Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:16])=[N:11][CH:12]=[C:13]([Br:17])[C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1ncc(Br)c(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
The above compound 3 (129 g, 599 mmol) was suspended in acetonitrile (1300 ml), and N-bromosuccinic acid imide (117 g, 659 mmol) was added, followed by stirring at room temperature for 90 minutes. Precipitated crystals were filtered, and washed with acetonitrile and diethyl ether to obtain 3-benzyloxy-5-bromo-2-methyl-pyridine-4-ol 4 (154 g, 88%) as a colorless crystal. NMR (DMSO-d6) δ: 2.06 (3H, s), 5.04 (2H, s), 7.32-7.42 (5H, m), 8.03 (1H, d, J=5.5 Hz), 11.82 (1H, brs).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.CCCCCC.[Li]CCCC.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>C(OCC)C>[CH:33]([NH:36][C:37]([C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1)=[O:38])([CH3:35])[CH3:34]
Reactant: CN(C)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)N=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)NC(=O)c1cc(N(C)C)cc(Oc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.17 h

Procedure:
0.75 g (0.0021 mol) of 2-bromo-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 15 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 1.4 ml of a 1.65M-hexane solution of BuLi (0.0021×1.1 mol) was added thereto, followed by stirring the suspension for about 10 minutes. After 0.35 g (0.0021×2.0 mol) of isopropyl isocyanate dissolved in about 10 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 5 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-saturated sodium bicarbonate water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane) and reversed phase column (Lobor LiCHroprep RP-10; eluting solution: acetonitrile/water), thereby obtaining an aimed product.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@@H:14](OS(C)(=O)=O)[C@@H:15]1[CH2:19][C@@H:18]([CH2:20][CH2:21][CH3:22])[C:17](=[O:23])[O:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1C(=O)N(C)CCC1>[N:1]([C@H:14]([C@H:15]1[O:16][C:17](=[O:23])[C@H:18]([CH2:20][CH2:21][CH3:22])[CH2:19]1)[CH2:13][O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: CCC[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CCC[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
7.49 g of sodium azide (115 mmol) was added to a solution of 29.1 g of methanesulfonic acid (R)-2-benzyloxy-1-[(2S,4R)-5-oxo-4-propyltetrahydrofuran-2-yl]ethyl ester obtained in Example (116d) (81.7 mmol) in N,N′-dimethylpropyleneurea (300 ml) at room temperature, and the mixture was stirred at 60° C. for two days. The reaction mixture was cooled and then poured into ice water, followed by extraction with diethyl ether. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1) to obtain 23.0 g of the title compound (yield: 93%).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[F:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15](=S)[NH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1.[C:23]([C:25]1([NH:34][C:35](=[O:45])[CH:36]([NH2:44])[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][CH3:41])[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]1)#[N:24].C(N(CC)C(C)C)(C)C>C1COCC1>[C:23]([C:25]1([NH:34][C:35](=[O:45])[CH:36]([NH:44][C:15]2[C:14]3[CH:21]=[CH:22][C:11]([F:10])=[CH:12][C:13]=3[O:18][C:17](=[O:19])[N:16]=2)[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][CH3:41])[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH3:33])[CH2:29][CH2:30]1)#[N:24]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CCC(C)(C)CC)CC1
Reactant: O=c1[nH]c(=S)c2ccc(F)cc2o1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1CCC(C#N)(NC(=O)C(CCC(C)(C)CC)Nc2nc(=O)oc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
2-Chloro-1-methylpyridinium iodide (365 mg, 1.43 mmol, 1.00 eq) was added to a suspension of 7-fluoro-4-thioxo-3,4-dihydro-benzo[e][1,3]oxazin-2-one (280 mg, 1.42 mmol, 1.00 eq), 2-amino-5,5-dimethyl-heptanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide (627 mg, 1.42 mmol, 1.00 eq), and N,N-diisopropyl ethylamine (1.00 mL, 5.74 mmol, 4.04 eq) in THF (10.0 mL). The reaction mixture was stirred at room temperature overnight, then concentrated, resuspended in ethyl acetate (50 mL) and washed with saturated Na2CO3 solution. The organic phase was dried (MgSO4) and concentrated and the resulting residue was chromatographed over silica gel using a gradient of methanol in dichloromethane as the eluant to provide 324 mg (47% yield) of the title compound; m/z calculated for C26H36F N5O3 485.6, found 486.5 (M+H)+.
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1C[O:37]CC1>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C@:4]2([CH2:1][CH2:2][CH2:3][OH:37])[O:9][C:8](=[O:10])[N:7]([C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])[CH2:12]3)[CH2:6][CH2:5]2)=[CH:32][CH:31]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OCc3ccccc3)C2)C(=O)O1
Product: O=C(OCc1ccccc1)N1CCC[C@H](N2CC[C@](CCCO)(c3ccc(F)cc3)OC2=O)C1
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of (S)-benzyl 3-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (78 mg, 0.17 mmol) in THF (3 mL) was added BH3 THF (0.5 mL, 1 mol/L) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then aqueous NaOH solution (3 mol/L, 0.2 mL) and H2O2 (30%, 0.4 mL) was added to the above mixture. The resulting mixture was stirred for 1.5 h. The mixture was extracted with EtOAc, and the combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (S)-benzyl 3-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (15 mg, 20%). LC-MS Method 2 tR=1.299 min, m/z=493.1; 1H NMR (CDCl3): 1.12-1.35 (m, 2H), 1.46 (m, 1H), 1.57-1.28 (m, 4H), 1.82-1.98 (m, 2H), 2.11 (m, 1H), 2.23 (m, 1H), 2.46-2.73 (m, 3H), 3.11 (m, 1H), 3.50 (m, 2H), 3.86-4.03 (m, 1H), 5.06 (m, 2H), 6.89-7.01 (m, 2H), 7.16 (m, 2H), 7.23-7.33 (m, 4H).
Reaction SMILES: [O:1]=[CH:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([C:14]#[N:15])=[N:11]2)=[CH:6][CH:5]=1.[BH4-].[Na+]>C1COCC1.CO>[OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([C:14]#[N:15])=[N:11]2)=[CH:6][CH:5]=1
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CC=O)cc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(-c2ccccc2)c2ccc(CCO)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(2-oxoethyl)-4-phenylquinoline-2-carbonitrile (1.5 g, 5.5 mmol) in THF (30 mL) and MeOH (10 mL) was added portionwise at 0° C. sodium borohydride (320 mg, 8.4 mmol). The mixture was stirred overnight at rt. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 concentrated under reduced pressure and purified on silica gel (eluting with ethyl acetate/hexanes, 1:1) to give the title compound. MS (+ESI): 275 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[PH2:7](=[O:9])[OH:8]>>[CH2:1]([PH:7](=[O:8])[OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCC
Reactant: O=[PH2]O
Product: CCCCCC[PH](=O)O

