Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1([C:3]2[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C(F)(F)F)cc3)nc2c1

Procedure:
A suspension of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.33 mmol, 1.00 equiv), 4-(trifluoromethyl)phenylboronic acid (69.9 mg, 0.37 mmol, 1.10 equiv), K3PO4 (142 mg, 0.67 mmol, 2.00 equiv), Pd(PPh3)4 (11 mg, 0.01 mmol, 0.03 equiv) in toluene (1 mL) was placed in a 10-mL sealed tube under an inert atmosphere allowed to react, with stifling, overnight at 100° C. in an oil bath. The reaction was quenched by the addition of 20 mL of water, and the solids were collected by filtration, resulting in 80 mg (59%) of methyl 2-phenyl-3-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])C=1C#N)#N.CO>C1(C)C=CC=CC=1>[C:1]([O:16][CH3:15])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccccc1
Yield: 96 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of neutral alumina (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl cinnamate is isolated in 96% yield whose NMR values are found matching with reported values as in example 1.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=12.[C:17](Cl)([Cl:19])=[O:18]>ClCCl.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[NH:10][C:11](=[O:12])[C:5]2=[CH:4][S:3][C:2]([CH3:1])=[C:6]12)=[O:18]
Reactant: Cc1scc2c1Nc1ccccc1NC2=O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
8.2 g (0.036 mol) of 4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one were suspended in 365 ml of dichloromethane and after the addition of 40 ml (0.08 mol) of a 20% phosgene solution in toluene the mixture was stirred for 7 days at ambient temperature. The solution formed was washed three times, each time with 80 ml of water, dried over sodium sulphate and the solvent was eliminated in vacuo. The desired compound was freed from contaminants by column chromatography on MN silica gel 60 (70-230 mesh ASTM) using dichloromethane/ethyl acetate/petroleum ether 5/5/4 (v/v) as eluant. 6.1 g (58% of theory) of colourless crystals were obtained, m.p. 238°-239° C., RF 0.77 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/ethyl acetate/petroleum ether 5/5/4 v/v).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[F:25]>C(O)C>[F:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Fc1cnccc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2ccncc2F)n1
Temperature: 25 °C
Yield: 5.1 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (152 mg, 1.1 mmol) was dissolved in absolute ethanol (20 mL), then triethylamine (200 μL, 1.4 mmol) and 4-(bromomethyl)-3-fluoropyridine (260 mg, 1.4 mmol) were added. The mixture was stirred over the weekend at room temperature. The solid was removed by filtration and washed with methanol. The filtrate was evaporated, and the residue was triturated in methanol, filtered, washed with water and diethyl ether, and then dried in vacuo to afford to 2-{[(3-fluoropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (14 mg, 7% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.41 (s, 2H), 6.00 (bs, 1H), 7.58 (t, J=5.7 Hz, 1H), 8.37 (dd, J=0.8 Hz, J=4.9 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H); LRMS (ES+) m/z 252 (100%, M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: COc1ccc(CCC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-methoxy-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH:33]=[CH:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:33]=[CH:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=2)=[CH:3][C:4]=1[NH:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Nc1cc(Br)cnc1Cl
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NC(C)C)c3)cc2s1
Temperature: 100 °C
Reaction time: 1.67 h
Yield: 35 %

Procedure:
5-bromo-2-chloro-N-isopropylpyridin-3-amine (127.6 mg, 0.511 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (191.5 mg, 0.602 mmol), potassium carbonate (317.8 mg, 2.299 mmol), and Pd(dppf)C12-DCM complex (42.9 mg, 0.0526 mmol) were suspended in 1,2-dimethoxyethane (2.0 ml) and water (0.5 ml). Argon was bubbled through the suspension for about 15 seconds, and then the flask was fit with a reflux condensor and placed in a preheated oil bath (100° C.) and stirred under argon for 100 minutes. The reaction was cooled to room temperature, concentrated, and treated with DCM and MeOH. These organic washings were decanted, concentrated, treated with water, and filtered. The solid was washed with water and the filtrate was discarded. Solid also washed with MeOH and Et2O, but the filtrate and solid contain product. The solid and filtrate were combined, concentrated, and purified on a silica gel column (25:1 to 20:1 DCM/MeOH to 15:1 DCM/2 N ammonia in MeOH) to afford N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (64.5 mg, 35% yield). MS (ESI pos. ion) m/z: 361. Calculated exact mass for C17H17ClN4OS 360.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]3([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:18][CH2:17]3)[N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+]>CO.O>[CH2:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C:14]2([N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=3)[C:15]2=[O:16])[CH2:21][CH2:20]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Yield: 100.3 %

