Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1>[Pd].CO.C(Cl)Cl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: Oc1cccc(-c2cnc3[nH]cc(C=Cc4ccccn4)c3c2)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: Oc1cccc(-c2cnc3[nH]cc(CCc4ccccn4)c3c2)c1
Reaction time: 48 h
Yield: 59.5 %

Procedure:
A suspension of 3-[3-(2-pyridin-2-yl-vinyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol (10 mg, 0.032 mmol) and 10 wt % Pd/C (1.7 mg, 0.0016 mmol) in 0.9 ml of a (1:1:1) mixture of MeOH/CH2Cl2/DMF was stirred for 2 days under H2 atmosphere. The mixture was adsorbed directly on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(2-pyridin-2-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol as a yellow solid (6 mg, 60% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.22 (t, J=7.5 Hz, 2H), 3.37 (t, J=7.5 Hz, 2H), 6.77 (d, J=7.5 Hz, 1H), 7.07 (s, 1H), 7.11 (d, J=7.0 Hz, 1H), 7.27 (m, 2H), 7.82 (m, 1H), 7.93 (d, J=7.0 Hz, 1H), 8.21 (s, 1H), 8.43 (m, 2H), 8.79 (d, J=5.5 Hz, 1H), 9.54 (broad s, 1H), 11.53 (s, 1H). MS: m/z 316 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[CH3:17].[N:18]1[N:19]([C:23]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:24]=2[C:25](O)=[O:26])[N:20]=[CH:21][CH:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:25](=[O:26])[C:24]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:23]=3[N:19]3[N:20]=[CH:21][CH:22]=[N:18]3)[CH2:9]2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(OCC2CCCCNC2)ccc1F
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCCCC(COc3ccc(F)c(C)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-6 (164 mg, 0.691 mmol) in DMF (4 ml) was treated with 1-7 (154 mg, 0.760 mmol), EDC (159 mg, 0.829 mmol), HOBT (127 mg, 0.829 mmol), and TEA (0.289 ml, 2.073 mmol). After stirring at RT for 30 min, the mixture was diluted with EtOAc, washed with water (3×s) and once with brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 100% EtOAc in Hex) to yield 1-8 as a pale yellow oil. Data for 1-8: LRMS m/z (M+H): 423.1.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#N.O=[C:20]1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:1]1[CH:20]=[C:14]([C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([OH:10])[CH:12]=2)[N:3]=[N:2]1)[CH3:9]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: N#Cc1cccc(O)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1cc(-c2cccc(O)c2)nn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl azidoacetate (14.9 g, 115 mmol) was dissolved in tert-butanol (200 mL), and 95% 3-hydroxybenzonitrile (13.7 g, 110 mmol) was added. A solution of sodium ascorbate (2.18 g, 11 mmol) in water (100 mL) was added, followed by a 0.3 M solution of copper sulfate under argon. The mixture was stirred at room temperature for 12 hours. The solution was evaporated to dryness in vacuo, the residue was dissolved in EtOAc (100 mL), dried (MgSO4), filtered, evaporated in vacuo to give the title compound as brown crystals in ˜100% (27.7 g) yield.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][C@:8]([CH2:14][CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])([CH3:13])[O:9]2)=[CH:4][C:3]=1[OH:30].C([O-])([O-])=O.[K+].[K+].[CH2:37](Br)[CH:38]=[CH2:39].CC(C)=O>O.CCOC(C)=O>[CH2:39]([O:30][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:12])[C:2]=1[CH3:1])[O:9][C@:8]([CH3:13])([CH2:14][CH2:15][CH2:16][C@H:17]([CH3:18])[CH2:19][CH2:20][CH2:21][C@H:22]([CH3:23])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:7][CH2:6]2)[CH:38]=[CH2:37]
Reactant: Cc1c(O)cc2c(c1C)O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1cc2c(c(C)c1C)O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2

