Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:36][NH2:37])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)[CH:28]=1)([CH3:22])([CH3:21])[CH3:20].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:36][NH:37][C:15](=[O:17])[CH:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12])=[C:2]([F:1])[CH:3]=2)[CH3:18])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)[CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Reactant: Cc1cccc(-c2cc(C(C)(C)C)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2cc(C(C)(C)C)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 121.8 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (66 mg, 0.18 mmol) and (5-tert-butyl-3′-methylbiphenyl-2-yl)methanamine (113 mg, 0.119 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (52 mg, 0.270 mmol), 1-hydroxybenzotriazole (36 mg, 0.27 mmol) and triethylamine (0.063 mL, 0.45 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography. N-((5-tert-Butyl-3′-methylbiphenyl-2-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanamide (example 21) (74 mg) was obtained as 81% yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1.[CH3:14]C1C(=O)NC(=O)NN=1.CC1N=NC(O[Si](C)(C)C)=NC=1O[Si](C)(C)C.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[C:8]([CH3:14])=[N:7]1
Reactant: Cc1n[nH]c(=O)[nH]c1=O
Reactant: O=c1cnn(CCCCCl)c(=O)[nH]1
Agent: Cc1nnc(O[Si](C)(C)C)nc1O[Si](C)(C)C
Agent: ClCCCCBr
Product: Cc1nn(CCCCCl)c(=O)[nH]c1=O

Procedure:
2-(4-Chloro-butyl)-6-methyl-2H-[1,2,4]triazine-3,5-dione were synthesized as described for the synthesis of 2-(4-Chloro-butyl)-2H-[1,2,4]triazine-3,5-dione starting from 6-methyl-2H-[1,2,4]triazine-3,5-dione which was converted into 6-methyl-3,5-bis-trimethylsilanyloxy-[1,2,4]triazine by the method described in working example 1 and thereafter reacted with 1-bromo-4-chloro-butane according to working example 2.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([N:26]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][NH:44][C@@H:45]([CH3:48])[CH2:46][OH:47])=[CH:39][CH:38]=2)=[N:29][N:28]=[N:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.O>C1(C)C=CC=CC=1>[OH:47][CH2:46][C@@H:45]([N:44]([CH2:43][C:40]1[CH:39]=[CH:38][C:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]2[N:26]([C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:27]=[N:28][N:29]=2)=[CH:42][CH:41]=1)[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH3:48]
Reactant: C[C@@H](CO)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Butyryl chloride (258 μL, 2.5 mmol) was added to a solution of intermediate (5a) (1.1 g, 2.1 mmol), and DIPEA (504 μL, 2.9 mmol) in toluene (20 mL) at 0° C. The solution was stirred at room temperature for 30 minutes. Water was added (20 mL), and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography gave intermediate (5b) as a white solid (942 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:12][CH3:13])(=[O:11])[CH2:7][C:8]([CH3:10])=O.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.[OH-].[Na+].[CH:24](Cl)(Cl)Cl>CN(C=O)C>[Br:14][C:15]1[CH:21]=[C:20]2[C:18](=[CH:17][CH:16]=1)[N:19]=[C:8]([CH3:10])[C:7]([C:6]([O:12][CH3:13])=[O:11])=[CH:24]2
Reactant: ClC(Cl)Cl
Reactant: COC(=O)CC(C)=O
Reactant: Nc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(Br)ccc2nc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To DMF (7.18 ml) was dropwise added phosphoryl chloride (8.64 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. To the mixture was added methyl acetoacetate (10 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0° C., and to the mixture was added 4-bromoaniline (16.78 g), and the mixture was stirred at 90° C. for 4 hours. To the reaction mixture was added chloroform, and the mixture was neutralized with 8N sodium hydroxide. The organic layer was washed with water and saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:2) and was recrystallized from ethyl acetate-hexane to give methyl 6-bromo-2-methylquinoline-3-carboxylate (6.02 g) as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16]N1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(C(C)(C)C)cc1

