Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].C([Li])CCC.C1C[O:20][CH2:19]C1>>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:1][CH2:2][C:3]#[C:4][CH2:19][OH:20]
Reactant: C#CCCOC1CCCCO1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: OCC#CCCOC1CCCCO1
Temperature: -23 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 8.0 mL (51 mmol) of 2-(3-butynyloxy)tetrahydro-2H-pyran in 150 mL of THF under nitrogen atmosphere at −23° C. was added dropwise a solution of 33 mL (53 mmol) of 1.6M butyllithium in hexanes, maintaining the temperature at −23° C. The resulting solution was stirred at 0° C. for 2 h, recooled to −23° C. and 2.4 g (76.5 mmol) of parafomaldehyde was added in several portions. The mixture was stirred at −23° C. for 1h and let warm to room temperature and stirred for 18 h. The reaction mixture was poured into a large excess of ice water and extracted with ether. The organics were washed with brine until neutral, dried over MgSO4, filtered and concentrated in vacuo. The residue was kugelrohr distilled to provide 7.26 g (77%) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol as a colorless liquid. EI Mass Spec: 185.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]#[N:12])=[N:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:15]=1[F:24].[BH4-].[Na+]>CO.[Co](Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH2:12])=[N:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Si:20]([CH3:22])([CH3:21])[CH3:23])=[CH:16][C:15]=1[F:24]
Reactant: COC(=O)c1cc(F)c(C#N)nc1Nc1ccc([Si](C)(C)C)cc1F
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(F)c(CN)nc1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
To a suspension of 6-cyano-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid methyl ester (5.7 g, 15.8 mmol) in methanol (130 mL) was added cobalt (II) chloride (7.5 g, 31.6 mmol). The reaction mixture was stifled for 10 minutes, then cooled to 0° C. and sodium borohydride (6.0 g, 158 mmol) was added in small portions over 30 minutes. The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 1 hour. The reaction was quenched by addition of concentrated hydrochloric acid (20 mL) and the mixture stirred for 15 minutes. The reaction mixture was filtered to remove a white solid, which was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The resultant residue was dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water then brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a brown solid (2.0 g, 34%). LCMS (method B): RT=2.77 min, [M+H]+=366.
Reaction SMILES: OC(C(F)(F)F)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:26][CH:25]([NH2:27])[CH2:24]4)[CH2:19][CH:18]=3)=[CH:16][C:11]=2[O:10][CH2:9]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:26][CH:25]([NH:27][C:37]([CH2:36][NH:35][C:33](=[O:34])[C:32]5[CH:40]=[CH:41][CH:42]=[C:30]([C:29]([F:44])([F:28])[F:43])[CH:31]=5)=[O:38])[CH2:24]4)[CH2:19][CH:18]=3)=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1-(4-benzo[1,3]dioxol-5-yl-cyclohex-3-enyl)-azetidin-3-ylamine TFA salt (as prepared in the previous step, 550 mg, 1.10 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet, 272 mg, 1.10 mmol) in DCM (10 mL) was treated with TEA (770 μL, 5.5 mmol) at room temperature. The mixture was treated with EDCI (Aldrich, 252 mg, 1.32 mmol), HOBT (Aldrich 149 mg, 1.10 mmol), and the reaction was stirred at room temperature for additional 6 hours. The reaction was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1)=[O:5])[CH3:2].[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32](O)=[O:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:29]([O:28][CH2:27][CH2:26][CH2:25][O:24][CH3:23])[CH:30]=2)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7]1)=[O:5])[CH3:2]
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C

