Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23](OCC)=[O:24])[CH2:18][CH2:17]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:28][NH2:29]>C(O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH:28][NH2:29])=[O:24])[CH2:18][CH2:17]2)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CN1CCN(Cc2c3ccccc3cc3ccccc23)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2c3ccccc3cc3ccccc23)CC1

Procedure:
Synthesized according to General Procedure C: 6{21} (6.82 g, 18.8 mmol, 1 equiv.), anhydrous hydrazine (1.8 mL, 56.4 mmol, 3 equiv.), ethanol (38.0 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{21} (3.56 g, 54%) as an orange semi-solid. 1H-NMR (500 MHz, CDCl3): δ 8.46 (d, 2H, J=8.5 Hz), 8.42 (s, 1H), 8.21 (br s, 1H), 8.01 (d, 2H, J=8.5 Hz), 7.53 (ddd, 2H, J=1.5, 6.5, 8.0 Hz), 7.47 (ddd, 2H, J=1.0, 6.5, 8.0 Hz), 4.45 (s, 2H), 3.87 (br s, 2H), 3.04 (s, 2H), 2.64 (br s, 4H), 2.47 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 131.3, 131.3, 129.2, 128.9, 127.5, 125.6, 124.9, 124.8, 60.4, 54.0, 53.7, 53.1.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:20][S:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]12[CH2:18][O:17][C:14]([CH3:19])([O:15][CH2:16]1)[O:13][CH2:12]2.[CH:32]1(C23OCC(CO)(CO2)CO3)[CH2:35]C[CH2:33]1>>[Na:1].[CH:19]1([C:14]23[O:15][CH2:16][C:11]([CH2:10][O:9][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([CH2:20][S:21]([C:23]5[NH:24][C:25]6[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=6[N:27]=5)=[O:22])[C:3]=4[CH3:2])([CH2:12][O:13]2)[CH2:18][O:17]3)[CH2:35][CH2:32][CH2:33]1
Reactant: OCC12COC(C3CCC3)(OC1)OC2
Reactant: Cc1c(OCC23COC(C)(OC2)OC3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Product: Cc1c(OCC23COC(C4CCC4)(OC2)OC3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 2.3 %

Procedure:
The same procedure as in the steps (24b) to (24f) of Example 24 was repeated using (1-cyclobutyl-2,6,7-trioxabicyclo[2.2.2]oct-4-yl)methanol obtained in the step (38a) above to obtain the title compound (56 mg, 2.3%) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([CH2:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:18])[C:6]2[C:19]([N:36](CC)[C:37](=O)[C:38](F)(F)F)=[C:20]([C:23]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][OH:34])[CH2:28][CH2:27]3)=[O:24])[N:21]([CH3:22])[C:5]=2[CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([C:3]1[N:8]([CH2:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:18])[C:6]2[C:19]([NH:36][CH2:37][CH3:38])=[C:20]([C:23]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][OH:34])[CH2:28][CH2:27]3)=[O:24])[N:21]([CH3:22])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(c(N(CC)C(=O)C(F)(F)F)c(C(=O)NC3CCN(C(=O)CO)CC3)n2C)c(=O)n1CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCNc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2cc(CC)n(CC(=O)c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
A mixture of the compound of Reference Example 25 (50 mg, 0.10 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (24 mg, 0.13 mmol), HOBt (21 mg, 0.16 mmol), WSCD (30 mg, 0.16 mmol) and triethylamine (21 mg, 0.21 mmol) in DMF (2 ml) was stirred at room temperature for 2 days. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted twice with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluate, ethyl acetate) to give 6-ethyl-3-[ethyl(trifluoroacetyl)amino]-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (40 mg, 65%) as a colorless amorphous solid. A mixture of the 6-ethyl-3-[ethyl(trifluoroacetyl)amino]-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (40 mg, 0.065 mmol) and potassium carbonate (18 mg, 0.13 mmol) in methanol (3 mL) was stirred at room temperature for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (22 mg, 65%) as beige crystals.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:7]([Cl:16])=[N:8][CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>ClCCl>[Cl:16][C:7]1[C:6]([N:5]=[C:1]=[S:2])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: COC(=O)c1cnc(Cl)c(N)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cnc(Cl)c(N=C=S)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 76.1 %

