Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[CH3:13][C:2]([O:1][C:23](=[O:24])[CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C)(C)OC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.5 %

Procedure:
To a -30° C. solution of 2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (1.05 g, example 1, Step 2) in dichloromethane (20 mL) was added 3-phenylpropionyl chloride (1.68 g) in dichloromethane (10 mL) followed by pyridine (791 mg) and the mixture was allowed to warm up slowly to 25° C. and stirred for 12 h. Ethyl acetate was added to the mixture and it was washed with 1N HCl, brine, dried over magnesium sulfate filtered and the solvent was evaporated under vacuum. Purification by silica gel chromatography afforded 1.36 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[N:13][NH:14][C:15](=O)[C:10]=2[N:9]=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:15]1[N:14]=[N:13][CH:12]=[C:11]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][C:10]=12
Reactant: O=c1[nH]ncc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)nncc32)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(2-chloro-phenyl)-1-(4-chloro-phenyl)-1,5-dihydro-imidazo[4,5-d]pyridazin-4-one (I-2g, 22 mg, 0.062 mmol) in POCl3 (3 ml) was heated under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in toluene and again concentrated. This procedure was repeated twice. The residue was then taken up in CH2Cl2, and H2O was added. The pH of the aqueous solution was adjusted via addition of sat'd aq NaHCO3 until the pH was neutral (˜7). The CH2Cl2 layer was separated and the aqueous solution was extracted with CH2Cl2 (3×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give I-2h as a pale yellow oil (22 mg): +APCI MS (M+1) 375.0/377.0; 1H NMR (CDCl3) δ 7.18–7.23 (2H, m), 7.35–7.48 (5H, m), 7.56–7.60 (1H, m), 9.22 (1H, s).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][O:14]C(=O)C)[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][OH:14])[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Reaction time: 2 h
Yield: 45.3 %

Procedure:
1-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-2-azetidinone (1.94 g, 7.15 mmol) is dissolved in anhydrous methanol (20 ml) cooled to 0° and a solution of NaOMe (0.36 mmol) in MeOH (0.5 ml) is added to the mixutre stirred at 0° for 2 hours. HOAC (0.1 ml) is added the mixture is evaporated under vacuum and the residue is taken up in CH2Cl2 ; washed with water, 5% NaHCO3, dried and evaporated to a pale yellow oil This is chromatographed on silica gel using EtOAc as eluant, to give 1-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-2-azetidinone 0.743 g (45%).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]1=[O:24])[C:5](O)=[O:6].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:62][C:63]1([CH3:75])[O:67][C@H:66]([CH2:68][N:69]2[CH:73]=[CH:72][C:71]([NH2:74])=[N:70]2)[CH2:65][O:64]1>CN(C)C=O.C(OCC)(=O)C>[CH3:62][C:63]1([CH3:75])[O:67][C@H:66]([CH2:68][N:69]2[CH:73]=[CH:72][C:71]([NH:74][C:5](=[O:6])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=[CH:16][CH:15]=4)=[CH:10][C:9]3=[O:24])[CH2:3][CH:2]([CH3:25])[CH3:1])=[N:70]2)[CH2:65][O:64]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3ccccc23)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3ccccc23)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A solution of (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (0.37 g, 1.11 mmol) in N,N-dimethylformamide (4.27 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.55 mL, 3.33 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.73 g, 1.66 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.24 g, 1.22 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (75 mL) and was washed with a saturated aqueous ammonium chloride solution (1×150 mL), a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 10-30% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.43 g, 76%) as a light orange solid: HR-ES-MS m/z calculated for C29H34N4O5 [M+H]+ 519.2602, observed 519.2604; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.3 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.41-1.69 (m, 2H), 1.70-1.85 (m, 1H), 3.74 (dd, J=8.3, 5.9 Hz, 1H), 4.00 (dd, J=8.3, 6.5 Hz, 1H), 4.11 (t, J=5.6 Hz, 2H), 4.28-4.44 (m, 2H), 4.65-4.77 (m, 2H), 4.90 (dd, J=10.4, 4.7 Hz, 1H), 6.46 (d, J=2.1 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.54-7.67 (m, 4H), 7.91 (d, J=8.2 Hz, 1H), 7.99-8.09 (m, 2H), 10.80 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][C:24]1[CH:33]=[C:32]([C:34](O)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:37])[CH:30]=2)[N:25]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:34]([C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH3:37])[CH:30]=4)[N:25]=[C:24]([CH3:23])[CH:33]=3)=[O:35])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: Cc1ccc2nc(C)cc(C(=O)O)c2c1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: Cc1ccc2nc(C)cc(C(=O)N3CCCC[C@@H]3COc3cccc4c3C(N)=NS(=O)(=O)N4)c2c1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2,6-dimethylquinoline-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.12-1.53 (m, 2H), 1.58-1.84 (m, 4H), 1.98 (s, 3H), 2.64 (s, 3H), 3.02 (m, 1H), 3.19 (m, 1H), 4.18 (dd, 1H, J=9.9, 3.1 Hz), 4.95 (t, 1H, J=10.2 Hz), 5.45 (m, 1H), 6.66 (m, 1H), 7.01 (d, 1H, J=8.2 Hz), 7.27 (s, 1H), 7.38 (s, 1H), 7.46-7.61 (m, 2H), 7.81 (d, 1H, J=8.6 Hz), 7.98 (br s, 1H), 8.26 (br s, 1H), 10.94 (s, 1H). MS 494 (MH+).
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:19][CH:20]1[C:31](=[O:32])[N:22]2[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]([CH3:27])[S:26][C@H:21]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:19][CH:20]2[C:31](=[O:32])[N:22]3[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]([CH3:27])[S:26][C@H:21]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CON=C(C(=O)O)C1=CSCCO1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)C1=CSCCO1
Yield: 57.6 %