Procedure:
A mixture of (3S*,4R*)-4-(isopropylamino-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.58 g, 8.2 mmol), 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid (1.93 g, 8.04 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.3 g, 9.02 mmol) and triethylamine (4.57 μL, 32.81 mmol) in CH2Cl2 (50 mL) is refluxed for 2 h and then quenched by the addition of aqueous NaHCO3 solution. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 50:50 to 0:100 and then AcOEt/MeOH 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.76 min.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]([CH3:26])[CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)[CH3:3].[NH2:27][C:28]1[N:33]=[C:32](Cl)[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:27][C:28]1[N:33]=[C:32]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]([CH3:26])[CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH3:3])[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N(C)C1CN(C(=O)OC(C)(C)C)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N(C)C2CN(C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (S)-3-((5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)(methyl)amino)azetidine-1-carboxylate (27.4 mg, 0.060 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (17.20 mg, 0.102 mmol) in DMSO (2 mL) was added triethylamine (0.046 mL, 0.330 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 5 hours. The solvent was removed with a stream of nitrogen. The crude title compound was used without further purification. ESI-MS m/z [M+H]+ calc'd for C25H33N9O2, 492. found 492.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[CH3:33][CH:34]([CH3:38])[C:35](=[O:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([C:35]([OH:37])([CH:34]([CH3:38])[CH3:33])[CH3:36])[CH:16]=[CH:17][CH:18]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(Br)c1
Reactant: CC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(C)(O)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: -40 °C
Yield: 43.3 %

Procedure:
Compound 78 (2.00 g; 5.78 mmol) was dissolved in tetrahydrofuran (20 ml). While the solution was stirred at −40° C. under nitrogen atmosphere, n-butyl lithium in n-hexane (1.56 M: 3.7 ml; 5.8 mmol) was added dropwise. After completion of the addition, the mixture was cooled to −75° C., an 3-methyl-2-butanone (2.00 g) in a small amount of tetrahydrofuran was added dropwise thereto. The resultant mixture was gradually brought to room temperature, and the reaction was stopped by dropwise addition of saturated aqueous ammonium chloride solution, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 0.86 g of the target compound as brown oily matter (yield: 43.3%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH2:6](O)[C:7]#[CH:8].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14])#[N:11].C(O)(=O)C>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4].ClCCl>[C:10](/[C:12](=[CH:6]\[CH:7]=[CH:8]\[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])/[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14])#[N:11]
Reactant: CCCCCCCCOC(=O)CC#N
Reactant: C#CCO
Reactant: CCNCC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)/C(C#N)=C/C=C/N(CC)CC
Temperature: 52 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
Diethylamine (14.5 ml, 0.14 mol) and propargyl alcohol (6.81 ml, 0.117 mol) are dissolved in 100 ml of toluene. 34.5 g of manganese dioxide (activated, <5 μm; 3.4 equiv.) are added portionwise while controlling the strong exotherm (temperature <50° C.) and the mixture is left stirring at 52° C. for 20 hours. The reaction mixture is filtered. The yellow filtrate is poured into a reactor surmounted by a Dean and Stark apparatus. n-Octyl cyanoacetate (23 g, 0.117 mol) and catalyst (0.1 equiv., 0.667 ml of acetic acid and 1.2 ml of N,N-diethylamine) are added with stirring and the reaction mixture is brought to reflux. It is left at reflux for 5 hours 30 minutes. After cooling, dichloromethane is added and washing is carried out once with a saturated sodium bicarbonate solution and then once with water. The organic phase is dried and then concentrated under vacuum. The brown red oil obtained is chromatographed on a silica column (gradient of eluents: heptane/AcOEt 90:10 to 80:20). 26 g (yield: 72%) of the pure fractions of the derivative of Example 4 are thus obtained in the form of an orange-coloured gum which crystallizes; recrystallization from heptane gave the derivative of Example 4 in the form of a yellow powder:
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=C(C=C)[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[C:16]([OH:20])(C)([CH3:18])[CH3:17].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:42]C)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:17]([C@H:16]([OH:20])[CH2:18][OH:42])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: C=Cc1cccc2cc(C)c(CC)nc12
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1nc2c([C@H](O)CO)cccc2cc1C
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
2.0 g of 2-ethyl-3-methyl-8-vinylquinoline, 65 ml of t-butanol and 65 ml of water are introduced into a 250 ml round-bottomed flask. The solution is cooled to 0° C. on an ice bath and 16.8 g of AD-mix-α (complex based on K2OsO2(OH)4, Fe(CN)6 and dihydroquinidine 1,4-phthalazinediyl diether as ligand) are added. Stirring is continued for 18 h at 0° C. and a solution of 12.6 g of sodium sulphite in 30 ml of water is added. The mixture obtained is stirred for 1 h at room temperature and is then extracted with ethyl acetate (2×200 ml). The organic phase is dried over magnesium sulphate and concentrated. The residue is purified by column chromatography on silica (elution solvent: 3/7 ethyl acetate/heptane). 2.0 g (yield: 86.5%) of (+)-2-ethyl-3-methyl-8-(1(S),2-dihydroxyethyl)quinoline are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:13])[C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:15]([O:12][C:6]1[C:5]([CH3:13])=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: Cc1ccc2ccc(O)c(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2ccc(OC(C)C)c(C)c2n1
Yield: 24.1 %