Procedure:
Thiophosgene (6.367 g, 55.37 mmol) in dichloromethane (10 mL) was added to a mixture of methyl 5-amino-6-chloronicotinate (8.61 g, 46.14 mmol) and sodium carbonate (9.781 g, 92.29 mmol) in dichloromethane (200 mL). The reaction mixture was stirred for four days at ambient temperature. The reaction mixture was washed with water and brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 12:1 hexane:ethyl acetate to afford methyl 6-chloro-5-isothiocyanatonicotinate (8.03 g, 76.1% yield) as a white solid: 1H NMR (CDCl3) δ 3.97 (s, 3H), 8.09 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Z-Pro (7.5 gm, 0.03 mole) and N-Hydroxysuccinimide (3.45 gm, 0.03 mole) were dissolved in cold dioxane and dicyclohexylcarbodiimide (DCC) (6.18 gm, 0.03 mole) was added with rapid stirring. The mixture was stirred overnight at room temperature and the next day the solid dicyclohexylurea (DCU) was filtered off. The solvent was removed and the oil was recrystallized from isopropyl alcohol. Crystals of Z-Pro-OSu formed with scratching. Yield 8.4 gm. Melting point 86.5°-87.5° C.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:6][C:5]1=[O:24])[CH:2]=[CH2:3].Cl.[NH2:27][C@@H:28]([CH2:32][CH3:33])[C@@H:29]([OH:31])[CH3:30].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C@H:8]([C@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[OH:6])[CH2:9][C@:4]([CH3:25])([CH2:1][CH:2]=[CH2:3])[C:5]([NH:27][C@@H:28]([CH2:32][CH3:33])[C@@H:29]([OH:31])[CH3:30])=[O:24])[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Reactant: CC[C@H](N)[C@H](C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@@H](CC)[C@H](C)O
Temperature: 25 °C

Procedure:
To a 10 mL round-bottom reaction flask was added (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (750 mg, 1.998 mmol), (2S,3S)-3-aminopentan-2-ol hydrochloride (837 mg, 6.00 mmol, reference: J. Org. Chem., 2003, 68 (26), 9948), and triethylamine (1966 μl, 13.99 mmol). The vessel was fitted with a reflux condensor and heated to 85 to 95° C. for 2d. The reaction was cooled to RT and diluted with ethyl acetate and washed with 1N HCl (2×20 mL) and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography using 40 to 50% ethyl acetate in hexanes afforded (S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:13]([CH2:27][CH2:28][CH3:29])[C:14]([C:16]1[CH:17]=[C:18]([CH:23]=[C:24](I)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])[CH3:12]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([N:13]([CH2:27][CH2:28][CH3:29])[C:14]([C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])[CH3:12]
Reactant: c1cocn1
Reactant: CCCN(CC)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (106 mg, 1.5 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.0 mL, 1.7 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 4.6 mL, 4.6 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-{[ethyl(propyl)amino]carbonyl}-5-iodobenzoate (535 mg, 1.45 mmol) in anhydrous tetrahydrofuran (1.8 mL) followed by palladium(0)tetrakis(triphenylphosphine) (120 mg, 0.10 mmol). The reaction mixture is heated at reflux for 2 h. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound. ESI MS m/z 317.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>C(O)(=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCc1ccc(N)cc1
Solvent: CC(=O)O
Product: CCOC(=O)CCNc1ccc(CC)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-ethyl aniline (10.00 g) in acetic acid (20 mL) was added ethyl acrylate (8.26). The mixture was heated to 70° for 3.5 hours. The mixture was allowed to cool to room temperature. The mixture was partitioned between dichloromethane and water, and was extracted three times. The combined organics were washed once with brine, dried with sodium sulfate, filtered, and concentrated. The mixture was taken on to the next step. MS (ESI+) for C13H19NO2 m/z 223.1 (M+H)+.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@@H:8]([OH:9])[C@H:4]2[CH2:3][NH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=1.C(N(CC)CC)C>C(O)C>[F:18][C:17]([F:20])([F:19])[C:13]1[N:12]=[C:11]([N:2]2[CH2:3][C@@H:4]3[C@H:8]([OH:9])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)[CH:16]=[CH:15][CH:14]=1
Reactant: O[C@@H]1CC[C@@H]2CNC[C@@H]21
Reactant: FC(F)(F)c1cccc(Br)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 80 °C