Procedure:
A solution of 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer, 1.4 g.), dry N,N-dimethylformamide (0.59 ml.) and phosphoryl chloride (1.17 g.) in dry ethyl acetate (12.3 ml.), and a solution of 7-amino-2-methyl-3-cephem-4-carboxylic acid (1.35 g.) and trimethylsilylacetamide (5.75 g.) in ethyl acetate (40 ml.) were treated in a similar manner to that of Example 14 to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer, 1.45 g.)
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]([NH:16][C:17]3[C:18]([CH3:26])=[N:19][C:20]([O:24][CH3:25])=[N:21][C:22]=3[CH3:23])[N:12]([CH2:27][CH2:28][CH2:29]O)[C:11]=2[C:10]([C:31]([O:33][CH3:34])=[O:32])=[CH:9][CH:8]=1.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.[Cl-].[NH4+].C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:17]3[C:22]([CH3:23])=[N:21][C:20]([O:24][CH3:25])=[N:19][C:18]=3[CH3:26])[CH2:29][CH2:28][CH2:27][N:12]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)nc(OC)nc3C)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 76.5 %

Procedure:
Methanesulfonyl chloride (4.57 mL, 57.8 mmol) was added to a stirred solution of methyl 4-chloro-1-(3-hydroxypropyl)-2-[(2-methoxy-4,6-dimethylpyrimidin-5-yl)amino]-1H-benzimidazole-7-carboxylate (Reference example 127, 11.9 g, 28.9 mmol) and triethylamine (12.1 mL) in tetrahydrofuran (400 mL) at 0° C. The mixture was stirred at 0° C. for 50 min, and concentrated in vacuo. A mixture of the resulting mesylate and potassium carbonate (12.0 g, 86.8 mmol) in N,N-dimethylformamide (200 mL) was stirred at 80° C. for 2 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (8.88 g, 22.1 mmol, 76% in 2 steps).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH2:24][C:22]1[C:23]2[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[CH:16][N:17]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCOCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2C1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(4-benzyloxyphenyl)-7-(tetrahydropyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (2.83 g), 10% palladium on carbon (1.41 g), ammonium formate (2.31 g) and ethanol (250 ml) was boiled under reflux under nitrogen with stirring for 1.5 hours. The mixture was cooled to ambient temperature, filtered, then the filtrate cooled and filtered. The filtrate was evaporated to give a solid 4-[4-amino-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenol.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+].O>C(O)C>[F:17][CH:2]([F:1])[C:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(C(F)F)c2ncccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 112 %