Procedure:
The title compound was prepared from n-hexene and 50% aqueous phosphinic acid by an analogous procedure to that described in J. Inorg. Nucl. Chem., 1965, 27, 697.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][O:13][C:12](=[O:15])[C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].BrCC(C1C=CC(OC)=C([F:46])C=1)=O>>[F:46][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][O:13][C:12](=[O:15])[C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1Cl
Reactant: COc1ccc(C(=O)CBr)cc1F
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1F

Procedure:
Following the procedures for the preparation of 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one using 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone provided the title compound. 1H NMR (500 MHz, d6-DMSO): δ 8.42-8.38 (m, 1H), 8.16-8.05 (m, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.49-7.39 (m, 2H), 7.66 (d, J=8.2 Hz, 1H); 7.58 (t, J=7.2 Hz, 1H), 7.42-7.36 (m, 1H), 7.29-7.20 (m, 2H), 7.17-7.10 (m, 2H), 5.45 (s, 2H), 5.23 (s, 2H), 3.85 (s, 3H). MS: M+H: m/z=442.2 and HPLC: 92%, (Condition-J).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:26]([F:29])([F:28])[F:27])=[CH:10]\[C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(=[S:32])C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([SH:32])([C:26]([F:28])([F:27])[F:29])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(O)=S
Reactant: N#Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 5-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-[1,2,4]triazol-1-yl-benzonitrile (100 mg) was added thioacetic acid (6 eq.) and triethylamine (4 μL). To dissolve the suspension more thioacetic acid (400 μL) was added. The solution was stirred under argon at room temperature for 20 hours. To this mixture was added a minimum of dichloromethane and then isolute. The suspension was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 5-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-[1,2,4]triazol-1-yl-benzonitrile (108 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]O)[CH2:17][CH2:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1>ClCCl>[Cl:3][CH2:22][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1
Reactant: O=S(Cl)Cl
Reactant: OCCC1CCN(c2nccc3ccccc23)CC1
Solvent: ClCCl
Product: ClCCC1CCN(c2nccc3ccccc23)CC1

