Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(F)c(C#N)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(F)c(C#N)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of compound methyl (3-cyano-4-fluorophenyl)acetate (200 mg, 1.03 mmol) in 15 mL of anhydrous THF was cooled to −78° C. NaHMDS (1.11 mmol) was added to the reaction dropwise at −78° C. After the addition, the mixture was stirred at −78° C. for 1 h and then CH3I (160 mg, 1.33 mmol) was added to the reaction dropwise at −78° C. The reaction was warmed to room temperature slowly and stirred at ambient temperature over night. The reaction was quenched with NH4Cl solution, extracted with EtOAc. The orgianic layer was washed with saturated chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified via preparative TLC to afford methyl 2-(3-cyano-4-fluorophenyl)propanoate.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1([C:35]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([S:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH2:5][CH2:4]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCC1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(S(=O)(=O)c2cccc3ccccc23)CC1)C1CCCCC1
Yield: 95.6 %

Procedure:
To a solution of 4-aminomethyl-1-(1-naphthylsulfonyl)piperidine (608 mg, 2.0 mmol) and triethylamine (303 mg, 3.0 mmol) in dichloromethane (30 mL) stirring at room temperature under argon, was added cyclohexanecarbonyl chloride (325 mg, 2.2 mmol) in a single portion. After 2 h the solvent was evaporated under vacuum, and the residue was slurried with diethyl ether and filtered. The filtrate was evaporated, and purification by column chromatography (silica gel, ethyl acetate in hexane) provided 4-(N-cyclohexylcarbonylaminomethyl)-1-(1-naphthylsulfonyl)piperidine (793 mg, 96% yield) as a gum.
Reaction SMILES: [IH:1].[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:9][C:10](=[NH:13])SC)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH2:22][CH2:23][CH2:24]N>ClC1C=CC=CC=1Cl>[IH:1].[C:2]1([CH:8]([NH:9][C:10]2[N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][N:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCCN
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Agent: I
Solvent: Clc1ccccc1Cl
Product: CN1CCCN=C1NC(c1ccccc1)c1ccccc1

Procedure:
To 38.43 grams (0.10 mole) of 1-diphenylmethyl-2-methyl-2-thiopseudourea hydroiodide in 270 milliliters of o-dichlorobenzene was added 8.81 grams (0.10 mole) of N-methyl-1,3-diaminopropane, and the resulting mixture was allowed to reflux for about 21 hours to produce the desired 2-diphenylmethylamino-1,4,5,6-tetrahydro-1-methylpyrimidine product. Thereafter, the mixture was allowed to cool, the solvent was decanted off and isopropanol was added to the residue to obtain 35.0 grams (86 percent yield) of a 2-diphenylmethylamino-1,4,5,6-tetrahydro-1-methylpyrimidine hydroiodide salt. After successive recrystallizations from acetone-ether and acetone-isopropanol, a purified product was obtained having a melting point (151°) 169°-171° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[O:8])=[CH:12][CH:11]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: Clc1ccc(I)cc1
Product: Cc1ccc(=O)n(-c2ccc(Cl)cc2)c1
Yield: 75 %

Procedure:
The reaction of 5-methyl-2-(1H)-pyridone and 1-chloro-4-iodobenzene (Aldrich Chemical Company) in the procedure of Example 1 yields 1-(4'-chlorophenyl)-5-methyl-2-(1H)-pyridone as a white crystalline solid in 75% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)c(OC)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(OC)c(OC)c3)c2)=C(C)C1=O
Yield: 34.9 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,4-dimethoxyaniline (0.100 g, 0.196 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.032 g, 0.0685 mmol, 35%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([N+:14]([O-])=O)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH3:2]>C(O)C.[Pd]>[NH2:14][C:13]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CCOc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc2cccnc2c1N

Procedure:
7-Ethoxy-8-nitroquinoline (2.62 g, 12.0 mmole) in absolute ethanol (200 mL) was shaken with 10% palladium on carbon (0.10 g) under hydrogen (50 psi) for 3 hr. The catalyst was filtered off and the filtrate concentrated to 10 mL. The title compound crystallized as yellow needles (1.86 g, 82%); mp 94°-95°. Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.16; H, 6.47; N, 14.87.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[N:24]=[C:23]([CH:25]=O)[CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:27]([C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[C:31]=1[NH2:32])([CH3:29])[CH3:28].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH:1]1([NH:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]2[N:24]=[C:23](/[CH:25]=[N:32]/[C:31]3[C:33]([CH:37]([CH3:38])[CH3:39])=[CH:34][CH:35]=[CH:36][C:30]=3[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=Cc1cccc(-c2c(CNC3CCCCC3)ccc3ccccc23)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(-c2c(CNC3CCCCC3)ccc3ccccc23)n1
Temperature: 25 °C