Procedure:
2,8-Dimethylquinolin-7-ol (1.0 g, 2.31 mmol), 2-iodopropane (0.785 g, 4.62 mmol) and potassium carbonate (0.957 g, 6.93 mmol) in acetone (15 mL) were heated to 70° C. in a sealed tube for 18 hours. After cooling, water (20 mL) was added and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-isopropoxy-2,8-dimethylquinoline (120 mg, 24.1% yield) as an oil
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2]>CC(O)=O.O.[Fe]>[Cl:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([O:14][C:9]2[C:8]([NH2:24])=[C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:12]=[C:11]([CH3:13])[N:10]=2)=[C:16]([CH3:23])[CH:17]=1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1N
Temperature: 60 °C

Procedure:
A mixture of (1-ethyl-propyl)-[6-methyl-3-nitro-2-(4 chloro-2,6-dimethyl-phenoxy)-pyridin-4-yl]-amine (100 mg, 0.265 mmol) and iron (73 mg, 1.33 mmol) in 12 ml of AcOH/H2O (1:1) was heated at 60° C. for 3 hours. The mixture was concentrated to dryness. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound. 1H NMR (CDCl3) δ 7.04 (s, 2H), 6.12 (s, 1H), 3.60 (brs, 2H), 3.28 (m, 1H), 2.14 (s, 3H), 2.10 (s, 6H), 1.45-1.80 (m, 4H), 0.97 (t, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:28][C@@H:29]1[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]1>CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:28][C@@H:29]2[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]2)=[N:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H](CO)C1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OC[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Yield: 78.7 %

Procedure:
To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (100 mg, 0.301 mmol) was added DMSO (1 ml), ((1S,3R)-3-aminocyclopentyl)methanol (104 mg, 0.903 mmol) and TEA (0.21 ml, 1.51 mmol). The crude mixture was stirred at 100° C. for 20 hours, followed by LCMS. The crude reaction mixture was cooled, was diluted with EtOAc (60 mL), washed H2O (60 mL×2), brine (60 mL), dried over Na2SO4, and reduced. The crude was adsorbed onto silica gel, and purified by silica gel chromatography, 40-80% EtOAc/Heptane, 12 g ISCO silica column, resulting in ((1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentyl)methanol (101 mg, 0.237 mmol). LCMS (m/z): 427.1 (MH+). retention time=0.69 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([OH:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:15][CH:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(O)CSc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(CSc1ccc(Cl)cc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 42.0 g (0.172 mole) of 1-(p-chlorophenylthio)hexan-2-ol and 21.6 g (0.189 mole) of methane sulfonyl chloride in 100 ml of toluene is slowly added 20.8 g (0.206 mole) of triethylamine over a 1/2 hour period at less than 15° C. When the addition is completed, the mixture is stirred for 1/2 hour, and is allowed to warm to ambient temperature.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:13]([O-])=O)[CH3:2].CC(=O)OCC>[Pd].CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:5][C:4]=1[NH2:13])[CH3:2]
Reactant: CCc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1ccc(S(C)(=O)=O)cc1N
Yield: 94.6 %

Procedure:
The title compound of step 1 (0.6 g, 2.6 mmol) and palladium on carbon (0.18 g) in CH3OH (20 mL) was hydrogenated at 1 atm. for 6 h. Silica gel chromatography (PE:EA=6:1) gave the title compound (0.49 g, 94%) as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[I:11]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: C1CCOC1
Product: Clc1ncnc2[nH]cc(I)c12