Procedure:
0.5 g (2.0 mmol) of methyl 8-difluoromethyl-5-quinolinecarboxylate was dissolved in 5 ml of ethanol, 0.43 g (10.5 mmol) of sodium hydroxide and 1 ml of water were added, and the mixture was stirred at 25° C. for 20 hours. The solvents were subsequently removed, the residue was taken up in water, washed twice with methylene chloride and adjusted to pH 1 using 10 N hydrochloric acid, and the precipitate was filtered off with suction. Drying gave 0.5 g of 8-difluoromethyl-5-quinolinecarboxylic acid (colorless crystals);
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16](O)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:44]1([C:50]([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(OCC)C.C(OCC)(=O)C.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:55]2[CH2:54][CH2:53][CH:52]([C:50]([N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:51])[CH2:57][CH2:56]2)=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(C1CCNCC1)N1CCCCC1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(C(=O)N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.8 %

Procedure:
The following was added sequentially to anhydrous DMF (2 mL): 1-(4-fluorobenzyl)-1H-indole-2-carboxylic acid (50 mg, 0.186 mmol), Hunig's Base (0.065 ml, 0.371 mmol), EDC (46.3 mg, 0.241 mmol), HOBT (37.0 mg, 0.241 mmol), and piperidin-1-yl(piperidin-4-yl)methanone (36.4 mg, 0.186 mmol). The solution was allowed to stir at room temperature for 24 h. At this time, a 1:1 solution of diethylether/ethyl acetate (5 mL) was added, and this was washed with aqueous 10% Na2CO3 (3×2 mL). The extract was then dried with anhydrous MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (20 g silica, 80% EtOAc/Hex) to provide 29 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:6]([C@H:9]([C@H:12]([CH3:14])[OH:13])[O:10][CH3:11])[O:7][CH3:8])[CH:4]=[O:5].N1C=CN=C1.Cl[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[C:24]([Si:21]([CH3:23])([CH3:22])[O:5][C@H:4]1[C@H:3]([O:2][CH3:1])[C@H:6]([O:7][CH3:8])[C@@H:9]([O:10][CH3:11])[C@H:12]([CH3:14])[O:13]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@H]([C@@H](OC)[C@H](C=O)OC)[C@H](C)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1OC
Reaction time: 72 h
Yield: 41.2 %