Procedure:
A solution of 9.80 g (28.0 mmol) of 6-{2-[(cyclohexylamino)methyl]-1-naphthyl}pyridine-2-carbaldehyde, 5.55 g (31.0 mmol) of 2,6-diisopropylaniline, 0.1 g of TsOH in 100 ml of dry ethanol was refluxed for 10 h in argon atmosphere. The resulting mixture was cooled to room temperature and then evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate-triethylamine=10:1:1, vol.). Yield 10.8 g (77%) of yellow powder. Anal. Calc for C35H41N3: C 83.45; H 8.20; N 8.34. Found: C 83.59; H 8.06; N 8.41.1H NMR (CDCl3): δ 8.39 (m, 1H, 3-H in Py), 8.35 (s, 1H, CHN), 8.00 (m, 1H, 4-H in Py), 7.87-7.92 (m, 2H, 4,8-H in naphthyl), 7.63 (m, 1H, 3-H in naphthyl), 7.54 (m, 1H, 3-H in Py), 7.37-7.47 (m, 3H, 5-H in Py and 6,7-H in naphthyl), 7.09-7.17 (m, 3H, 3,4,5-H in naphthyl), 3.69 (m, 2H, CH2N), 3.01 (sept, J=6.8 Hz, 2H, CH in 2,6-diisopropylphenyl), 2.29 (m, 1H, CH in Cy), 1.61-1.72 (m, 4H, Cy), 1.52-1.54 (m, 2H, Cy), 1.19 (d, J=6.8 Hz, 12H, CH3 in 2,6-diisopropylphenyl), 1.09-1.11 (m, 2H, Cy), 0.94-0.99 (m, 2H, Cy).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Fc1cc(F)c2c(c1)NCC2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(F)cc(F)cc21
Yield: 59.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 310 mg of 4,6-difluoro-2,3-dihydro-1H-indole, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 225 mg of 2-[2-(4,6-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:9]=1)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>O1CCOCC1>[CH3:3][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:33](=[O:34])[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:24][CH:25]=2)[N:9]=1)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: CC(C)(c1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1)S(C)(=O)=O
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(c1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
(4-{4-[1-Methyl-1-(methylsulfonyl)ethyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)amine (1.5 g, 3.98 mmol) was dissolved in dioxane (15 mL). Sodium bicarbonate (503 mg, 5.98 mmol) was added, followed by phenyl chloroformate (0.502 mL, 3.98 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 20 mL DCM and 20 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (700 mg).
Reaction SMILES: [NH2:1]N.C[N:4](/[CH:6]=[C:7]1/[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:11]/1=O)C>C(O)C>[NH:1]1[C:11]2[CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C:7]=2[CH:6]=[N:4]1
Reactant: NN
Reactant: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C1

Procedure:
A solution of hydrazine (3 mL) and tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (19.22 g) in ethanol (40 mL) was heated at 85° C. in a sealed tube for 4 h. Solvent was removed under reduced pressure, and the residue was triturated with dichloromethane (160 mL) and ethyl acetate (15 mL). The resulting solid was filtered. The filtrate was concentrated and the resulting solid was triturated again. The combined solids were used in the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[O:33][N:32]=[C:31]([CH3:34])[CH:30]=4)[CH:24]=3)[CH2:20][C:19](=[O:35])[NH:18][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-chloro-5-dimethylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M6) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (68 mg).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:27])[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[C:23]2=[N:24][S:25][N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].Cl>C1COCC1.O>[N:26]1[S:25][N:24]=[C:23]2[C:18]([S:15]([NH:14][C:8]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=3[C:6]([OH:27])=[O:5])(=[O:17])=[O:16])=[CH:19][CH:20]=[CH:21][C:22]=12
Reactant: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12
Reaction time: 18 h
Yield: 99.9 %