Procedure:
2.20 ml (30.10 mmol) of thionyl chloride are added dropwise to a solution of 3.09 g (12.10 mmol) of 2-[1-(1-isoquinolyl)-4-piperidyl]ethanol, prepared in step 2.1, in 30 ml of dichloromethane. The reaction mixture is then refluxed for 5 hours.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C1C(=O)N(Br)C(=[O:14])C1.C([O-])(O)=O.[Na+]>O>[CH3:8][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccccc1
Yield: 95.9 %

Procedure:
Methyl phenyl sulphide (20 g, 161.03 mmol) was added to a mixture of methanol (100 ml) and water (20 mL). NBS (34.39 g, 1.2 eq) was added in portions maintaining the temperature between 0° and 5° C. The mixture was stirred at the same temperature until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 (10%, 60 ml). The pH of the resulting reaction mixture was adjusted to a value between 7 and 8 with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (2×125 mL). The combined organic layer was washed with water (2×125 mL) and concentrated to ⅓ of the volume. Heptane (20 mL) was added and then removed by distillation to give 21.64 g (95.9%) of the desired product as colourless oil.
Reaction SMILES: [BH4-].[Na+].O.[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:11][C@H:10]1[CH:12]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])S(C1C=CC(C)=CC=1)(=O)=O)=[O:8])[CH3:5]>O1CCCC1>[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:11][C@H:10]1[CH2:12][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[O:8])[CH3:5]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Sodium Borohydride (2.3 g, 58.55 mol) was suspended in tetrahydrofuran (150 mL) and 4 mL of water was added. (13.3 g, 33.46 mmol) of trans-2-[tert-Butoxycarbonylamino-(toluene-4-sulfonyl)-methyl]-cyclopropanecarboxylic acid ethyl ester was added portionwise (0.8 g portions) and the temperature was kept to 18-30° C. After 1.5 h water (4 mL) and 0.4 g (10.15 mmol) of sodium borohydride were added again. The resulting mixture was quenched with ammonium chloride 2M (300 mL) and 100 mL of 1M K2CO3 and stirring was continued for 0.5 h. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (300 mL) and the combined organic layers were dried over MgSO4 and concentrated to dryness under vacuum and purified with column chromatography on silica with heptane/AcOEt (9/1) to obtain 7.5 g (92.1% yield) of the title compound. as a white solid. MS (m/e): 244.1 (M+H+)
Reaction SMILES: [O:1]=[C:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[BH4-].[Na+]>>[OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: O=C(CCC1CCC(=O)N1)Cc1cccc(Oc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2cccc(Oc3ccccc3)c2)N1
Yield: 71.8 %

Procedure:
Analogous to the procedure described for Example 1A, Step B, 5-[3-oxo-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (923.6 mg, 2.86 mmol) was reduced with NaBH4 (54 mg, 1.4 mmol). Purification by medium pressure chromatography (1:1 hexanes:EtOAc to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2to 10% MeOH in CH2Cl2) provided 5-[3-hydroxy-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (668.3 mg). 1H NMR (CDCl3) δ7.31 (m, 2H), 7.23 (m, 1H), 7.08 (m, 1H), 6.97 (d, 2H), 6.91 (d, 1H), 6.84 (m, 2H), 3.80 (m, 1H), 3.73 (m, 1H), 2.77-2.03 (m, 2H), 2.40 (m, 2H), 2.24 (m, 1H), 1.75-1.41 (m, 5H); MS 326.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22]>>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8]([NH:22][C:18]2[S:17][CH:21]=[CH:20][N:19]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1cccnc1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccnc1

