Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[CH3:12][O:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH3:12][O:13][C:14]1[CH:32]=[CH:31][C:17]([C:18](=[C:4]2[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)[C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)c2ccc(NS(C)(=O)=O)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
Titanium tetrachloride (0.66 mL, 6.06 mmol) was slowly added to a slurry of Zn powder (0.81 g, 12.4 mmol) in dry THF (14 mL). The reaction mixture was heated at reflux for 2.5 h. A solution of 3,3,5,5-tetramethyl-cyclohexanone (0.86 mL, 4.91 mmol) and N-[4-(4-methoxy-benzoyl)-phenyl]-methanesulfonamide (179) (0.5 g, 1.64 mmol) in dry THF (14 mL) was added to the reaction mixture and heated at reflux for another 2 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL) followed by 10% K2CO3 (10 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was loaded onto silica gel and purified by flash chromatography with a hexanes:EtOAc gradient (100:0 to 60:40) to give 0.5 g (71%) of the title compound 180 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (s, 6H), 0.87 (s, 6H), 1.24 (s, 2H), 1.88-1.89 (m 4H), 2.95 (s, 3H), 3.70 (s, 3H), 6.83 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H), 7.08 (m, 4H), 9.66 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[H][H]>[Pd].CO>[C:8]([C:5]1[CH:4]=[C:3]([NH2:12])[CH:2]=[CH:7][CH:6]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cccc(N)c1

Procedure:
1-Bromo-4-tert-butyl-2-nitro-benzene (18 g) was reduced as described in General Method 3 using 10% palladium on charcoal (1 g) and MeOH (100 mL) in a hydrogen atmosphere (50 psi). The catalyst was filtered, and the solvents were evaporated. The residue was taken in EtOAc (100 mL) and washed with saturated sodium bicarbonate solution and H2O. The solution was dried and concentrated. The residue was purified by flash chromatography to give 3-tert-butyl-phenylamine. MS (APCI): 150 (M+H).
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[F:23][CH:24]([F:56])[C:25]1[CH:29]=[C:28]([CH:30]([F:32])[F:31])[N:27]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]3[S:43][CH:44]=[C:45]([C:47](=[O:55])[CH2:48][CH:49]4[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]4)[N:46]=3)[CH2:38][CH2:37]2)=O)[N:26]=1>C1(C)C=CC=CC=1>[F:23][CH:24]([F:56])[C:25]1[CH:29]=[C:28]([CH:30]([F:32])[F:31])[N:27]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]3[S:43][CH:44]=[C:45]([C:47](=[O:55])[CH2:48][CH:49]4[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]4)[N:46]=3)[CH2:38][CH2:37]2)=[S:10])[N:26]=1
Reactant: O=C(CC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C(CC1CCCCC1)c1csc(C2CCN(C(=S)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
At room temperature, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (194 mg) was added to a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (200 mg) in toluene (2 ml). The reaction mixture was stirred at 60° C. for 2 hours. After removal of the solvent under reduced pressure, the residue was purified chromatographically. This gave 1-[2-(1-{2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanethioyl}-piperidin-4-yl)-1,3-thiazol-4-yl]-2-cyclohexylethanone (101 mg, 49%).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[C:24]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)[CH:23]=2)=[O:20])=[CH:38][C:39]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(I)c3)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 225-227° C.; 1H NMR (300 MHz, DMSO-d6) δ: 10.82 (1H, s), 8.35 (1H, d, J=2.1 Hz), 8.27 (1H, s), 8.13 (1H, s), 7.99-8.03 (1H, dd, J=2.1 and 8.1 Hz), 7.81-7.84 (1H, d, J=8.7 Hz), 7.76 (1H, s), 7.66-7.68 (2H, m), 7.46-7.49 (1H, d, J=9.0 Hz), 6.76-6.80 (1H, d, J=9.3 Hz), 4.40 (1H, m), 2.32-2.34 (2H, m), 2.17 (3H, brs), 1.87-1.97 (2H, m), 1.71-1.76 (2H, m). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C28H24ClF3N6O: 276.0821. found: 276.0819.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: COc1ccc(CC2CCCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)cc1
Yield: 28 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-methoxybenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 28% yield: mp 116-118° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.39-7.23 (m, 5H), 7.08 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.00 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.29-4.20 (m, 1H), 3.97-3.88 (m, 1H), 3.76 (s, 3H), 3.37-3.27 (m, 1H), 2.82-2.67 (m, 2H), 2.63 (s, 3H), 2.08-1.93 (m, 1H), 1.92-1.71 (m, 2H), 1.62-1.44 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 166.3, 156.7, 152.3, 151.1, 146.2, 131.9, 124.9, 124.2, 122.9, 121.9, 121.7, 113.4, 107.9, 49.3, 42.2, 38.3, 38.1, 30.7, 18.8, 15.3, 11.4; MS (ES+) m/z 450.2 (M+1).
Reaction SMILES: [O:1]([CH2:8][CH:9]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[O:1]([CH2:8][CH:9]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C(O)C(COc2ccccc2)N2CCC(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(O)C(COc2ccccc2)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
A solution of 2.5 g (+) threo 1-phenoxymethyl-1-(4-benzylpiperidin-1-yl)-2-p-nitrophenyl-2-hydroxy-ethane and 0.5 g of Pd/C 10% in 25 ml of ethanol was hydrogenated at normal pressure at 30° C. After removal of the catalist, the solution was concentrated to small volume affording 1.7 g of (+) threo 1-phenoxymethyl-1-(4-benzylpiperidin-1-yl)-2-p-aminophenyl-2-hydroxy-ethane, m.p. 146-147° C.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:3]1=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:20][N:21]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C=O)C>[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:25][CH2:24][CH2:23][C:22]([N:21]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[CH3:20])=[O:27])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:3]1=[O:4]
Reactant: Cn1c(=O)ccc2cc(O)ccc21
Reactant: CN(C(=O)CCCCl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)CCCOc1ccc2c(ccc(=O)n2C)c1)C1CCCCC1

