Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CC(C)=O>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: O=C1NCc2cc(O)ccc21
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1NCc2cc(OCc3cccc(F)c3)ccc21
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 5-hydroxy-2,3-dihydro-isoindol-1-one (2.4 g, 16 mmol), potassium carbonate (2.4 g, 18 mmol) and 3-fluorobenzyl bromide (3.3 g, 18 mmol) in acetone (40 mL) was heated under reflux for 22 h. After cooling to RT the mixture was filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 90:10) to afford the title product (2.8 g, 67%) as a white solid. MS m/e=257.2 (M+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1.Cl[C:13]1[S:14][C:15]([C:18]#[N:19])=[CH:16][N:17]=1>C1COCC1>[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH:11][C:13]2[S:14][C:15]([C:18]#[N:19])=[CH:16][N:17]=2)[CH:8]=[CH:7][N:6]=1
Reactant: COc1nccc(N)n1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc(Nc2ncc(C#N)s2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flame dried flask under argon (g) was charged with sodium hydride (33 mg, 60% dispersion, 0.83 mmol) and 1.5 mL anhydrous THF. 2-Methoxy-pyrimidin-4-ylamine (26 mg, 0.21 mmol) was added slowly. After the resulting bubbling ceased, 2-chloro-thiazole-5-carbonitrile (30 mg, 0.21 mmol) was added and the reaction was heated to reflux. After 2 hours, the reaction was cooled to room temperature, the THF was removed in vacuo, and the mixture was diluted with water and adjusted to pH 7 with 1M HCl (aq). The resulting precipitate was filtered, washed with water and air dried. The resulting solid was purified by flash column chromatography (eluted with a gradient 85:15 hexane/EtOAc to EtOAc) to give a pure sample of the title compound. 1H-NMR (300 MHz, DMSO-d6) 12.61 (s, 1H), 8.36 (d, 1H, J=6.4 Hz), 6.73 (d, 1H, J=5.6 Hz), 4.02 (s, 3H). mp>250.
Reaction SMILES: CN(C)[C:3](=[CH:9][CH:10]=[C:11]([S:26][CH3:27])[C:12](=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.C([OH:32])C>>[OH:32][C:3](=[CH:9][CH:10]=[C:11]([S:26][CH3:27])[C:12](=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCO
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(N2CCCCC2)cc1)N(C)C
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SC)C(=O)c1ccc(N2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The procedure is as in Example 4, starting with ethyl 2-dimethylamino-5-methylthio-6-oxo-6-(4-piperidinophenyl)-2,4-hexadienoate (23.5 g) and 1N hydrochloric acid (139 cc) in ethanol (139 cc). The mixture is stirred for 16 hours at a temperature in the region of 20° C. After purification by chromatography on a silica column with dichloromethane as eluent and a second chromatography on a second silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluents; the corresponding eluate is concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallized in boiling isopropyl ether (100 cc). Ethyl 2-hydroxy-5-methylthio-6-oxo-6-(4-piperidinophenyl)-2,4-hexadienoate (3 g), m.p. 65° C., is thereby obtained.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][CH:7]=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:22]([O:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][CH:7]=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:3])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=CCC12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC(C)C1C(=O)N2C(C(=O)OCc3ccccc3)=CCC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzyl 6-(α-Hydroxyethyl)-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (I) (18 mg) is dissolved in 1 ml of pyridine (Py) and 0.2 ml of acetic anhydride (Ac2O). The mixture is stirred at 25° C. for 3 hours and then evaporated to dryness to give oily residue. The residue is dissolved in 0.2 ml chloroform and chromatographed on two 20×20 cm, 250μ silica gel TLC plates (Rf 0.56, 20% ethylacetate/chloroform) to give 4 mg. of the desired product (II) which shows nmr (CDCl3, 60 MHZ) resonances at 2.02 (s, OAc), 6.48 (t, vinyl proton) and 7.40 ppm (m, aromatic protons) and ir (CHCl3) carbonyl vibrations at 1780 (β-lactam) and 1740 cm-1 (esters).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.O.CN([CH:22]=[O:23])C>>[OH:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:22]=[O:23]
Reactant: Oc1cc2ccccc2cc1O
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(O)c(O)cc2ccccc12
Reaction time: 4 h