Procedure:
A solution of methyl 4-tert-butylphenylacetate (3.0 g), 1,3-dibromo-5,5-dimethylhydantoin (3.28 g) and azobisisobutyronitrile (AIBN, 0.01 g) in carbon tetrachloride (100 ml) was stirred in a 70° oil bath for hours. After cooling the mixture was filtered through Celite® and the filtrate was evaporated to give an oily residue of methyl α-bromo-4-tert-butylphenylacetate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[N:27]1([C@@H:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:34]3[CH2:35][CH2:36][CH2:37][C@@H:32]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:33]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: C1CNC[C@H](N2CCCC2)C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@@H](N4CCCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-3-(pyrrolidin-1-yl)piperidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=9.09 Hz, 1 H) 1.72-1.96 (m, 4 H) 1.96-2.11 (m, 2 H) 2.16 (br. s., 1 H) 2.43 (s, 3 H) 2.82-3.35 (m, 3H) 3.35-3.87 (m, 5 H) 4.26 (br. s., 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 2 H) 8.11 (d, J=8.08 Hz, 2 H) 8.57 (d, J=2.02 Hz, 2 H) 9.83 (br. s., 1 H); ESI-MS m/z [M+H]+ 457.3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]2[NH:16][N:15]=NN=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17](O)(=[O:19])[CH3:18]>>[CH3:18][C:17]1[O:19][C:12]([CH2:11][S:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[N:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(SCc2nnn[nH]2)cc1
Reactant: CC(=O)O
Product: Cc1nnc(CSc2ccc([N+](=O)[O-])cc2)o1
Temperature: 25 °C

Procedure:
To 5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole (4.0 g) was added anhydrous acetic acid, and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure. The obtained residue was dissolved in ethyl acetate/THF, washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 2-methyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,3,4-oxadiazole (3.3 g).
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>O1CCOCC1.[Cu](I)I>[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[C:24][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[CH:5][N:6]=1
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
6-Chloronicotinic acid methyl ester (500 mg; 2.93 mmol) was suspended in 1,4-dioxane (3 ml) in a 5 ml reaction vial. To the vessel was added dichlorobis(triphenylphosphine) palladium(ii) (70 mg; 3 mol %), copper iodide (12 mg), n,n-diisopropylethylamine (0.63 ml; 3.5 mmol) and 3,3-dimethylbut-1-yne (0.44 ml; 3.5 mmol). The vessel was sealed and the mixture was heated at 80° C. for 24 hrs. The solvents were evaporated to dryness and 20 ml of tetrahydrofuran and 20 ml of 10N NaOH was added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (590 mg; 99%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([CH:18]([CH2:20][N:21]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]#[CH:31])[OH:19])=[CH:13][C:12]=1[Cl:39]>C(NCC)C.C1COCC1.[Cu]I>[NH2:10][C:11]1[C:12]([Cl:39])=[CH:13][C:14]([CH:18]([CH2:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]#[C:31][C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[OH:19])=[CH:15][C:16]=1[Cl:17]
Reactant: C#CCOCCCCCCN(Cc1ccccc1)CC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: COc1cccnc1Br
Agent: [Cu]I
Solvent: CCNCC
Solvent: C1CCOC1
Product: COc1cccnc1C#CCOCCCCCCN(Cc1ccccc1)CC(O)c1cc(Cl)c(N)c(Cl)c1
Yield: 77.7 %

Procedure:
A solution of 2-bromo-3-methoxypyridine (2 g), 4-amino-3,5-dichloro-α-[[(phenylmethyl)[6-[(2-propynyl)oxy]hexyl]amino]methyl]benzenemethanol (5.74 g), BTPC (150 mg), copper (I) iodide (15 mg) in diethylamine (20 ml) and THF (10 ml) was stirred under nitrogen overnight. The solution was concentrated in vacuo to give a brown oil which was purified by FCC eluting with System C (95:5:1) to give the title compound as a brown oil (4.6 g), t.l.c. (System A 80:20:1) Rf 0.6.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>C(O)(C)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([NH:20][C:23](=[O:26])[CH2:24][CH3:25])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:9])=[CH:21][CH:22]=1)([OH:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Reactant: CCC(=O)Cl