Procedure:
1.75 Grams of 1-methyl-6-hydroxycarbostyril, 1.8 g of K2CO3 and 0.5 g of KI are added to 50 ml of DMF, and then 2.8 g of N-methyl-N(4-chlorobutyryl)cyclohexylamine is added gradually dropwise to this solution at 60° to 70° C. under agitation, followed by additional 4-hour agitation at the same temperature and removal of the solvent by distillation. The residue is dissolved in 200 ml of chloroform, washed with diluted hydrochloric acid, a 1% aqueous NaOH solution and water and then dried with anhydrous Na2SO4. After filtering off the inorganic matter, the mother liquor is concentrated and the residue is crystallized from petroleum ether. The obtained crystals are recrystallized from benzene-ligroin to produce 0.6 g of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)-propoxy]carbostyril in the form of colorless needle-like crystals with melting point of 118.5°-119.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Product: Cc1cc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)c(Cl)cc1Cl
Yield: 24.5 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 2,4-dichloro-5-methylbenzene sulfonyl chloride (14.3 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) yielding 4.7 mg (24%) of the title compound. MS (ESI+) calcd for C14H11Cl2N5O2S 383.001051, found 383.000871.
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][O:4][NH2:5].[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>C(Cl)(Cl)Cl>[CH:13]([NH:16][C:17]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:18])([CH3:15])[CH3:14]
Reactant: NOCC(O)CN1CCCCC1
Reactant: CC(C)N=C=O
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)NOCC(O)CN1CCCCC1

Procedure:
O-(2-hydroxy-3-piperidino-propyl)-hydroxylamine (1,74 g, 0,01 mol) was dissolved in 25 ml abs. chloroform and under stirring, 0,98 ml (0,01 mol) isopropyl isocyanate was added. The reaction was monitored by chromatography. At the end of the reaction the solution was evaporated and the oily residue purified by column chromatography. The oil thus obtained was crystallized with methanol-ether.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][CH3:13])[C:5](=[O:10])[CH2:6][C:7](=[O:9])[CH3:8])[CH2:2][CH3:3].CC(O[Na])=O.O.[Cl-].[C:21]1([N+:27]#[N:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:11]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:10])[C:6](=[N:28][NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7](=[O:9])[CH3:8])[CH2:12][CH3:13]
Reactant: CCCN(CCC)C(=O)CC(C)=O
Reactant: N#[N+]c1ccccc1
Agent: CC(=O)O[Na]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCCN(CCC)C(=O)C(=NNc1ccccc1)C(C)=O
Yield: 14.5 %

