Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[CH2:14]([NH2:16])[CH3:15].[H-].[Na+]>CS(C)=O>[CH2:14]([NH:16][C:3](=[O:13])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH3:15]
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: CCN
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCNC(=O)Cc1ccc(OC)cc1

Procedure:
Using the procedure for Example 22, (4-methoxy-phenyl)-acetic acid methyl ester Compound 22a was reacted with ethylamine and sodium hydride in DMSO at room temperature to provide N-ethyl-2-(4-methoxy-phenyl)-acetamide Compound 24a. Compound 24a was reacted with borotribromide in dichloromethane to yield N-ethyl-2-(4-hydroxy-phenyl)-acetamide Compound 24b.
Reaction SMILES: [CH2:1]([N:5]([CH3:38])[C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[C:17]([C:29]1[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=1)[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=1)[CH2:19][CH3:20])[CH2:2][CH2:3][CH3:4].[Br-].[Br-].[Br-].B.O>C(Cl)Cl>[CH2:1]([N:5]([CH3:38])[C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[C:18]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)[CH2:19][CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)CCCCCCCCCC=C(c1ccc(OC)cc1)C(CC)c1ccc(OC)cc1
Agent: B
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CCCCN(C)C(=O)CCCCCCCCCCC(=C(CC)c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To the above dimethoxy amide 4 (117 mg, 0.22 mmol) in CH2Cl2 (1 ml) at 0° C. was added, under argon, 1.0M borane tribromide (675 μl). The solution was stirred for 1 hour, then poured into water and extracted with ether (3×). The organic solution was washed with water, dried on magnesium sulfate, and evaporated to dryness. The residue was purified by "Flash chromatography" on silica gel (Kieselgel 60, Merck, under 0.063 mm, 30 g). Elution with mixture of hexane-ethyl acetate (4:1 v/v) gave N-butyl,N-methyl-12,13-Bis(4-hydroxyphenyl)-12-pentadecenoic amide (EM-142, compound 5 with x=10) (34 mg, 31%), colorless oil, IR νmax (neat) 3300, 1600 cm-1 ; UV γmax (log ε)=235 (4.25) nm; 1H-NMR (δ, CDCl3), 0.76 (3H, t, J=7.3 Hz, --C2CHH3), 0.96 (3H, t, J=7.3 Hz, N(CH2)3 CH3), 2.05-2.20 (4H, m, CH2 --C=C--C2 --), 2.35 (2H, t, J=7.0 Hz, --CH2CON--), 2.97 and 3.00 (3H, s, --NCH3), 3.29 and 3.41 (2H, 2t, J=7.3 Hz, --N--CH2 --), and 6.59-7.09 (8H, m, H--Ar) ppm; MS m/e=493 (M+). ##STR74##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]2)[C:13]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(OC2C=CCCC2)C(=O)O)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(OC2C=CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
To a solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid (50 mg, 0.15 mmol) in dichloromethane (10 mL) at 25° C. was added 2-aminothiazole (22 mg, 0.22 mmol), BOP reagent (96.2 mg, 0.22 mmol) and triethylamine (0.06 mL, 0.44 mmol). The mixture was stirred at 25° C. for 16 h, then was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide (1×10 mL), 1N hydrochloric acid (1×10 mL) and brine ( 1×10 mL), then were dried over sodium sulfate, filtered and evaporated under reduced pressure. The product was purified by chromatography (Biotage Flash 40S column, 60/40 hexanes/ethyl acetate) to furnish rac-2-(3-chloro-4-methanesulfonyl-phenyl)-2-(cyclohex-2-enyloxy)-N-thiazol-2-yl-acetamide (39 mg, 63% yield) as a glassy solid: EI-HRMS m/e calculated for C18H19N2O4S2Cl (M+) 426.0475, found 426.0479.
Reaction SMILES: Cl[CH:2]([CH2:15][CH3:16])[C:3]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][OH:8])=[O:4].[H-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:15]([C@H:2]1[O:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:3]1=[O:4])[CH3:16]
Reactant: CCC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H]1OC[C@@H](c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-N-[(1R)-2-hydroxy-1-phenylethyl]butanamide from Step A (2.75 g, 11.4 mmol) in THF (200 mL) at 0° C. was added NaH (983 mg of a 60% dispersion in oil, 24.6 mmol) and the mixture was stirred at ambient temperature for 18 h. Saturated aqueous NaHCO3 (20 mL) was added and the mixture was extracted with EtOAc (3×40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—75:25 to 0:100, to give the title compound. MS: m/z=206 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](B(O)O)=[CH:14][N:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:13][CH:14]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: OB(O)c1cncc2ccccc12
Reactant: Clc1cc(Br)c2nccn2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1cc(-c2cncc3ccccc23)c2nccn2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.5 %