Procedure:
Benzyl 3-(4-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.16 g, 2.32 mmol) and lithium hydroxide (0.15 g, 3.48 mmol) in methanol (10 mL) and water (1 mL) were stirred at 45° C. for 20 h. The reaction was partially evaporated under vacuum, the residue acidified with 6M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), and evaporated to give product as a white solid (1.13 g, quant.); 1H NMR (DMSO-d6); δ1.89 (d, J=14 Hz, 2H); 2.27-2.33 (m, 2H); 3.56 (m, 2H); 3.98-4.01 (m, 2H); 5.14 (d, 13.6 Hz, 2H); 5.23 (s, 2H); 6.91 (t, J=7.6 Hz, 1H); 6.96 (d, J=8 Hz, 2H); 7.27 (dd, J=7.6
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:6](=[O:32])[N:5]([CH3:33])[C:4]=2[N:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:36]=1[C:42]([F:45])([F:44])[F:43].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:2]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C:6](=[O:32])[N:5]([CH3:33])[C:4]=3[N:3]=2)=[CH:37][C:36]=1[C:42]([F:43])([F:44])[F:45]
Reactant: Cn1c(=O)n(CCOCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCOCCOC2CCCCO2)c(=O)c2c1nc(Oc1ccc(Cl)c(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.28 mmol, intermediate 11) in DMF (5 mL) was added 4-chloro-3-(trifluoromethyl)phenol (81 mg, 0.45 mmol) and potassium carbonate (76 mg, 0.55 mmol). The mixture was stirred at 80° C. overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 2.112 min; LCMS MH+-THP 573.
Reaction SMILES: Cl.Cl.Cl.[CH:4]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:22][C:23]#[N:24])[CH2:21][NH:20][CH2:19]4)[CH:17]=3)[N:10]3[CH:25]=[CH:26][N:27]=[C:9]3[CH:8]=2)[CH2:6][CH2:5]1.C(#N)C.FC(F)(F)S(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O>O>[CH:4]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:22][C:23]#[N:24])[CH2:21][N:20]([CH2:37][C:38]([F:41])([F:40])[F:39])[CH2:19]4)[CH:17]=3)[N:10]3[CH:25]=[CH:26][N:27]=[C:9]3[CH:8]=2)[CH2:6][CH2:5]1
Reactant: N#CCC1(n2cc(-c3nc(C4CC4)cc4nccn34)cn2)CNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC#N
Product: N#CCC1(n2cc(-c3nc(C4CC4)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Reaction time: 15 h
Yield: 59.9 %

Procedure:
To a mixture of 2-(3-(4-(7-cyclopropylimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile trihydrochloride (100 mg; 0.233 mmol) and acetonitrile (2 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (108 mg; 0.466 mmol) and TEA (118 mg; 1.17 mmol). The mixture was stirred in a sealed vial for 15 hours. Water (40 mL) was added and the mixture was extracted into methylene chloride (3×30 mL). The combined extracts were dried (sodium sulfate and magnesium sulfate), filtered and concentrated under reduced pressure. The material was purified by chromatography on silica gel, eluting with methylene chloride/6% ammonium hydroxide in methanol (98:2-96:4 gradient) to give the desired product as a white foam (56 mg). MS (apci) m/z=402.1 (M+H).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[F:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:15])[C:13]#[N:14])[CH:11]=1>C(O)C>[F:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:15])[C:13](=[NH:14])[O:1][CH2:2][CH3:3])[CH:11]=1
Reactant: CC[O-]
Reactant: CC(C#N)n1cc(F)cn1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=N)C(C)n1cc(F)cn1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of sodium ethoxide, prepared by adding solid sodium metal (64.4 mg, 2.80 mmol) to ethanol (10 mL), was added a solution of 2-(4-fluoro-1H-pyrazol-1-yl)propanenitrile (390 mg, 2.80 mmol) in ethanol (2 mL). The reaction mixture was stirred at 70° C. for 18 h. The mixture was cooled to room temperature and used without further purification. MS (EI+) (M+) 186; GCMS retention time: 1.27 min (Method O).
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])=[CH2:4].[N:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CCOCC>[CH2:21]([O:20][C:18]([N:17]1[CH2:1][CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH2:4][N:16]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH3:22]
Reactant: C=C(CC)CC/C=C(\C)CCC=C(C)C
Reactant: CCOC(=O)N=NC(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)N1CC=C(CCC=C(C)CCC=C(C)C)CN1C(=O)OCC
Temperature: -20 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of the (E)-β-farnesene-containing product of Example 1 (14.5 g) in ether (20 ml) is cooled to -20° C. and diethyl azodicarboxylate (8.7 g) is slowly added with stirring. The mixture is stored at -20° C. overnight and then at 4° C., the reaction being shown by n.m.r. to be complete after 8 hours at 4° C. The mixture is then subjected to fractional distillation to give the adduct, 1,2-bis(ethoxycarbonyl)-4-(4,8-dimethyl-3,7-nonadienyl)-1,2,3,6-tetrahydropyridazine (I) as a yellow oil (8 g, 43%) 180°-185° C./0.3τ; nD20 1.4938; M+ (m/z as % of base peak): 378(2.9); δ(CCl4) 1.30 (t, 6H), 1.70 (m, 9H), 2.08 (m, 8H), 3.60-4.40 (m, 4H), 4.26 (q, 4H), 5.20 (m, 2H), 5.60 (br, t, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[N:12]12CCN(CC1)C[CH2:13]2>>[C:13]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])#[N:12]
Reactant: C1CN2CCN1CC2
Reactant: O=C(Cl)OCc1ccccc1
Product: N#CC(=O)OCc1ccccc1
Yield: 12180.4 %