Procedure:
(+)-γ-tocopherol (Ex-1D-1) (300 mg, 0.72 mmol), K2CO3 (199 mg, 1.44 mmol), allyl bromide (182 μL, 1.44 mmol) and acetone (8 mL) were charged to a 50 mL RBF. The reaction was heated to reflux for 20 h after which time it was deemed complete by TLC (1:5 EtOAc:Hept). The reaction was diluted with water (10 mL). The aqueous layer was separated and washed with DCM (3×10 mL). The combined DCM layers were dried over Na2SO4, filtered and concentrated by rotary evaporation to yield a pale yellow oil. The oil was flashed through a silica plug (1:1: DCM:Heptane). After concentration of the eluent, (R,R,R)-6-allyloxy-2,7,8-trimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman (Ex-1D-2) was obtained as a clear, colorless oil (334 mg, >100%), which was used without further purification.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=[O:12])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C1C=CC=CC=1.II.[C:28](O)(=[O:30])C>C(O)C.CCOCC>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH:7]1[C:6]2[C:10](=[CH:11][CH:3]=[CH:4][CH:5]=2)[C:9]([O:12][CH2:28][OH:30])=[C:8]1[CH3:13]
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Reactant: COC(=O)CBr
Agent: II
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)CC1C(C)=C(OCO)c2ccccc21
Reaction time: 3 h

Procedure:
A solution of 13.4 g. of 6-methoxy-2-methyl-indanone and 19.3 g. of methyl bromoacetate in 45 ml. benzene is added over a period of 5 minutes to 21 g. of zinc amalgam (prepared according to Org. Syn. Coll., vol. 3) in 110 ml. benzene and 40 ml. dry ether. A few crystals of iodine are added to start the reaction, and the reaction mixture is maintained at reflux temperature (ca. 65°) with external heating. At 3 hour intervals, two batches of 10 g. zinc amalgam and 10 g. bromoester are added, and the mixture is then refluxed for 8 hours. After addition of 30 ml. ethanol and 150 ml. of acetic acid, the mixture is poured into 700 ml. of 1:1 aqueous acetic acid. The organic layer is separated, and the aqueous layer is extracted twice with ether. The combined organic layers are washed thoroughly with water, ammonium hydroxide and water. Drying over sodium sulfate, evaporation of solvent in vacuo followed by pumping at 80° (bath temp.) (1-2 mm.) gives crude methyl(1-hydroxy-2-methyl-methoxy-indenyl)acetate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][C:13]=2[CH3:22])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.FC(F)(F)C(O)=O>FC(F)(F)CO.CCOC(C)=O>[CH:19]1([C:15]2[CH:16]=[C:17]([CH3:18])[C:12]([O:11][C:4]3[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=[C:2]([NH:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[N:3]=3)=[C:13]([CH3:22])[CH:14]=2)[CH2:21][CH2:20]1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]ccc12
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2[nH]ccc12
Temperature: 90 °C
Yield: 15.8 %

Procedure:
To a suspension of 2-chloro-4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidine (75 mg, 0.24 mmol) and 4-aminobenzonitrile (113 mg, 0.96 mmol) in 2,2,2-trifluoroethanol (4 mL) in a sealed tube was added trifluoroacetic acid (0.15 mL, 1.92 mmol). The resulting solution was heated at 90° C. for 3 days. The reaction was diluted with EtOAc (50 mL), washed with NaHCO3 (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2:Acetone=90:10) yielded 15 mg (16%) of 4-(4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzonitrile as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl[C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Reactant: Nc1ccncc1Cl
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Nc4ccncc4Cl)ncnc32)CC1

