.39 mmol) was taken up in 100 mL of 6N HCl and heated to reflux for 48 h. The reaction was then cooled to room temp and diluted with 50 mL of water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (3:1 hexane/ethyl acetate) Yield 4.66 g. 1H NMR (CDCl3, 300 MHz): δ 2.47 (s, 3H), 6.05 (bs, 1H), 7.12 (s, 1H), 7.33 (d, J=9, 1H), 7.95 (d, J=9, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[CH:19]=[CH:18][NH:17][N:16]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23]>C(#N)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[CH:19]=[CH:18][N:17]([CH2:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[N:16]=1
Reactant: Fc1cccc(F)c1-c1cc[nH]n1
Reactant: C=CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOC(=O)Cn1ccc(-c2c(F)cccc2F)n1
Yield: 97.1 %

Procedure:
Potassium carbonate (1.53 g) was added to an acetonitrile (10 mL) solution of 3-(2,6-difluorophenyl)-pyrazole (1 g) and allyl 2-bromoacetate (1.49 g), and refluxed for 3 hours. The resulting product was extracted with acetate and diluted hydrochloric acid added thereto at room temperature. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the resulting concentrate was purified through silica gel column chromatography (chloroform) to obtain allyl 2-{3-(2,6-difluorophenyl)pyrazol-1-yl}acetate (1.5 g).