Solvent: CC(C)O
Product: CCC(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1
Yield: 62 %

Procedure:
The procedure of Example 4 was repeated to react 2-(4-carboxybenzamido)-4-aminobenzoic acid with propionyl chloride, and the reaction product was treated as in Example 4 except that isopropyl alcohol was used as a solvent for recrystallization. The product obtained was a 62% yield of 2-(4-carboxybenzamido)-4-propionamidobenzoic acid having a melting point in the range of from 284° to 286° C. (decompose).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=[CH2:24])[C:11]1=[O:25])=[O:4].[Li+].[CH3:33]C([N-]C(C)C)C.CI>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:14][O:13][C@:12]([CH2:22][CH:23]=[CH2:24])([CH3:33])[C:11]1=[O:25])=[O:4].[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:14][O:13][C@@:12]([CH2:22][CH:23]=[CH2:24])([CH3:33])[C:11]1=[O:25])=[O:4]
Reactant: C=CC[C@H]1OCC(C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Product: C=CC[C@]1(C)OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-((R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (120 mg, 0.27 mmol, 1.0 equiv) in THF (1.0 mL) at −78° C. was added LDA (0.16 mL, 2.0 M in THF, 0.32 mmol, 1.2 equiv) and the resulting solution was stirred at −78° C. for 20 minutes. To the solution was then added methyliodide (192 mg, 1.35 mmol, 5.0 equiv). The solution was warmed to room temperature and the stirred at this temperature for 30 minutes. The reaction was quenched by addition of sat. aq. NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, EtOAc/heptane 25% to give product 3-((2S,5R)-2-Allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester 18 mg and product 3-((2R,5R)-2-Allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester 50 mg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])C=CC=CC=1.Cl>C1COCC1.C(OCC)(=O)C.O>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:18]
Reactant: COc1ccccc1C(=O)Oc1ccccc1
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(=O)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 59 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 2-Methoxy-benzoic acid phenyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(2-Methoxy-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.53 g, 8.3 mmol) as yellow solid in 59% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][CH2:26][C:27](OCC)=[O:28].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:26]([CH2:25][CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[C:27]2=[O:28])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCc1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCc2cccs2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 4-(2-thienyl)butanoate (1.5 eq., prepared in Synthetic Example 17) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(2-thienyl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 175 to 176° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:26]([N:29]=[C:30]=[O:31])([CH3:28])[CH3:27]>C1COCC1.CN(C=O)C>[CH:26]([NH:29][C:30](=[O:31])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)([CH3:28])[CH3:27]
Reactant: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)[C@H]1CN2CCC1CC2
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)OCc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
35 mg (0.10 mmol) of (3R)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo-[2.2.2]octane-3-carboxamide are dissolved in 1 ml of a 1:1 THF/DMF mixture. 17 mg (0.21 mmol) of isopropyl isocyanate are added, and the mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 23 mg (52% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].C[O:20][C:21](=O)[CH2:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=O.[Cl-].[NH4+]>>[C:4]([C:3]1[C:21](=[O:20])[CH:22]=[C:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[NH:1][C:2]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)#[N:5]
Reactant: COC(=O)CC(=O)c1ccc(C(=O)OC)cc1