Procedure:
By the procedure described in Example 3, with the exception that 3-chloro-4-aminopyridine was used instead of 2-fluoro-4-(methylsulfonyl)aniline, isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A was converted into Example 120. 1H NMR (500 MHz, CDCl3) δ ppm 1.24 (d, J=6.60 Hz, 6 H) 1.59-1.64 (m, 2 H) 1.66-1.74 (m, 2 H) 2.85-2.93 (m, 2 H) 3.44-3.47 (m, 2 H) 4.25-4.29 (m, 4 H) 4.80-4.87 (m, 1 H) 4.87-4.94 (m, 1 H) 7.60 (s, 1 H) 8.09 (s, 1 H) 8.31 (d, J=6.05 Hz, 1 H) 8.44 (s, 1 H) 8.75 (d, J=5.50 Hz, 1 H). LRMS (ESI): 433.3/435.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2.[Cl-].[Na+].ClC1C=CC=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1ccccc1CSc1nc2ncccc2[nH]1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1ccccc1CS(=O)c1nc2ncccc2[nH]1
Reaction time: 0.25 h

Procedure:
In a mixture of 1 ml of methanol and 30 ml of chloroform was dissolved 1.5 g of 2-[2-(methylamino)benzylthio]imidazo[4,5-b]pyridine. To the resulting solution was portionwise added under chilling with ice and aqueous sodium chloride solution to -5° C. 1.08 g of m-chloroperbenzoic acid (purity: 80%) over a period of 20 min., maintaining the temperature of the solution at -5° C.±3° C. The reaction mixture was stirred for additional 15 min. at the same temperature, and to the mixture was added a saturated NaHCO3 solution. The resulting mixture was then stirred. The organic phase was separated and extracted with two poritons of 14 ml of 0.1N NaOH. The alkaline extracts were combined and neutralized by NH4Cl, and the deposited oil was extracted with chloroform. The chloroform extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and placed under reduced pressure to distill of the solvent. The residue was crystallized by addition of acetonitrile to give 2-[2-(methylamino)benzylsulfinyl]imidazo[4,5-b]pyridine. m.p.: 120° C. (decompn.).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25].O>O1CCCC1>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1cc(C=O)oc1C
Reactant: Cc1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1cccnc1C(O)c1cc(C)c(C)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
2-Bromo-3-methylpyridine (1.53 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6M n-butyllithium/n-hexane solution (5.7 ml) was added dropwise to the solution at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1.00 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raised to room temperature while stirring. Water was added to the reaction solution to stop the reaction. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(3-methyl-pyridin-2-yl)-methanol (1.17 g, yield 61%).
Reaction SMILES: [OH-].[Na+].C([N:6]1[C:16]2[CH2:15][CH:14]3[N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:10]([CH2:11][N:12]([C:28](=[O:30])[CH3:29])[CH2:13]3)[C:9]=2[CH:8]=[N:7]1)(=O)C>C1COCC1.C(OCC)(=O)C.O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:17]2[CH:14]3[CH2:13][N:12]([C:28](=[O:30])[CH3:29])[CH2:11][CH:10]2[C:9]2[CH:8]=[N:7][NH:6][C:16]=2[CH2:15]3)(=[O:19])=[O:20])=[CH:26][CH:25]=1
Reactant: CC(=O)N1CC2Cc3c(cnn3C(C)=O)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Aqueous sodium hydroxide (3 N, 0.56 mL, 1.70 mmol) was added to a stirring solution of 1-[5-acetyl-12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-dien-10-yl]-ethanone (240 mg, 0.567 mmol) in THF (2 mL). The reaction mixture was stirred for 3 h at room temperature and subsequently diluted with ethyl acetate (10 mL) and water (5 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×5 mL). The organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by preparative HPLC to give 1-[12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-dien-10-yl]-ethanone as a white solid. Retention time (min)=1.242, method [1], MS(ESI) 381.0 (M+H); 1H NMR (300 MHz, CDCl3) (rotamers) δ 7.68-7.58 (m, 2H), 7.44 and 7.41 (2×s, 1H), 7.38-7.30 (m, 2H), 5.32-5.20 (m, 1H), 4.78 and 4.55 (2×d, J=13.2 Hz, 1H), 4.48-4.35 (m, 1H), 3.90-3.54 (m, 2H), 3.08-2.62 (m, 3H), 2.00 and 1.61 (2×s, 3H).
Reaction SMILES: [C:1](=[O:9])([O-:8])[O:2][CH:3](C(Br)C)[CH3:4].[CH3:10][O:11]/[N:12]=[C:13](/[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)\[C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([O-:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[S:30][N:29]=[C:28]([CH3:31])[N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:15].[Na+].[C:43](OCC)(=O)[CH3:44].O>CN(C)C=O>[CH3:10][O:11]/[N:12]=[C:13](/[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)\[C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([O:34][CH:43]([O:8][C:1]([O:2][CH2:3][CH3:4])=[O:9])[CH3:44])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[S:30][N:29]=[C:28]([CH3:31])[N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: CCOC(C)=O
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nc(C)ns3)CS[C@H]12)c1cscn1
Reactant: CC(Br)C(C)OC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)C1=C(CSc2nc(C)ns2)CS[C@@H]2C(NC(=O)/C(=N\OC)c3cscn3)C(=O)N12
Reaction time: 3 h