Procedure:
Tri-O-methylrhamnose (20.0 g, 97.0 mmol) was dissolved in CH2Cl2 (400 mL) and treated with imidazole (10.0 g, 147 mmol) and chloro-tert-butyldimethyl silane (TBSCl; 20.0 g, 132 mmol). After 3 days (d), the reaction mixture was partitioned between water (H2O) and CH2Cl2, and the organic layer was washed with brine, dried over sodium sulfate (Na2SO4) and concentrated. The crude residue was further purified by chromatography on silica gel (10-20% ethyl acetate (EtOAc) in petroleum ether as eluant) to give the title compound (12.8 g, 82%) as a clear syrup in a 20:80 α:β ratio. The physical properties of the major β-epimer are: 1H NMR (CDCl3) δ 4.55 (s, 1H), 3.58 (s, 3H), 3.48 (m, 1H), 3.45 (s, 3H), 3.40 (s, 3H), 3.00 (m, 3H), 1.24 (d, J=6.2 Hz, 3H), 0.80 (s, 9H), 0.05 (s, 6H); EIMS m/z 263 ([M-tBu]+, 1), 88 (100).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I.Cl>O.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:15])[N:3]=1
Reactant: II
Reactant: Oc1cccnc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
2-Bromo-pyridin-3-ol (5 g) is dissolved in water (150 ml) and thereto are added sodium carbonate (6.15 g) and iodine (7.65 g) and the mixture is stirred at room temperature for 2 hours. Thereto are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give 2-bromo-6-iodo-pyridin-3-ol (4.52 g). MS (m/z): 300/302 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:20]=[C:21]([C:23]([CH3:26])=[CH:24][CH:25]=1)[NH2:22]>CN(C=O)C>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:21]([NH:22][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH:20]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Cc1ccc(Cl)cc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)cc1Nc1ncnc(Cl)n1
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (3 g, 20 mmol) was dissolved in DMF (20 mL) under N2 and cooled to 0° C. DIEA (2.58 g, 20 mmol) was added, followed by 3-chloro-6-methylaniline (2.83 g, 20 mmol). The reaction solution was stirred with gradual warming to RT. The reaction was quenched after 3 h with water, then extracted 3 times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered, and concentrated. The crude was eluted through a 17×2.5 cm column of silica gel (25%, 40%, 60% EtOAc/Hexane step gradient) giving (5-chloro-2-methyl-phenyl)-(4-chloro-[1,3,5]triazin-2-yl)-amine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: Ic1ccc(N(Cc2ccncc2)c2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccncc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 73.9 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (72 mg) was reacted with N-(4-iodophenyl)-N-((pyridin-4-yl)methyl)pyrimidin-2-amine (93 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyridin-4-ylmethyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (99 mg). Column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=1/2→1/3) was used for purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:24])[CH2:13][NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:17])=[CH:11][C:5]=2[CH2:4][O:3]1.[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:24])[CH2:13][N:14]([C@@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][OH:17])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN[C@H](CO)c3ccccc3)ccc2O1
Reactant: O=CCCCCCOCCCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)[C@H](CO)c3ccccc3)ccc2O1
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a cloudy mixture of (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanol (500 mg) and crude 6-(4-phenylbutoxy)hexanal (400 mg) in CH2Cl2 (3 ml) under nitrogen was added sodium triacetoxyborohydride (433 mg) in one portion. A gelatinous mixture formed initially which thinned over a 15 min period. The resulting light yellow solution was stirred for 18 h before it was partitioned between ethyl acetate (10 ml) and saturated aqueous NaHCO3 (30 ml). The aqueous layer was extracted with ethyl acetate (3×20 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo to give the title compound (725 mg).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:32])([F:20])[F:33])[CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-[3-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.79 (m, 2H), 7.57-7.70 (m, 7H), 3.84 (s, 2H); MS (ESI−) M/Z 456 (M−H)−.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(CC)CC.[CH3:11][C:12]([CH3:43])([CH3:42])[C:13](=[O:41])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([C:37](Cl)=[O:38])[CH:31]=[CH:30]3)([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:40].Cl>O>[CH3:1][N:2]([CH3:3])[C:37]([C:32]1[CH:31]=[CH:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13](=[O:41])[C:12]([CH3:43])([CH3:42])[CH3:11])=[C:17]([CH3:40])[CH:18]=3)([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:28]=2)[CH:33]=1)=[O:38]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)Cl)ccc2c1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
Treat a solution of dimethylamine (2.0 M in THF) (0.12 mL, 0.25 mmol) and Et3N (0.034 mL, 0.25 mmol) in CH2CL2 (3 mL) with 6-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carbonyl chloride (0.057 g, 0.123 mmol) in CH2CL2 (1 mL). Stir the mixture at RT for 16 h; dilute with CH2CL2 and water. Acidify the resulting mixture to pH 1 using 5N HCl. Separate the organic layer from the aqueous layer. Wash the organic layer with brine, dry over Na2SO4, and filter. Concentrate the filtrate to give the title compound as a yellow solid (0.033 g, 57%). MS (ES) m/e 474 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14](F)[CH:13]=1>CN(C=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[C:16]([CH:17]=1)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: Cc1ccc(Br)cc1F
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1OC1CCN(C)CC1
Reaction time: 0.5 h

Procedure:
Add sodium hydride (60% dispersion in oil, 880 mg, 22 mmol) to a solution of 4-hydroxy-1-methyl-piperidine (2.304 g, 20 mmol) in DMF (12 mL), stir. After 30 min., add 4-bromo-2-fluorotoluene (4.159 g, 22 mmol) and beat at 70° C. After 21 hr., quench the reaction with saturated NaHCO3 solution, extract with ether three times, combine the organic layers, wash with saturated NaCl solution, dry over Na2SO4, filter and concentrate to give a residue. Purify by chromatography (silica gel, eluting with 6% 2M NH3-methanol in CH2Cl2) provides of the title compound as a slightly yellow oil (3.90 g, 69%). Mass spectrum (ion spray): m/z=284.0 (M+1); 1H NMR (CDCl3, ppm): 7.01 (m, 3H), 4.35 (m, 1H), 2.66 (m, 2H), 2.36 (m, 2H), 2.34 (s, 3H), 2.19 (s, 3H), 2.03 (m, 2H), 1.85 (m, 2H).