Procedure:
Phosphorous oxychloride (1.9 ml) was added to a solution of 2,3-dihydroxynaphthalene (3.2 g) in DMF (26 ml) at 0° C. The reaction mixture was kept for four hours at 100° C. Water (50 ml) was added to the cooled mixture and the resulting oily suspension refluxed for 20 min. The cool reaction mixture was poured into ice, filtered, washed with water and recrystallized from 2-propanol-water. Yield: 0.1 g, melting point 129-134° C.
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[O:27]=[C:21]([CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CC(=O)CCl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Temperature: 0 °C
Yield: 17.5 %

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.5 g, 1 eq.) was suspended in dimethylformamide (DMF) (15 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (230 mg, 2.5 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and methyl 4-chloro-3-oxobutanoate (0.360 g, 1 eq.) was added. The reaction was stirred at room temperature overnight. The reaction was poured onto 50 mL water and extracted with dichloromethane (2×50 mL). The organic extracts were combined, washed with water (2×50 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, giving 360 mg of crude product. Additional material was recuperated from the aqueous phase through extraction with ethyl acetate (3×50 mL). The ethyl acetate extracts were combined, washed with water (2×50 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, giving additional 135 mg of crude product. The crude product, 3-oxo-4-(6-oxo-6,11-dihydro-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-5-yl)butanoate was used without purification. LCMS: 326 [M+H].
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[C:9]([OH:10])=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([CH2:19][OH:20])=[N:6][CH:5]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CN(C)C=O>[CH2:12]([O:11][C:8]1[C:7]([CH2:19][OH:20])=[N:6][CH:5]=[C:4]([C:9]=1[OH:10])[C:3]([NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1cnc(CO)c(OCc2ccccc2)c1O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1cnc(CO)c(OCc2ccccc2)c1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
The compound 18 (3.76 g, 13.0 mmol) was dissolved in dimethylformamide (38 ml), and 4-fluorobenzylamine (2.44 ml, 21.3 mmol) was added, followed by stirring at 120° C. for 2 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure, followed by dilution with ethyl acetate. Thereafter, this was washed with 2N hydrochloric acid and water, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 5-benzyloxy-N-(4-fluoro-benzyl)-4-hydroxy-6-hydroxymethyl-nicotinic acid amide 10 (3.59 g, 72%) as a beige crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].COC1C=CC(CNC2CCC2)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Agent: COc1ccc(CNC2CCC2)cc1
Solvent: CO
Product: COc1ccc(CNc2cccc(C(=O)OC(C)(C)C)c2)cc1

Procedure:
253A was prepared from 4-methoxybenzaldehyde and tert-butyl 3-aminobenzoate following the procedure as described in 4A. HPLC: Rt=3.82 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=314.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:36][C:37]1[C:38]([CH3:47])=[C:39]([CH:44]=[CH:45][CH:46]=1)[C:40]([NH:42][CH3:43])=[O:41]>C(O)(C)C>[CH3:43][NH:42][C:40](=[O:41])[C:39]1[CH:44]=[CH:45][CH:46]=[C:37]([NH:36][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[CH2:10][CH2:9]3)[N:5]=[CH:4][N:3]=2)[C:38]=1[CH3:47]
Reactant: FC(F)(F)Oc1ccc(COC2CCN(c3ncnc(Cl)n3)CC2)cc1
Reactant: CNC(=O)c1cccc(N)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ncnc(N3CCC(OCc4ccc(OC(F)(F)F)cc4)CC3)n2)c1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 15.1 %