Reactant: N#CC=C(N)c1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: COC(=O)c1ccc(-c2cc(=O)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)[nH]2)cc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of 3-amino-3-(4-phenoxyphenyl)acrylonitrile (0.517 g, 2.188 mmol) and methyl 4-(3-methoxy-3-oxopropanoyl)benzoate (2.068 g, 8.75 mmol) was microwaved at 230° C. for 20 min. After cooling to room temperature, the mixture was poured into saturated ammonium chloride (25 mL) and extracted with ethyl acetate (80 mL). The ethyl acetate phase was washed with saturated ammonium chloride (10 mL), water (10 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-80% ethyl acetate in hexanes, gave impure products. The material was triturated with dichloromethane. The white solid was collected by filtration to give methyl 4-(5-cyano-4-oxo-6-(4-phenoxyphenyl)-1,4-dihydropyridin-2-yl)benzoate (0.598 g, 65% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.25 (1H, br. s), 8.17 (2H, br. s), 8.02 (1H, br. s), 7.71 (2H, br. s), 7.40 (2H, t, J=7.91 Hz), 7.24 (1H, br. s), 7.03-7.16 (4H, m), 6.62 (1H, br. s), 3.95 (3H, s); MS (ES+) m/z: 423 (M−H); LC retention time: 4.118 min (analytical HPLC Method A).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][C:6]=1[F:19])[CH3:2].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.O1CCCC1.C(OCC)C.[Cu]I.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>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:7][C:6]=1[F:19])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1F
Temperature: 70 °C
Yield: 94.6 %

Procedure:
A solution of ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6, 1.82 g, 6 mmol) in triethyl amine (12 mL) and anhydrous tetrahydrofuran (30 mL) was treated with copper(I)iodide (0.12 g, 0.6 mmol) and sparged with argon. Dichlorobis(triphenylphosphine)palladium(II) (0.43 g, 0.6 mmol) was added followed by (trimethylsilyl)acetylene (3.6 mL, 24 mmol) and the resulting reaction mixture was heated at 70° C. overnight. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as an orange oil (1.5 g, quantitative).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([C:18]([CH3:20])=[CH2:19])[N:9]=2)=[CH:4][CH:3]=1.[BH4-].C([N+](CC)(CC)CC)C.C([O-])(O)=[O:32].[Na+]>CO.COCCOC.O>[OH:32][C:18]([C:10]1[CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)([CH3:20])[CH3:19]
Reactant: O=C([O-])O
Reactant: C=C(C)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)n1
Agent: CC[N+](CC)(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2)nc(C(C)(C)O)c1
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-methylphenyl)-6-(prop-1-en-2-yl)pyridine-4-carboxylate (191 mg, 0.71 mmol) in methanol (3.6 mL) and DME (3.6 mL) was added cobalt(II)mesotetraphenylporphine (2.4 mg, 3.6 mop. After 30 min, tetraethylammonium borohydride (170 mg, 1.17 mmol) was added in 3 portions over 1 h. Saturated aqueous NaHCO3 was added. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 90% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (165 mg). MS 286.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[N:35][CH:36]=1.O>CN(C=O)C>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:34]1[N:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[CH:32][CH:33]=1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COCCOc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of N-(4-(4-Hydroxy-2,6-dimethylphenyl)-thiazol-2-yl)isonicotinamide (5-3, 0.98 g, 3.0 mmol) in DMF (10 mL) were added cesium carbonate (1.95 g, 6.0 mmol, 2.0 equiv) and Cu (58.5 mg, 0.90 mmol, 0.3 equiv). The mixture was stirred at 100-110° C. for 1.0 h and added with 5-bromo-2-(2-methoxyethoxy)pyridine (17-2, 1.04 g, 4.5 mmol). The solution heated at 130° C. for 24 h. The reaction mixture was added with water (40 mL) and extracted with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 17 (0.94 g) in 66% yield: 1H NMR (500 MHz, CDCl3) δ 8.81 (d, 2 H), 7.93 (d, 1 H), 7.88 (d, 2 H), 7.32 (m, 1 H), 6.82 (d, 2 H), 6.57 (s, 2 H), 4.45 (t, 2 H), 3.75 (t, 2 H), 3.44 (s, 3 H), 1.99 (s, 6 H), ESI-MS=m/z 477.2 (M+H)+.