Procedure:
Benzyl chloroformate (13.7 g; 0.08 mol) and 1,4-diazabicyclo [2.2.2] octane (60 mg; 0.54 mmol) were added to a dry reaction vessel under a dry nitrogen atmosphere. Trimethylsilyl nitrile (8 g; 0.08 mol) was added dropwise over about 1 hr. The mixture was maintained at between 20°-30° C. until the reaction reached completion in about 3 hr. After distilling off the trimethylsilyl chloride, 10.6 g product was isolated as a clear liquid (bp 70-72/1 mm Hg.) Yield: 82%; purity 98% 1H-NMR: δ7.3,m(5H); δ5.26, s(2H); IR: 2250 cm-1 (CN), 1760 cm-1 (CO).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][C:7]([CH3:12])=[C:8]([F:11])[C:9]=1[F:10])=[O:4].[OH-:15].[Na+].Cl>>[F:10][C:9]1[C:8]([F:11])=[C:7]([CH3:12])[NH:6][C:5]=1[C:3]([OH:4])=[O:15]
Reactant: [OH-]
Reactant: Cc1[nH]c(C(=O)C(Cl)(Cl)Cl)c(F)c1F
Agent: Cl
Agent: [Na+]
Product: Cc1[nH]c(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2,2-Trichloro-1-(3,4-difluoro-5-methyl-1H-pyrrol-2-yl)ethanone (Intermediate 80; 1.03 g) was added to an aqueous solution of NaOH (18 ml) at 0° C. under N2. The mixture was stirred at room temperature for a further 2 h, cooled to 0° C. and acidified with HCl to ˜pH 2. A brown precipitate of product was collected by filtration. The crude product was purified by column chromatography on silica gel elution with EtOAc/hexanes (1:1). Trituration with DCM (1 ml)/pentane (6 ml) gave the title compound as a pale brown solid (306 mg). M.p. 140° C. (dec.). MS (ES) MH+: 160, 161 for C6H5F2NO2; NMR (CDCl3): 2.15 (s, 3H), 11.5 (s, 1H), 12.8 (brs, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]#[CH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>>[Si:1]([O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])/[CH:10]=[CH:11]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C#CC(CCCCC)O[Si](C)(C)C(C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C(C)(C)C