Procedure:
The tricyclic nucleoside 6.7 was synthesized starting from 4-chloro-1H-pyrrolo[2,3-d]pyrimidine 2.1. The nucleobase 2.1 was treated with N-iodosuccinimide in THF at room temperature for 4 hr to provide 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 6.1. Then 6.1 was converted to the corresponding sodium salt with sodium hydride in acetonitrile and reacted with bromo-sugar 2.4 ((i) Helv. Chim. Acta. 1995, 78, 486; (ii) WO 02/057287, 2002), to give nucleoside 6.2. which was directly converted to 4-amino-5-iodo-7-[3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-methyl-β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine 6.3. A Stille coupling reaction between nucleoside 6.3 and Z-3-tributylstannylacrylate provided compound 6.4. The cyclization of compound 6.4 was accomplished by heating in DBU/dioxane overnight to afford the protected tricyclic nucleoside 6.5, which was then treated with boron trichloride in CH2Cl2 to produce nucleoside 6.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([CH2:20][OH:21])[CH:9]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=[O:23]>C(#N)C.O.[O-]Cl.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]=[C:10]([C:20]([OH:23])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: OCc1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Temperature: 35 °C
Reaction time: 20 h

Procedure:
[4-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol (17.4 g, 55 mmol) was dissolved in acetonitrile (235 mL). Phosphate buffer (pH 6.7, 220 mL) and 2,2,6,6-tetra-methylpiperidine 1-oxyl radical (TEMPO, 0.6 g) was added and the solution was warmed to 35° C. To this warm solution under argon was added with stirring over 2 h simultaneously a solution of NaOCl2 (12.4 g) in water (58 mL) and NaOCl (0.85 mL, 10% solution) in water (35 mL). Stirring was continued for 20 h at 35° C. after which time the solution was cooled to room temperature and quenched by addition of in sequence water (420 mL), 2 N NaOH solution (65 mL) and Na2SO3 solution (17.1 g in 285 mL water). This mixture was stirred for 30 min and acidified with 2 N HCl (175 mL). The mixture was extracted once with ethyl acetate/THF (800/150 mL), and once with ethyl acetate (500 mL). Organic phases were washed with brine (800 mL), pooled and dried with Na2SO4. The solvent phase was concentrated to a volume of ˜100 mL, n-heptane (150 mL) was added and the solvent phase was concentrated again to ˜100 mL. This was repeated twice. n-Heptane (100 mL) was added. The product precipitated upon stirring, was filtered off and dried to give the title compound as a white solid (18.4 g, quant.), LC-MS (UV peak area/ESI) ˜100%, 332.029 (M+H)+.
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([C:23]1[NH:24][C:25](=[N:28][C:29](=[O:32])[CH2:30][Cl:31])[S:26][CH:27]=1)[C:7]([O:9]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:1]([O:4][N:5]=[C:6]([C:23]1[NH:24][C:25](=[N:28][C:29](=[O:32])[CH2:30][Cl:31])[S:26][CH:27]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)ON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(=NC(=O)CCl)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)ON=C(C(=O)O)c1csc(=NC(=O)CCl)[nH]1
Yield: 79.1 %

Procedure:
In 16.5 ml of anisole there were suspended 6.10 g of benzhydryl 2-acetoxyimino-2-(2-chloroacetylimino- 4-thiazolin-4-yl)acetate(syn-isomer) and under ice-cooling and stirring, 65.7 ml of trifluoroacetic acid was added dropwise. The mixture were stirred at that temperature for 15 minutes, after which the trifluoroacetic acid was distilled off under reduced pressure. To the residue was added n-hexane, whereupon an oily product separated out. The product was washed well with n-hexane ad the n-hexane was discarded after being removed by decantation. This procedure was carried out once again. To the oily residue was added ether, whereupon a crystalline powder separated out. Following the addition of a small amount of ether, the crystalline powder was collected by filtration, washed with a small amount of ether and dried. By the above procedure there were obtained 3.125 g of 2-acetoxyimino-2-(2-chloroacetylimino-4-thiazolin-4-yl)-acetic acid (syn-isomer).