Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([Cl:29])[C:25]([C:30]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[N:24]3)=[C:19]([C:41]([N:43]3[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]3)=[O:42])[CH:18]=1)=[O:16])(=[O:13])=[O:12])[N:7]([CH2:53][CH3:54])[CH2:6][CH2:5]2.[CH:55](/B(O)O)=[CH:56]\[CH2:57][CH3:58].[O-]P(=O)=O.[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH:55](/[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([Cl:29])[C:25]([C:30]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[N:24]3)=[C:19]([C:41]([N:43]3[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]3)=[O:42])[CH:18]=1)=[O:16])(=[O:12])=[O:13])[N:7]([CH2:53][CH3:54])[CH2:6][CH2:5]2)=[CH:56]\[CH2:57][CH3:58]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3cc4c(cc3Br)CCN4CC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Reactant: CC/C=C/B(O)O
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Product: CC/C=C/c1cc2c(cc1S(=O)(=O)NC(=O)c1ccc(-n3nc(C(=O)N(CCCC)CCCC)c(Cl)c3C)c(C(=O)N3CCc4ccccc4C3)c1)N(CC)CC2
Temperature: 90 °C
Yield: 71.2 %

Procedure:
To a sealed tube containing 1-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 71, 16 mg, 0.019 mmol) in dioxane (1.0 mL) was added (E)-but-1-enylboronic acid (8 mg, 0.076 mmol), Pd2(dba)3 (9 mg, 10 μmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (9 mg, 0.019 mmol) and potassium metaphosphate (5 mg, 0.038 mmol). The reaction mixture was purged with nitrogen for 1 min and then heated at 90° C. for 16 h. The reaction mixture was then diluted with EtOAc and 1N aq. HCl solution. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (11 mg, 64%) as a pale yellow solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.06-8.05 (m, 1H), 7.94 (br s, 1H), 7.65-7.63 (m, 1H), 7.30-7.11 (m, 6.5H), 6.93 (d, J=7.0 Hz, 0.5H), 6.05-5.95 (m, 1H), 4.75-4.50 (m, 2H), 3.95-3.55 (m, 1H), 3.49-3.41 (m, 2H), 3.25 (t, J=6.8 Hz, 2H), 3.15-3.10 (m, 2H), 3.00-2.96 (m, 3H), 2.90-2.65 (m, 2H), 2.33 (s, 2H), 2.28 (s, 1H), 2.21-2.18 (m, 2H), 1.58-1.02 (m, 11 H), 1.03-0.95 (m, 5H), 0.93-0.87 (m, 3H), 0.77 (t, J=7.3 Hz, 2H), 0.69 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 813.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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.COCCOC.CCO>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:19][CH2:20]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3Cl)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.11 g, 0.327 mmol), 2-chlorophenylboronic acid (51 mg, 329 μmol), 5 mL DME/EtOH (4:1), 0.5 mL 2M K2CO3 and tetrakis(triphenylphosphine)palladium (20mg) was stirred at 90° C. for 1 h. The reaction mixture was cooled to RT. The crude product was purified via flash chromatography (silica gel) with 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the crude compound (120 mg) as a yellow solid. The compound was further purified by HPLC by dissolving the crude product in methanol (˜20 mg/mL) and injecting at a rate of about 0.500 mL per injection onto the Gilson preparatory HPLC. Pure product fractions were collected, combined, basefied with sodium bicarbonate (saturated, aqueous), extracted with CH2Cl2, separated, dried over sodium sulfate, and concentrated via rotary evaporation to give pure title compound (28.8 mg) as a white solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][S:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([Cl:34])=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:8]1=2)(O)=[O:2].[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42]([NH2:45])(=[O:44])=[O:43]>>[Cl:34][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[CH:33][C:24]([CH2:23][O:22][C:20]3[CH:19]=[CH:18][C:9]4[O:10][CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH:7]([S:6][CH2:5][CH2:4][C:1]([NH:45][S:42]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[CH3:35])(=[O:44])=[O:43])=[O:2])[C:8]=4[CH:21]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: Cc1ccccc1S(N)(=O)=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