Procedure:
18.5 g (0.1 mol) of N,N-dipropyl-3-oxobutyramide, 12 g (0.146 mol) of CH3COONa, 20 ml of water, 75 ml of ethanol and a solution of 0.1 mol of phenyldiazonium chloride were treated as described in preparation 2. The precipitated solid was filtered and dried in vacuo yielding 4.2 g of the title compound. M.p.=79°-80° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[O:23])[CH:18]=[CH:19][CH:20]=1>CN(C)C=O>[F:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2cccc(F)c2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.9 g of m-fluorophenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.[CH3:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([CH2:30][C:31]1[CH:32]=[C:33]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:34]=[CH:35][CH:36]=1)(=[O:28])=[O:29]
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: CS(=O)(=O)Cc1cccc(Br)c1
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CS(C)(=O)=O)c3)cc2C1

Procedure:
The title compound was prepared from N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide and (3-bromophenyl)methyl methyl sulfone in a similar manner to Example 16.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.O.ON1C2C=CC=CC=2N=N1.[CH3:22][N:23]1[CH2:28]C[O:26][CH2:25][CH2:24]1.CN(C)CC(O)=O.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:25](=[O:26])[CH2:24][N:23]([CH3:28])[CH3:22])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromoindoline (0.5 g, 2.52 mmol), 1-hydroxybenzotriazole hydrate (0.387 g, 2.52 mmol), N-methylmorpholine (1.11 mL, 10.1 mmol) and 2-(dimethylamino)acetic acid (0.299 g, 2.9 mmol) in N,N-dimethylformamide (9.5 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.678 g, 3.53 mmol) and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with water (100 mL) and extracted with 1:1 ether/ethyl acetate (2×120 mL). The combined organic layers were washed with water (2×80 mL) and brine (2×80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column eluting with a gradient of from 0% to 5% methanol in dichloromethane to provide the title compound. MS DCI (+) m/z 283.0 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.N[C:24]1[CH:29]=CC=C[CH:25]=1>>[C:1]1([NH:4][C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([B:14]3[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:12][CH:13]=2)=[O:6])[CH:3]=[CH:2][CH:29]=[CH:24][CH:25]=1
Reactant: Nc1ccccc1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(NC(=O)Nc3ccccc3)cc2)OC1(C)C

Procedure:
A procedure analogous to that used for the preparation of 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was used, using aniline as the amine component.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](OCC)=[O:12])[CH2:2]1.[BH4-].[Na+].[NH4+].[Cl-]>CO.C1COCC1>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH2:2]1
Reactant: CCOC(=O)C1=Cc2ncccc2OC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: OCC1=Cc2ncccc2OC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
A solution of intermediate (24) (0.0032 mol) in methanol (dry) (2 ml) and THF (dry) (16 ml) was stirred at 0° C. NaBH4 (0.0128 mol) was added portionwise at 0° C. The reaction mixture was stirred for 5 hours at room temperature. A 10% NH4Cl solution was added and this mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent evaporated, yielding 0.45 g of 2H-pyrano[3,2-b]pyridine-3-methanol (intermediate 25).
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][Si](C(C)(C)C)(C)C)=[C:17]([O:29][Si](C(C)(C)C)(C)C)[CH:16]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([C:8]1[N:12]=[C:11]([CH:13]=[CH:14][C:15]2[CH:16]=[C:17]([OH:29])[C:18]([OH:21])=[CH:19][CH:20]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=Cc2nc(Cc3ccccc3)no2)cc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc(C=Cc2nc(Cc3ccccc3)no2)cc1O
Temperature: 5 °C
Reaction time: 3 h