Procedure:
1-Bromoethylethyl carbonate (472 mg) was added to a solution of sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (536 mg) in dimethylformamide (5 ml) under cooling with ice. The mixture was stirred for 3 hr and then poured into a mixture of ethyl acetate (120 ml) and water (20 ml, adjusted to pH3 with dil. HCl) with stirring. The ethyl acetate layer was separated, washed successively with water (20 ml, adjusted to pH 3 with dil. HCl), 10% aqueous K2HPO4 solution (20 ml) twice, and saturated saline water (20 ml), drived over MgSO4, concentrated in vacuo, and the residue was added dropwise to petroleum ether. The formed crystals were filtered and dried in vacuo to give the title compound (325 mg). This product was found to contain the Δ2 isomer.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.B.CO.O>C1COCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: B
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCCCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
3-(3-Trifluoromethyl-phenyl)-propionic acid (12.4 g, 57 mmol) was dissolved in THF (160 ml) in an inert atmosphere and cooled to 0° C. followed by slow addition of borane in THF (85 ml, 85 mmol). Stirring was continued at 0° C. for 1 h and at rt for 24 h. The mixture was cooled to 0° C. and methanol (100 ml) and water (100 ml) was carefully added. The organic solvents were removed under reduced pressure. The remaining aqueous layer was extracted with DCM (3×100 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silicagel, DCM/methanol=9/1) to give 10.97 g (94%) of 3-(3-trifluoromethyl-phenyl)-propan-1-ol. LC-MS: tR=0.87 min; [M+H]+=no ionisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][C:13]1=[O:19].[C-]#N.[K+].C(N(CCOCCOC)CCOCCOC)COCCOC>C(#N)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([CH:14]1[C:15](=[O:18])[CH2:16][CH2:17][NH:12][C:13]1=[O:19])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCNC(=O)C1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCNC(=O)C1C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (2.1 g) in dry acetonitrile (10 ml) was added at ambient temperature to a stirred solution of piperidine-2,4-dione (1.13 g) and dry triethylamine (1.31 g) in dry acetonitrile (50 ml) and the mixture stirred at ambient temperature for 18 hours. Potassium cyanide (0.06 g) dry triethylamine (3.1 g) and tris-(3,6-dioxaheptyl)amine (0.5 ml) were added successively and the mixture stirred at ambient temperature for 24 hours. The mixture was evaporated under reduced pressure and the residue dissolved in dichloromethane (50 ml). The dichloromethane solution was washed successively with 2N hydrochloric acid (2×30 ml) and water (3×30 ml), dried over magnesium sulphate and evaporated under reduced pressure to give a brown solid which was purified by column chromatography to give 3-(3,4-dichlorobenzoyl)piperidine-2,4-dione (0.37 g) mp 171.5°-174.5° C., as a cream crystalline solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)=[CH:5][C:4]=1[O:30][CH3:31].CCN(C(C)C)C(C)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>C(Cl)Cl>[CH:41]1([S:44]([N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[N:15]5[C:11]([S:12][CH:13]=[CH:14]5)=[N:10][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[C:4]([O:30][CH3:31])[CH:5]=4)[CH:22]=[CH:21][N:20]=3)[CH2:29][CH2:28]2)(=[O:46])=[O:45])[CH2:43][CH2:42]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCNCC3)n2)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCN(S(=O)(=O)C4CC4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
The 4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[piperidin-4-yl]pyrimidin-2-amine hydrochloride (0.25 g, 0.50 mmol) in methylene chloride (DCM) (12 ml) was cooled to 0° C. and was treated with Hunig's base (440 μl, 2.5 mmol). The mixture was kept at 0° C. for 30 minutes then the cyclopropyl-sulfonyl chloride (72 μl, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for one hour. The mixture was diluted with methylene chloride (10 ml) and was washed water (2×10 ml) and a saturated aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient (ethyl acetate/hexanes, 30-75%), affording 0.253 g (96%) of the title compound as a pale yellow solid. M.p.: 146-148° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.72 (br. s, 1H), 8.13 (d, J=5.1 Hz, 1H), 7.45 (d, J=4.3 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.26 (dd, J=11.3, 8.2 Hz, 1H), 7.25 (br. S, 1H), 7.15 (ddd, J=8.2, 4.7, 2.0 Hz, 1H), 6.41 (d, J=5.1 Hz, 1H), 3.95-3.86 (m, 1H), 3.83 (s, 3H), 3.68-3.61 (m, 2H), 3.06-2.96 (m, 2H), 2.60-2.52 (m, 1H), 2.08-1.96 (m, 2H), 1.66-1.54(m, 2H), 1.04-0.94 (m, 4H). LCMS: 529 [M+H]. Calc. for C24H25N6O3S2F.0.13 water.0.7 diethyl ether: C, 54.31; H, 5.25; N, 14.18. Found C, 54.32; H, 4.89; N, 14.19.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[Li][CH2:14]CCC.CI>C1COCC1>[Cl:12][C:7]1[N:8]=[C:9]([Cl:11])[C:10]2[C:2]([CH3:14])=[CH:3][NH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c[nH]c2nc(Cl)nc(Cl)c12
Temperature: -78 °C