11-(2-Carboxyethylthio)-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and 2-methylbenzenesulfonamide were used and reacted in the same manner as in Example 39 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1.C(N(CC)CC)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])[CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CN2CCN(S(=O)(=O)c3ccccc3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To 2-Chloro-7-methyl-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (100 mg) in anhydrous DCM (2 ml) and triethylamine (1.5 equiv., 60 μl) at 0° C. was added benzenesulfonyl chloride (1.3 equiv., 45.5 μl) and the reaction mixture was allowed to warm up to room temperature overnight. Chloroform/brine extraction and purification on silica gave 2-chloro-6-(4-benzenesulfonyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (104 mg).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([C:11]1[S:12][CH:13]=[C:14](Br)[N:15]=1)=[O:10])[CH2:2]2.C(O)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[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>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([C:11]1[S:12][CH:13]=[C:14]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[N:15]=1)=[O:10])[CH2:2]2
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(c1nc(Br)cs1)N1CC2CCC(C1)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(c1nc(-c2ccc(Cl)cc2)cs1)N1CC2CCC(C1)O2
Temperature: 92.5 °C
Yield: 57.6 %

Procedure:
To a solution of 8-oxa-3-azabicyclo[3.2.1]octan-3-yl(4-bromothiazol-2-yl)methanone (Step-1 of compound 67, 1.1 g, 3.63 mmol) in a mixture of toluene:ethanol (5 ml:15 ml) were added (4-chlorophenyl) boronic acid (0.85 g, 5.44 mmol) and potassium carbonate (1.25 g, 9.07 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.36 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC; the reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with mixture of 10% methanol in dichloromethane (2×50 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 25% ethyl acetate in hexanes as an eluent to obtain the title compound (0.7 g, 57.8%). MS: m/z 335 (M+1).
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]2=[N:7][C:6]=1[CH3:16].Br.Br.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=[C:28]2[NH:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=[C:28]2[NH:36][CH:37]2[CH2:38][CH2:39][N:40]([CH2:3][CH2:4][C:5]3[C:10](=[O:11])[N:9]4[C:12]([CH3:15])=[CH:13][S:14][C:8]4=[N:7][C:6]=3[CH3:16])[CH2:41][CH2:42]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 62.8 %

Procedure:
A mixture of 5.52 parts of 6-(2-bromoethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 7.3 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 6.4 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 5 parts (62.8%) of 6-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 141.0° C. (compound 1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)c1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 66A (0.023 g, 0.076 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.013 g, 42% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.47 (m, 2 H), 2.28 (s, 3 H), 2.39 (m, 1 H), 2.78 (m, 6 H), 3.22 (m, 1 H), 3.54 (m, 4 H), 3.84 (d, J=9.93 Hz, 1 H), 3.93 (m, 1 H), 4.04 (s, 1 H), 4.25 (m, 3 H), 4.45 (d, J=6.99 Hz, 1 H), 6.88 (d, J=9.93 Hz, 1 H), 7.05 (m, 7 H), 7.24 (m, 4 H), 7.32 (m, 1 H), 7.54 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:26](I)[CH2:27][CH2:28][CH3:29]>O1CCCC1>[CH2:9]([O:8][C:7]1[C:2]([NH:1][CH2:26][CH2:27][CH2:28][CH3:29])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCI
Reactant: Nc1ncccc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCNc1ncccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2-amino-3-benzyloxypyridine (2.50 g, 12.5 mmol) dissolved in tetrahydrofuran (10 mL) and cooled to 0° C. was slowly added a solution of 1N lithium hexamethyldisilazide in tetrahydrofuran (12.5 mL, 12.5 mmol). The ice bath was removed and the solution stirred for 30 minutes. The bath was replaced and n-butyl iodide (2.30 g, 1.4 mL, 12.5 mmol) was added to the solution. After the addition was complete, the bath was removed and the solution stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo and the residue dissolved in ethyl acetate (25 mL). The solution was washed with water (25 mL) and brine (25 mL), dried and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane afforded the desired product as an offwhite solid (2.75 g, 86% yield). 1H NMR (CDCl3, 300 MHz) δ 0.95 (t, J=7 Hz, 3 H), 1.42 (sextet, J=7 Hz, 2H), 1.60 (m, 2H), 3.44 (dt, J=7 Hz, 1 Hz, 2H), 4.92 (bt, 1H), 5.06 (s, 2H), 6.45 (dd, J=8 Hz, 6 Hz 1H), 6.86 (dd, J=8 Hz, 1 Hz, 1H), 7.37 (m, 5H), 7.73 (dd, J=6 Hz, 1 Hz, 1H). MS (DCl/NH3) m/e 257 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]([O:12][CH3:13])=[O:11])=[C:5]2[C:9]=1[NH:8][CH:7]=[N:6]2.[H-].[Na+].C([N:35]1[C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[CH:53]=[CH:52][C:49]([CH2:50]Br)=[CH:48][CH:47]=2)=[N:38][N:37]=[N:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>CN(C=O)C.C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[S:3][C:4]([C:10]([O:12][CH3:13])=[O:11])=[C:5]2[C:9]=1[N:8]=[CH:7][N:6]2[CH2:50][C:49]1[CH:52]=[CH:53][C:46]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[C:39]2[NH:35][N:36]=[N:37][N:38]=2)=[CH:47][CH:48]=1
Reactant: COC(=O)c1sc(C)c2[nH]cnc12
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1sc(C)c2ncn(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
To a solution of methyl 4-methylthieno[3,4-d]-imidazole-6-carboxylate (0.20 g) in DMF (2 ml) was added sodium hydride (60% oil, 48 mg) under ice-cooling. The mixture was stirred for 15 minutes, and there which was added 4-[2'-(N-trityltetrazol-5-yl)phenyl]benzylbromide (0.68 g), followed by stirring for one hour at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography to give the first fraction and the second fraction. The oily substance obtained from the first fraction was dissolved in chloroform (3 ml) - methanol (12 ml), to which was added 1N-HC1 (0.5 ml), and the mixture was stirred for one hour at room temperature. The solvent was evaporated in vacuo. To the residue was added water, whose pH was adjusted to 3-4 with 1N NaOH, followed by extraction with chloroform. The extract was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography. The crystals thus obtained were recrystallized from ethyl acetate -hexane to afford colorless needles (0.12 g, 28%), m.p. 188°-189° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH:20]=[O:21].Cl.N>CCOCC.C1C=CC=CC=1>[CH3:28][O:27][C:23]1[CH:22]=[C:19]([CH:20]([C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=2)[OH:21])[CH:18]=[C:17]([O:16][CH3:15])[C:24]=1[O:25][CH3:26]
Reactant: Cc1ccnc(Br)c1C
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCOCC
Product: COc1cc(C(O)c2nccc(C)c2C)cc(OC)c1OC
Temperature: -40 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
40 g of 2-bromo-3,4-dimethylpyridine dissolved in 50 ml of anhydrous ether are slowly added, with agitation and under a nitrogen atmosphere, to 300 ml of a 0.9 M solution of butyl-lithium in ether cooled to -40° C. The resulting mixture is agitated for 2 hours at this temperature, and 50 g of 3,4,5-trimethoxybenzaldehyde dissolved in 200 ml of anhydrous benzene are added, and the mixture kept at a temperature below -25° C. Agitation is performed for 1 hour at -15° C, and the reaction is continued until ambient temperature is reached. The mixture is poured on to ice and dilute hydrochloric acid, the acid layer is made alkaline with a current of ammonia, while cooling externally with ice. The precipitate is collected by filtration, supplying 62.6 g of (II). Yield 96%. An analysis sample is crystallized from alcohol (m.p. = 104-6° C). Analysis: C17H21NO4. Calculated: C = 67.31, H = 6.98, N = 4.62. Found: C = 67.23, H = 7.33, N = 4.57.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:18][CH:17]([C:19]([NH2:21])=[O:20])[CH2:16][CH:15]([C:22]([NH2:24])=[O:23])[CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:18][CH:17]([C:19]([NH2:21])=[O:20])[CH2:16][CH:15]([C:22]([NH2:24])=[O:23])[CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)C1CC(C(N)=O)CN(S(=O)(=O)c2cccc([N+](=O)[O-])c2)C1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: NC(=O)C1CC(C(N)=O)CN(S(=O)(=O)c2cccc(N)c2)C1