Procedure:
To a solution of 2-chloro-4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazine (500 mg, 1.28 mmol) in isopropanol (4 mL, 3 mL/mmol) was added DIPEA (0.4 mL, 1.92 mmol) and 3-amino-N,2-dimethylbenzamide (211 mg, 1.29 mmol) and the reaction was stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×30 ml). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided N,2-dimethyl-3-((4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazin-2-yl)amino)benzamide (100 mg, 16%) as a solid. Observed mass (M+1): 517.1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CO>[F:14][C:2]([F:13])([F:1])[C:3]([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:8]1)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCOC(CNC(=O)C(F)(F)F)C1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 1 (6.37 g) in methanol (250 ml) under nitrogen was added benzylchloroformate (4.7 ml) and triethylamine (6.3 ml). The mixture was stirred at 22° C. for 1 h before the volatiles were removed in vacuo. The residue was purified by Biotage flash chromatography on a 90 g silica cartridge eluting with 33% ethyl acetate in cyclohexane, to give the title compound as a white solid (4.4 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10].C([C:17]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:18]=1[S:19](Cl)(=[O:21])=[O:20])(=O)C>O>[OH:10][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][OH:13])[S:19](=[O:21])([C:18]1[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][CH:17]=1)=[O:20]
Reactant: CC(=O)c1cc(N)ccc1S(=O)(=O)Cl
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N1,N1 -bis(2-hydroxyethyl) sulfanilamide was prepared as follows. (This method was taken in part from G. DiModica and E. Angeletti, Gazz. chim. ital., 1960, 90, 434-9 [CA 55:11344d].) A mixture of sodium carbonate (55.6 g), D.I. water (120 mL), and diethanolamine (57.8 g) was stirred and heated to 60°-70° C. Acetylsulfanilyl chloride (116.8 g) was added as a solid over an hour. D.I. water (225 mL) was added in portions during the acetylsulfanilyl chloride addition to keep the mixture stirrable. The mixture was stirred for an additional 3 hours at 60°-70° C., then allowed to cool to room temperature for about 16 hours. The solids were isolated by filtration and washed with 200 mL cold D.I. water.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:3]1=[O:25].C(=O)([O-])[O-:27].[Na+].[Na+].OO>C(O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([NH2:12])=[O:27])[C:5]=2[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:3]1=[O:25]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C#N)cccc21
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(N)=O)cccc21
Temperature: 25 °C
Yield: 33 %

Procedure:
To a suspension of 1′-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carbonitrile (0.25 g, 0.75 mmol) in ethanol (30 mL) was added saturated aqueous sodium carbonate (3 mL) and 30% w/w aqueous hydrogen peroxide (3 mL). The reaction mixture was heated at reflux for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated in water to afford 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.09 g, 33%) as a colorless solid: mp>250° C. (water); 1H NMR (300 MHz, CDCl3) 7.59 (s, 1H), 7.43-7.36 (m, 1H), 7.24-7.13 (m, 3H), 6.28 (s, 1H), 5.98 (s, 1H), 5.15 (d, J=8.1 Hz, 1H), 4.57 (d, J=8.1 Hz, 1H), 4.16-3.99 (m, 4H), 3.13 (s, 3H); MS (ES+) m/z 352.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1(C)C=CC(S(O[CH:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)(=O)=O)=CC=1.[OH-].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:21]1[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]1)[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Brc1ccc2c(ccn2C2CCC3(CC2)OCCO3)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromoindole (8.472 g, 43.216 mmol), [CAS: 10075-50-0]), toluene-4-sulfonic acid, 1,4-dioxa-spiro[4.5]dec-8-yl ester (13.5 g, 43.216 mmol) [C.A.S. 23551-05-9]; (prepared according to the procedure described in J. Chem. Soc., Perkin Trans. 1 2002, 20, 2251-2255) and powdered potassium hydroxide (13.239 g, 235.958 mmol) in DMSO (300 ml) was stirred at 80° C. for 6 h. Subsequently, the mixture was cooled to room temperature and poured into ice water. The resulting aqueous mixture was extracted with Et2O, dried (Na2SO4), and the volatiles were evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; DCM/heptane 1:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D11 (2.897 g, 19.93%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][OH:14])[O:9]2)=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>C1COCC1>[OH:14][CH2:13][CH:8]1[O:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]3[NH:1][C:15](=[O:16])[NH:12][C:11]3=2)[CH2:6][CH2:7]1
Reactant: Nc1ccc2c(c1N)OC(CO)CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc3c(c2[nH]1)OC(CO)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a solution of (7,8-diamino-chroman-2-yl)-methanol (194 mg, 1 mmol) in THF (50 mL) was added 1,1′-carbonyldiimidazole (CDI) (81 mg, 1.5 mmol). The resulting solution was stirred for 8 hours at room temperature and the solvent was evaporated in vacuo to a residue. The residue was purified by chromatography (50% CH2Cl2-hexanes) to give 139 mg (63% yield) of the title compound: mp 240° C.; 1H NMR (400 MHz, CDCl3) δ1.65 (m, 1H), 2.01 (m, 1H), 2.70 (m, 2H), 3.55 (m, 1H), 3.63 (m, 1H), 4.05 (m, 1H), 4.68 (bs, 1H, OH), 6.41 (d, J=7.9, 1H), 6.60 (d, J=7.9, 1H), 10.36 (s, 1H), 10.37 (s, 1H); IR: 3250, 3080, 2980, 1700, 1500, 1210 cm−1; MS 220 [M]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1.[NH2:17][C@@H:18]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:17][C@H:18]([CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])[CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:15])[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.58 mmol) [prepared according to the procedure of Example 176], 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (176 mg, 0.54 mmol) [prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (336 mg, 0.72 mmol) in chloroform (6 mL). DIEA (520 μL, 2.98 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (336 mg, 0.61 mmol, quant.): LC-MS (ES) m/z=526 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)=[O:41]>O>[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][C:2]2[C:7]([C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=3)=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:44][CH:43]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Cl)CC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 100 °C