Procedure:
(3aR,4R,6aS)-Octahydrocyclopenta[c]pyrrol-4-ol (1.65 g, 12.97 mmol) from Example 29, 2-bromo-6-(trifluoromethyl)pyridine (3.66 g, 16.22 mmol) and triethylamine (7.23 mL, 51.9 mmol) were combined in ethanol (7.23 mL). The reaction was heated at 80° C. for 24 hours and the solvent was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 0-40% ethyl acetate/hexane as eluent to give the title compound and the title compound of Example 31: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.47 (t, J=7.9, 1H), 6.94 (d, J=7.2, 1H), 6.53 (d, J=8.6, 1H), 6.38 (d, J=4.1, 1H), 4.47-4.38 (m, 1H), 4.12 (dd, J=11.0, 4.3, 1H), 3.70-3.63 (m, 1H), 3.53 (t, J=10.0, 1H), 3.38 (dd, J=10.4, 4.6, 1H), 2.80-2.73 (m, 1H), 2.72-2.64 (m, 1H), 1.97-1.74 (m, 3H), 1.64-1.56 (m, 1H); MS (ESI+) m/z 273 (M+H)+.
Reaction SMILES: [PH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].[N:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[N+]=[N-]>>[CH2:2]([P:1]([CH2:4][CH3:5])([NH:6][Si:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH3:3]
Reactant: CCPCC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: CCP(CC)(=N[Si](C)(C)C)N[Si](C)(C)C
Yield: 72 %

Procedure:
This compound was synthesized as above by using Et2PH instead of Ph2PH. Et2PH (2.00 mL, 17.4 mmol, d=0.7862) and N3SiMe3 (5.00 mL, 35.8 mmol, d=0.868, 95%) were refluxed overnight in a round bottom flask with a reflux condenser under a positive pressure of nitrogen. After 12 hours the product was distilled through a short path distillation apparatus (0.01 mm, 56-60° C.) to yield a clear liquid (3.30 g, 72%). 1H NMR (C6D6): δ 1.12 (overlapping dq, CH2, 4H), 0.84 (overlapping dt, CH3, JHP=17.3 Hz, JHH=7.4 Hz, 6H), 0.73 (br s, NH, 1H), 0.29 (s, SiCH3, 18H). 13C{1H} NMR (C6D6): δ 26.6 (d, PCH2CH3, JCP=78.2 Hz), 6.5 (d, PCH2CH3, JCP=3.7 Hz), 3.3 (exchange broadened s, SiMe3); 31P{1H} NMR (C6D6): δ 20.1. Analysis calculated for C10H29N2PSi2: C, 45.41; H, 6.06; N, 4.81. Found: C, 68.73; H, 6.13; N, 4.73.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=2[N:15]=[CH:16][CH:17]=1>C(O)C.C1COCC1.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:13]=12
Reactant: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc(N)cc3F)ccnc21
Reaction time: 8 h

Procedure:
115 mg (0.29 mmol) of N-(2-fluoro-4-nitrophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine are dissolved in 10 ml of a mixture of ethanol/THF (1:1). 13 mg (0.06 mmol) of platinum(IV) oxide are added, and the mixture is stirred under an atmosphere of hydrogen under atmospheric pressure overnight. The suspension is then filtered through Celite and the solvent is removed under reduced pressure.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)[OH:5])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.O>[CH3:21][S:22]([O:5][CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:9]=[CH:8][N:7]=1)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])(=[O:24])=[O:23]
Reactant: CCC(CC)C(O)c1ncnn1Cc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)C(OS(C)(=O)=O)c1ncnn1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol (0.368 g, 1.32 mmol) in pyridine (15 mL) at 0° C. was added methanesulfonyl chloride (0.61 mL, 7.9 mmol) and the solution was slowly warmed to room temperature. The mixture was diluted with H2O, extracted twice with EtOAc and dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:29])=[C:22]([C:2]2[CH:3]=[N:4][C:5]([N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9](=[O:11])[CH3:10])=[N:6][CH:7]=2)[CH:21]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: CC(=O)N(Cc1ccccc1)c1ncc(Br)cn1
Product: CC(=O)N(Cc1ccccc1)c1ncc(-c2cc(Cl)ccc2O)cn1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.16 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2O)n1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Temperature: 100 °C
Yield: 66.8 %