Yield: 91.9 %

Procedure:
A solution of 1-(3-nitro-benzenesulfonyl)piperidine-3,5-dicarboxylic acid diamide (Example 47, 1.5 g, 4.2 mmol) in 300 ml of methanol was hydrogenated in Parr apparatus at 25 Psi over 0.1 g of the palladium catalyst (10% palladium on carbon) for 1.5 h. Filtration of the catalyst and solvent removing gave 1.26 g (92%) of the desired product as a light-gray solid. MS (ES) m/z 327.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:35])[N:6]([CH:34]=1)[C@@H:7]1[O:33][C@H:11]([CH2:12][O:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:9]([OH:10])[CH2:8]1.[OH-].[K+].[CH2:39](Cl)[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>O1CCOCC1>[F:1][C:2]1[C:3](=[O:36])[NH:4][C:5](=[O:35])[N:6]([CH:34]=1)[C@@H:7]1[O:33][C@H:11]([CH2:12][OH:13])[C@@H:9]([O:10][CH2:39][C:40]2[O:44][CH:43]=[CH:42][CH:41]=2)[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: ClCc1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccco3)[C@@H](CO)O2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
To a solution of 1.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 30 ml cf dioxane were added 0.35 g of finely divided powder of potassium hydroxide and 0.29 g of furfuryl chloride, and the mixture was stirred at 80° C. for 2 hours. The solvent was evaporated off and the residue was dissolved in 30 ml of ethyl acetate The solution was washed with water, dried and concentrated. The residue was dissolved in 15 ml of 80% acetic acid and the solution was left to stand at 80° C. for 2 hours The solvent was evaporated off and the residue was dissolved in 30 ml of ethyl acetate, and the solution was washed with water, dried and concentrated. The residue was treated with chloroform and the insoluble matters were filtered and recrystallized from ethanol, thereby giving 0.37 g of 2'- deoxy-5 fluoro-3'-O-furfuryluridine.
Reaction SMILES: N[C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].CS(O)(=O)=O.C(ON=O)(C)(C)C.C(=O)(O)[O-].[Na+]>>[Br:8][C:3]1[C:2]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Br
Reactant: OCC(F)(F)F
Agent: CC(C)(C)ON=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Product: FC(F)(F)COc1cccnc1Br

Procedure:
A reactor vessel is charged with 3-amino-2-bromopyridine (2.0 g, 11.4 mmol), 2,2,2-trifluoroethanol (20 g, 200 mmol), and methanesulfonic acid (1.7 g, 18 mmol). The solution is heated to the range 65° C. to 70° C. and then t-butylnitrite (1.46 g of a 90% solution, 12.7 mmol) is added drop-wise to the vessel while maintaining the temperature at 55° C. to 70° C. After nitrogen evolution ceases, the solution is cooled, neutralized with aqueous saturated sodium bicarbonate solution and then extracted with MTBE. The solvent is removed by evaporation to obtain 2-bromo-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (2.85 g, crude yield of 96%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=2[Cl:24])=[N:3][CH:4]=1
Reactant: Oc1cccc(Cl)c1Cl
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(Cl)c2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,3-dichlorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.6 Hz), 8.10–7.99 (4H, m), 7.48–7.21 (5H, m), 5.45–5.34 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].Cl>C(OCC)C.C(O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: ON=Cc1c(Cl)cncc1Cl
Temperature: 0 °C
Yield: 98.2 %

Procedure:
Combine 3,5-dichloropyridine-4-carboxaldehyde (2.80 g, 0.016 mol) with hydroxylamine hydrochloride (1.13 g, 0.018 mol) and ice (50 g) in an ethanol/water (30 mL/30 mL) mixture. Add aqueous sodium hydroxide (1.63 g, 0.024 mol, in 20 mL of water) dropwise and stir for 4 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid and extracte with diethyl ether. Dry the combined extracts over sodium sulfate and concentrate in vacuo to give the desired crude oxime (3.00 g, 88%) as a light solid. MS(ES): (M+1)+ 190.9, 192.9 m/z.