Procedure:
LiOH.H2O (0.68 g, 16.2 mmol) was added to a stirred solution of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acid methyl ester (1.56 g, 4.06 mmol) in THF (15 mL) and water (5 mL). After 18 h, the solution was acidified to pH 2 with conc. HCl, diluted with water, and extracted with DCM (3×). The combined organic layers were dried (MgSO4), and concentrated to provide the title compound (1.50 g, 100%). HPLC: RT=9.48 min. MS (ESI−): mass calcd. for C13H8ClN3O4S2, 368.96; m/z found, 368/370 [M−H]. 1H NMR (500 MHz, CDCl3): 11.07 (s, 1H), 8.38 (dd, J=7.0, 1.0, 1H), 8.24 (dd, J=8.8, 1.0, 1H), 7.92 (d, J=2.5, 1H), 7.75 (d, J=9.0, 1H), 7.71-7.69 (m, 1H), 7.40 (dd, J=9.0, 2.6, 1H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[CH2:25]1[CH2:30][CH2:29][C:28]([CH2:35][NH2:36])([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]1.C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:36][CH2:35][C:28]2([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30][CH2:25][CH2:26][CH2:27]2)=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NCC2(CC(=O)O)CCCCC2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (30 mg, 0.09 mmol), gabapentin (96 mg, 0.56 mmol, TCI) and sodium methoxide (28 mg, 0.53 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes with 0.5% formic acid) to give the title compound in 11 mg. MS: (−) m/z 458.00 (M-1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[N+:20]([O-:34])[CH:21]=[CH:22][C:23]=1[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1cc[n+]([O-])cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A solution of tert-butyl{4-chloro-2-[(4-methylpyridin-3-yl)ethynyl]phenoxy}acetate (Intermediate 19; 110 mg; 0.31 mmol) in DCM (5 mL) was treated with 3-chloroperbenzoic acid (91 mg; 0.37 mmol) and stirred at RT for 2 hours. The solvents were removed under vacuum, the residue was taken up in EtOAc and the organic phase washed with a saturated bicarbonate solution twice, then with brine. The organic layer was then dried over MgSO4 and concentrated under vacuum to afford the title compound (110 mg, 96%) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: NCCN1CCOCC1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCN3CCOCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 2-morpholin-4-yl-ethylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (30 mg, 0.08 mmol). 8-Cyclohexyl-5-oxo-2-(2-morpholin-4-yl-ethylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (25 mg, 80%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H31N5O4: 430.24 (M+H). Found: 430.2.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:31])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: COCCN
Product: COCCNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 77.4 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 43 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5][O:4]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[CH:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:12]1([C:10](=[O:11])[CH2:9][N:7]2[CH2:6][CH2:5][O:4][C@H:3]([CH2:2][O:1][C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)[CH2:8]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=C(CN1CCO[C@H](CO)C1)N1CCc2ccccc21
Reactant: COc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OC[C@@H]2CN(CC(=O)N3CCc4ccccc43)CCO2)c1
Yield: 78.4 %

Procedure:
Essentially the same procedure was used to make compound 24s as was used for compound 18s (Example 16), with compound 48 (Example 7; 55 mg, 0.2 mmol), 3-methoxyphenol (0.032 ml, 0.3 mmol), triphenylphosphine (78 mg, 0.3 mmol), DEAD (0.05 ml, 0.3 mmol), and THF (1 ml). The crude residue was purified twice by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2) to afford the title compound as a colourless oil (60 mg; 78%). Analyses were performed on the free base, and the free base was converted to the HCl salt for testing.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2[C:7]([C:16]#[CH:17])=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:19])[CH2:3]1.I[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2[C:7]([C:16]#[C:17][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:19])[CH2:3]1
Reactant: C#Cc1c(N2CCOCC2)sc2c1CC(C)(C)CC2=O
Reactant: Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(C#Cc3ccc(O)cc3)c2C1
Reaction time: 0.83 h
Yield: 82.4 %

Procedure:
To a stirred solution of Example 38 (0.10 g, 0.35 mmol) and 4-iodophenol (0.11 g, 0.52 mmol) in diisopropylamine (7 mL) at 60° C. was added Pd(PPh3)2Cl2 (0.02 g, 0.03 mmol) followed by CuI (0.01 g, 0.05 mmol). After stirring for 50 minutes, the reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc (25 mL). The organics were then washed with sat. aqueous NaHCO3 (10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 3:1 EtOAc/hexanes) gave the title compound (0.11 g, 85%) as an off-white powder. δH (DMSO-d6) 9.89 (1H, br. s), 7.31 (2H, d, J 8.2 Hz), 6.79 (2H, d, J 8.2 Hz), 3.78 (4H, m), 3.68 (4H, m), 2.67 (2H, s), 2.35 (2H, s), 1.06 (6H, s). LCMS (ES−) 380.4 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][CH:23]2O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:23]2[C:24]3[C:20](=[C:19]([O:18][CH3:17])[CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: COc1cccc2c1CCC2O
Reactant: CCO[C@@H](CC(=O)OC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCO[C@@H](CC(=O)OC)c1ccc(OC2CCc3c(OC)cccc32)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.446 mmol) produced in Example 41 (41C) and 4-methoxy-1-indanol (110 mg, 0.669 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (87 mg, yield: 53%).