Procedure:
To a solution of 1-(5-Chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 2 (0.6 g, 2.0 mmol) in DMF (5 mL) were added potassium carbonate (0.84 g, 6.1 mmol), potassium iodide (0.34 g, 2.0 mmol) and 4-chlorobenzylbromide (0.38 g, 2.2 mmol). The resulting mixture was heated at 100° C. overnight. The mixture was poured into water (20 mL) and extracted with Et2O (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (Na2SO4) and the volatiles were removed in vacuo to give 0.56 g (71%) of 1-(2-Benzyloxy-5-chloro-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 3 as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:10]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:12]=[N:13][CH:14]=3)=[CH:7][CH:8]=2)[S:26]1
Reactant: O=C1CSC(=O)N1
Reactant: CN(Cc1cncc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Product: CN(Cc1cncc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Yield: 58.2 %

Procedure:
In a manner similar to that of Example 1(d), starting with 0.8 g (2.4 mmol) of N-[5-(4-formylphenyl)pyrid-3-ylmethyl]-N-methylbenzamide and 0.35 g (2.9 mmol) of 2,4-thiazolidinedione, 0.6 g (60%) of N-{5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][C:9]2[CH:10]=[C:11]([C:21]3[N:22](C(OC(C)(C)C)=O)[C:23]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[CH:24][CH:25]=3)[CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][CH2:17][C@H:16]([CH3:20])[O:15][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([C:21]2[NH:22][C:23]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[CH:24][CH:25]=2)[CH:12]=1)[O:8][C:7]1[CH:38]=[CH:39][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reaction time: 2.5 h
Yield: 93.9 %

Procedure:
t-Butyl 2-{3-(4-acetylphenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (73 mg, 0.133 mmol) synthesized in Example (39a) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (2.0 mL) was added dropwise with stirring under nitrogen atmosphere, and stirring was carried out at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-40%) to afford the desired compound (56 mg, yield 94%) as a pale yellow liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:21][CH2:22]2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 79 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}-2-methylpropan-1-one (30 mg, 0.068 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (27 mg, 0.102 mmol) to afford the desired product (27.4 mg, 79%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 8.77 (s, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.07-7.99 (m, 2H), 7.55-7.51 (m, 1H), 7.44 (dd, J=11.6, 2.2 Hz, 1H), 3.54-3.42 (m, 3H), 3.38-3.33 (m, 4H), 3.21-3.11 (m, 4H), 2.15-2.06 (m, 5H), 1.99 (d, J=11.0 Hz, 2H), 1.75-1.64 (m, 2H), 1.26 (d, J=6.9 Hz, 6H); ESI MS m/z 510 [C29H33ClFN3O2+H]+; HPLC 97.7% (AUC), tR=11.07 min.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:44]2[CH:53]=[N:52][C:51]3[NH:50][C:49](=[O:54])[CH2:48][O:47][C:46]=3[CH:45]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:44]4[CH:53]=[N:52][C:51]5[NH:50][C:49](=[O:54])[CH2:48][O:47][C:46]=5[CH:45]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OB(c2cnc3c(c2)OCC(=O)N3)OC1(C)C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
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: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)OCC(=O)N5)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (32.0 mg, 0.061 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (20.0 mg, 0.073 mmol) in dioxane (0.5 mL) was added Pd(PPh3)4 (3.5 mg, 0.003 mmol) and 2N K2CO3 (127 μL, 0.255 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 100° C. for 10 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O5S: 643.2; found: 643.3.