Procedure:
3-Benzyl-5-{2-[3,4-bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-vinyl}-[1,2,4]oxadiazole (compound of Example 4, Method B, Step 1) (4.60 g, 8.79 mmol) was dissolved in THF (30 mL) and cooled to 5° C. This was followed by addition of 1 M solution of TBAF in THF (12.72 mL, 43.95 mL) over a period of 15 min and allowed to warm to room temperature. After 3 h stirring at room temperature, the solvent was evaporated and the reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (30 mL) and stirred for 10 min followed by extraction with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[NH:4][N:3]=1.[CH3:11]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]([CH3:11])[N:3]=1
Reactant: Ic1n[nH]c2c1CCCC2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2c1CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 3-iodo-4,5,6,7-tetrahydro-1H-indazole (674 mg, 2.72 mmol) in THF (10 mL) at 0° C. was added KOtBu 1M in THF (3.8 mL, 3.8 mmol) and the mixture stirred at 0° C. for 30 min where it became a brown-reddish solution then added MeI (540 mg, 238 μL, 3.8 mmol). The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 18 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to an off-white solid. Then dissolved in toluene and purified by chromatography (115 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 15 min to afford the more polar desired 3-iodo-1-methyl-4,5,6,7-tetrahydro-1H-indazole (570 mg, 2.17 mmol, 80.0%) as an off-white solid. MS (M+H)+=263 (100% purity); 1H NMR (CDCl3) δ: 3.72 (s, 3H), 2.42-2.72 (m, 2H), 2.30 (t, J=6.0 Hz, 2H), 1.56-1.93 (m, 4H). The regioisomer 3-iodo-2-methyl-4,5,6,7-tetrahydro-2H-indazole (182 mg, 694 μmol, 25.6%) as also obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.[OH-:15].[Na+]>C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:15][CH2:13][CH:12]([OH:14])[CH2:11][O:10][CH2:13][CH:12]([OH:14])[CH2:11][O:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(OCC(O)COCC(O)COc2ccc(N)cc2)cc1

Procedure:
PEG (10 g) is treated at 50° with aliquots (20 ml) of 10% aqueous glycidyl p-nitrophenyl ether and with portions (10 ml) of 10% aqueous sodium hydoxide. After 36 hours the solution is neutralized with 2 N acetic acid and evaporated. The PEG ether is extracted from the residue with benzene and precipitated by the addition of excess petroleum ether (bp 30-40).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19])=[N+:2]=[N-:3].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>CN(C=O)C>[N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Reaction time: 24 h
Yield: 78.1 %

Procedure:
A solution of 25.0 g (93.6 mmol) of 5'-azido-5'-deoxythymidine (which can be prepared as in reference 36), 21.1 g (140 mmol) of t-butyldimethylsilyl chloride, and 12.7 g (187 mmol) imidazole in 190 ml of anhydrous DMF was stirred at RT under nitrogen for 18 hr. The DMF was removed under vacuum. The oil was partitioned between ether (500 ml) and 1N NaOH (2×300 ml). The aqueous layers were cooled with ice, and 650 ml of 1N HCl were added. The product was extracted with EtOAc (2×750 ml), and the organic layer was washed with brine, dried, and evap. After remaining under high vacuum for 24 hr, the oil crystallized to give 27.9 g of 5'-azido-3'-O-t-butyldimethylsilyl-5'-deoxythymidine as a white solid: NMR (300 MHz,d6-DMSO) δ11.34 (br,1H), 7.50 (s,1H), 6.16 (t,1H,J=7 Hz), 4.36 (m,1H), 3.84 (m,1H), 3.55 (m,2H), 2.34 (m,1H), 2.05 (m,1H), 1.79 (s,3H), 0.86 (s,9H), 0.08 (s,6H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[I:19]Cl>C(O)(=O)C>[C:1]([O:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([I:19])=[C:14]([F:18])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: ClI
Reactant: CC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5(R)-acetoxymethyl-3-(3-fluorophenyl)oxazolidin-2-one (6.33 g) in acetic acid (40 mL) was added iodine monochloride (1.91 mL), the mixture was stirred at room temperature for 18 hours, and then concentrated in vacuo. The resulting residue was dissolved with ethyl acetate, the mixture was washed with aqueous sodium hydrogencarbonate solution, 20% sodium sulfite solution and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give crude 5(R)-acetoxymethyl-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (9.48 g).