Procedure:
1.4 g 5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (4) (5.2 mmol) was dissolved in 200 mL of THF. After cooling to −78° C., 9.75 mL of BuLi (1.6M solution in Hexanes, 15.6 mmol) was slowly added over a period of 30 minutes, then stirred for 30 minutes at −78° C. before 396 uL of MeI (6.24 mmol) was dropwise added into the reaction mixture over a period of one hour. The reaction mixture was stirred at −78° C. for one more hour and quenched by adding 20 mL of saturated aqueous NH4Cl solution at this temperature. The reaction mixture was then partitioned between 100 mL of saturated NaHCO3 and 100 mL of EtOAc. The organic layer was separated and the aqueous layer is extracted with EtOAc (3×100 mL). Combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]([NH2:21])[C@H:12]1[OH:13].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:44](O)=[O:45])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]([NH:21][C:44](=[O:45])[C@H:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:37]=2)[NH:29][C:27]([O:26][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:28])[C@H:12]1[OH:13]
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)OC)cc1
Yield: 23.7 %

Procedure:
Methyl 1-(6-amino-9H-purin-9-yl)-3-[N-tert-butoxycarbonyl-O-methoxycarbonylmethyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronate (220 mg) was prepared by reacting methyl 1-(6-amino-9H-purin-9-yl)-3-amino-1,3-dideoxy-β-D-ribofuranuronate (577 mg) prepared in Example 62 with N-tert-butoxycarbonyl-O-methoxycarbonylmethyl-L-tyrosine (520 mg) prepared in Preparation 8 (2) according to a similar manner to that of Example 64, mp. 115°-120° (dec.).