Procedure:
Employing the protocol described in EXAMPLE 1, 3-cyclopentyl-2-pyridin-3-ylpropionic acid (Preparation 2, 0.96 g, 4.4 mmol) was condensed with thiazol-2-ylamine (0.88 g, 8.8 mmol) to give the title compound: RTA=3.05 min; m/z (ES+)=302.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:59]1([CH2:62][C:63](O)=O)[CH2:61][CH2:60]1>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:63]([CH2:62][CH:59]5[CH2:60][CH2:61]5)[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Reactant: O=C(O)CC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(CC2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (101 mg), N,N-diisopropylethylamine (0.130 ml), cyclopropylacetic acid (0.024 ml) and DMF (2 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (2.00 ml), and the mixture was stirred at 90° C. for 2 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (56.3 mg) as an off-white solid.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Li]CCCC.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1COCC1.C(OCC)(=O)C>[C:12]([NH:6][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)Cl
Reactant: C/C=C/C(N)=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C

Procedure:
Experimental Procedure: To a suspension of (E)-but-2-enamide (1.0 equiv) in 3.5 mL THF was added n-BuLi in hexanes (2.5 M,1.2 equiv) slowly at −78° C. The reaction mixture was warmed up to room temperature and stirred for 8 h before a solution of methacryloyl chloride (2.0 equiv) in 2 mL of THF was added drop wise at −78° C. The reaction mixture was allowed to warm up to rt overnight. The crude reaction mixture was diluted with ethyl acetate, and quenched with cold NH4Cl(aq, sat), and the organic layer separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. After filtration and evaporation under reduced pressure, the residue was purified by column chromatography to yield the pure compound.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1I.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:21]2[CH:22]=[C:23]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:24]=[CH:25][C:20]=2[F:19])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(F)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1
Temperature: 60 °C
Reaction time: 60 h

Procedure:
A mixture of (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3, 164 mg; 0.61 mmol), 1-fluoro-2-iodo-4-(methylsulfonyl)benzene (Intermediate 58, 184 mg; 0.61 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(ii) (27 mg; 0.04 mmol) and cuprous iodide (7 mg; 0.04 mmol) was degassed during two minutes under nitrogen then anhydrous THF (3 mL) and triethylamine (170 μL; 1.23 mmol) were added and reaction mixture was stirred at 60° C. for 60 hours. The solvent was evaporated and the residue was treated with an HCl solution (4 N in dioxane, 3.7 mL). After stirring for 16 hours, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:14])[CH2:3]1.[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)#[N:17]>C(O)C>[CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]3[NH:12][C:22]([C:21]4[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=4)=[N:13][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(C#N)cc4)[nH]c3cc21

Procedure:
4.1 g. 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydro-quinolin-2-one and 2.6 g. 4-cyanobenzaldehyde were stirred in 100 ml. ethanol for 7 days at 25° C. with the action of air. Subsequently, the reaction mixture was evaporated to 10 ml., mixed with 10 ml. water, filtered off with suction and recrystallised from ethanol/water (1:1 v/v) to give 5 g. of the title compound; m.p. 228 -233° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccncc1Br
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(c1ccncc1Br)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of 3-bromoisonicotinic acid (0.250 g, 1.238 mmol) in DMF (1.5 mL) was added pyrrolidine (0.097 g, 1.361 mmol), EDC (0.285 g, 1.485 mmol), and HOBt (0.227 g, 1.485 mmol) resulting in a homogenous solution. After stirring at room temperature 3 hours, the reaction mixture was dissolved in a saturated aqueous solution of sodium bicarbonate (20 mL) and extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide Intermediate 12A as a colorless oil (0.219 g, 0.850 mmol, 68.7% yield). HPLC Ret timea: 1.463 min. MS (ES): m/z=257.0 [M+H]+. 1H NMR (400 MHz, acetone) δ ppm 1.77-2.03 (m, 4 H) 3.20 (t, J=6.40 Hz, 2 H) 3.55 (t, J=6.65 Hz, 2 H) 7.38 (d, J=4.27 Hz, 1 H) 8.63 (d, J=4.77 Hz, 1 H) 8.78 (s, 1 H).