Procedure:
Irradiation of 3-(tert-butyldimethylsilyloxy)-1-octyne (48, 2.05 g, 8.53 mmol) and tributyltin hydride (2.30 mL, 8.53 mmol) under the conditions described above yielded 50: 1H NMR (CDCl3) δ 6.04 (d, J=19.0 Hz, 1H), 5.93 (dd, J1 =19.0 Hz, J2 =5.2 Hz, 1H), 4.04 (dd, J1 =6.1 Hz, J2 =5.6 Hz, 1H), 1.52, 1.34 (2m, 26H), 0.94 (m, 21H), 0.07 (s, 3H), 0.05 (s, 3H). 1H NMR analysis revealed that 50 was only 85% pure and presumably contained the same isomeric impurities as did 49.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:33]3[N:32]=[CH:31][N:30]=[C:27]([O:28][CH3:29])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1(OC2C3N=CN(C=3N=CN=2)[C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O[Si](C(C)(C)C)(C)C)C2)C2C=CC=C[C:37]=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+]>CCO>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:33]3[N:32]=[CH:31][N:30]=[C:27]([O:28][CH2:29][CH3:37])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CCOc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Yield: 95 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-methyl-2′-deoxyinosine, the ethyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol) and EtOH (1 mL) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) over 1 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 48.2 mg (95% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.16. 1H NMR (500 MHz, CDCl3): δ 8.50 (s, 1H, Ar—H), 8.26 (s, 1H, Ar—H), 6.50 (t, 1H, H-1′, J=6.4), 4.65 (q, 2H, OCH2, J=7.0), 4.61 (m, 1H, H-3′), 4.01 (q, 1H, H-4′, J=3.4), 3.87 (dd, 1H, H-5′, J=11.2, 3.9), 3.77 (dd, 1H, H-5′, J=11.2, 2.9), 2.61 (quint, 1H, H-2′, J=6.3), 2.44 (ddd, 1H, H-2′, J=12.9, 6.1, 3.9), 1.50 (t, 3H, CH3, J=7.3), 0.91 (s, 18H, tert-Bu), 0.09, 0.08 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 160.8, 152.0, 151.5, 140.5, 121.9, 87.9, 84.4, 71.8, 63.1, 62.7, 41.5, 26.0, 25.7, 18.4, 18.0, 14.5, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C24H45N4O4Si2 (M++H) 509.2979. found 509.2953.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2O)=[CH:12][CH:11]=1>CC(C)=O>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[O:4][CH3:1])=[CH:12][CH:11]=1
Reactant: Oc1cccc2ccc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2ccc(Br)cc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
Potassium carbonate (3.3 g, 23.9 mmol) and methyl iodide (1.5 ml, 23.9 mmol) were added to a solution of the product from Step D (2.7 g, 11.9 mmol) in acetone (40 ml) at room temperature and the mixture was stirred at 65° C. for 2 hours. The solids were filtered, rinsed with ethyl acetate and the filtrate was evaporated. The residue was dissolved in ethyl acetate and washed with water twice. The aqueous layers were extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulfate to give 7-bromo-1-methoxynaphthalene (2.5 g, 88%) after chromatography (19:1 heptane/ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 8.49 (d, J=2.1 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.7, 2.1 Hz, 1H), 7.39-7.43 (m, 2H), 6.85 (dd, J=5.4, 3.0 Hz, 1H), 3.15 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:13][C:14]([N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:13][C:14]([N:16]([CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:15])[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:33]
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CN
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2C)c1
Yield: 134.3 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with 2-[2-amino-N-(2-methylphenyl)acetamido]-N-methyl-N-phenylacetamide (1.2 g) and 3-methylphenyl isocyanate (1.3 g), and after recrystallisation in ethyl acetate, 2-{N-(2-methyl-phenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (2.3 g), m.p. 193° C., is obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>ClCCl>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 39.2 %

Procedure:
A solution of 0.050 g (0.20 mmol) of (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) in 1 ml of dichloromethane was treated with 0.030 g (0.20 mmol) of 3,4-dichlorophenyl isocyanate. After 1 h the reaction was evaporated and purified by flash silica gel column (dichloromethane/methanol 98/2 to 9:1) to yield 0.039 g (48%) of the titled compound as white foam. MS: 495.2 (M−H−, 2Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:11]=[N:12][NH:13][C:14]=3[CH2:15][CH2:16][CH:17]=2)=[CH:5][CH:4]=1.C1COCC1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:17][CH2:16][CH2:15][C:14]3[NH:13][N:12]=[CH:11][C:10]2=3)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=CCCc3[nH]ncc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2CCCc3[nH]ncc32)cc1
Reaction time: 4 h
Yield: 85.5 %

Procedure:
4-(4-Methoxyphenyl)-6,7-dihydro-1H-indazole (0.141 g, 0.62 mmol) is dissolved in EtOH (10 mL) and THF (4 mL) and 5% Pd/C (0.090 g) is added. The mixture is stirred under hydrogen (40 psi) for 4 hrs. The mixture is filtered through diatomaceous earth and the filtrate is evaporated to dryness. The residue is purified by silica gel chromatography eluting with 98:2 CH2Cl2:MeOH to give the title compound (0.121 g, 85%). ES/MS m/z 229 (M+1).