Procedure:
To a vial was added tert-butyl 4-(4-chloropyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (320 mg, 1.082 mmol), DMSO (5.4 mL), cesium carbonate (370 mg, 1.136 mmol), and (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (258 mg, 1.082 mmol) before sealing and heating to 100° C. for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure. The crude material was taken after purifying by column chromatography (10% methanol/dichloromethane), affording tert-butyl 4-(4-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate. MS (ESI, pos. ion) m/z: 498.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]([O:17][C:18](ON=C(C1C=CC=CC=1)C#N)=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([O:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCNCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.4 %

Procedure:
A solution of N-(3-aminopropyl)benzylamine (38 g, 231.71 mmoles) in dry tetrahydrofuran (300 mL) was cooled to 5° C. in an ice-alcohol bath. To this cold stirred solution 2-[[(tert-butyoxycarbonyl)oxy]imino]-2-phenylacetonitrile (BOC-ON) (56.58 g, 230 mmoles) in dry tetrahydrofuran (300 mL) was added slowly during a 6 hour period. After the addition of BOC-ON, the reaction mixture was stirred at room temperature under argon for an additional 6 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in ether (750 mL). The ether extract was washed with 5% sodium hydroxide solution (4×100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by flash column using a chromatograpay over a silica dichloromethane→methanol gradient. The pure fractions were pooled together and evaporated to give 49.5 g (81%) of product as oil: 1H nmr (deuteriochloroform): δ 1.42 (s, 9H, t-Boc), 1.65 (m, 2H, CH2CH2CH2), 2.70 (t, 2H, CH2NHCH2), 3.20 (m, 2H, BocNHCH2), 3.78 (s, 2H, ArCH2), 5.32 (br s, 1H, BocNH), 7.30 (m, 5H, ArH).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)CCCSCCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCSCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
Sodium hydride (60% dispersion in oil, 4.4 mg, 0.11 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (26.5 mg, 0.11 mmol) in THF (0.7 mL) at 0° C. After 1 h at 0° C., the mixture of aldehydes from step 4 above (˜0.10 mmol) in THF (0.5 mL) was added via cannula. The reaction was allowed to warm to room temperature. After 18 h at room temperature, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3×5 mL). The combined organic phase was washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→60% EtOAc/CH2Cl2, gradient) followed by preparative thin layer chromatography (silica, 5% MeOH/CH2CI2) afforded 6.8 mg (16%) of 4-{2-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-ethylsulfanyl }-butyric acid methyl ester.