Procedure:
A microwave vial was charged with a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.8 g, 3.44 mmol), isoquinolin-4-ylboronic acid (0.6 g, 1.734 mmol), dioxane (16 mL), tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.087 mmol), and K3PO4 (2.60 mL, 5.20 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 4 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (30-100% EtOAc/EtOAc/CH2Cl2, 1.2 L, then 50-100% B/EtOAc/CH2Cl2, B: 10% MeOH/EtOAc/CH2Cl2, 800 mL) to give the product (0.27 g, 55%). 1H NMR (400 MHz, CDCl3) δ ppm 9.41 (1H, s), 8.72 (1H, s), 8.66 (1H, d, J=4.53 Hz), 8.03-8.17 (1H, m), 7.90 (1H, s), 7.71 (3H, d, J=3.02 Hz), 7.26 (1H, d, J=4.53 Hz); LC/MS: Rt=1.35 min. LC/MS (Condition A): 281.13/283.13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]3SC)[CH:5]=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].CO>[Ni].CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:5]=[CH:4][C:3]=1[C:21]([F:24])([F:22])[F:23]
Reactant: CSC1C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)c(Cl)c3)cc21
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Cc2cc(Oc3ccc(C(F)(F)F)c(Cl)c3)ccc2N1
Temperature: 50 °C

Procedure:
A stirred mixture of 5-[(2-chloro-α,α,α-tri- fluoro-p-tolyl)oxy]-3-(methylthio)-2-indolinone (25.0 g, 0.067 mol) in a 5:1 mixture of methanol and dimethylformamide is heated to 50° C., under a nitrogen atmosphere, treated portionwise with an aqueous slurry of Raney nickel W-2 catalyst until disulfurization is complete as determined by chromatography, cooled to room temperature and filtered through a bed of diatomaceous earth. The filtrate is concentrated in vacuo, diluted with a 1:1 mixture of ethyl acetate and ether, washed with water, dried over MgSO4 and reconcentrated in vacuo to afford the title product as a tan solid, 16.5 g (75%), identified by 1HNMR analysis.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:4][CH:5]=1
Reactant: COC(=O)CCc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.60 g), methyl 3-(2-hydroxyphenyl)propionate (0.345 g), anhydrous potassium carbonate (0.529 g) and N,N-dimethylformamide (7 mL) was stirred at room temperature for 18 hrs., and further at 70° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (0.61 g, 70%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:27]=[C:28]1[NH:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:30][O:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:32]3[C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:30][O:29][C:28]3=[O:27])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2S(C)(=O)=O)CC1
Yield: 79.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 4-(4-bromo-2-methanesulfonylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester (2.24 g) described in Preparation Example 168 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.11 g), the title compound (2.34 g) was obtained.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>>[N+:17]([C:20]([CH3:21])=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)([O-:19])=[O:18]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Temperature: 105 °C
Yield: 40 %

Procedure:
5.00 g (33.3 mmol) piperonal (Aldrich, Milwaukee, Wis.), 12.8 g (167 mmol) ammonium acetate (Fluke), and 50 g (670 Mmol) nitroethane, 98% (Aldrich) were combined in a 100 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet. The reaction mixture was heated to 105° C. for 90 minutes and the solvent was removed under vacuum to give a dark yellow liquid which was recrystallized from cold methyl alcohol three times to give a yellow crystalline solid in 40% yield. 1H NMR spectra is shown in FIG. 1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)(=O)=O.[CH2:17]([Mg]Br)[CH:18]([CH3:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1.CN1CCCC1=O.C/C(/[O-])=C\C(C)=O.C/C(/[O-])=C\C(C)=O.C/C(/[O-])=C\C(C)=O.[Fe+3]>[CH2:17]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C[Mg]Br
Reactant: COc1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Fe+3]
Agent: CC(=O)/C=C(\C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1cccc(CC(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the compound (2 g) prepared in Example 32 in tetrahydrofuran (35 mL), 1-methyl-2-pyrrolidone (5.2 mL), tris(2,4-pentanedionato)iron(III) (413.5 mg), and isobutyl magnesium bromide (2M diethyl ether solution, 4.68 mL) were added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was added with a saturated aqueous ammonium chloride solution and the mixture was extracted with t-butyl methyl ether. The organic layer was successively washed with a saturated aqueous ammonium chloride solution, water, and brine, dried and concentrated. Thus, the obtained residue was purified by silica gel column chromatography (hexane:tetrahydrofuran=50:1 to 20:1) to thereby give the title compound (922.5 mg) having the following physical properties.
Reaction SMILES: N[C@H](C=O)CCSC.[CH2:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[CH2:10][CH3:11].[CH2:19]1[O:29][C:22]2([CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)[O:21][CH2:20]1.[Cl-].[NH4+]>C1COCC1>[CH2:19]1[CH2:20][O:21][C:22]2([CH2:23][CH2:24][C:25]([OH:28])([C:15]3[CH:16]=[CH:17][C:12]([CH2:9][CH2:10][CH3:11])=[CH:13][CH:14]=3)[CH2:26][CH2:27]2)[O:29]1
Reactant: CCCc1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CSCC[C@H](N)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Metal magnesium in an amount of 12 g was suspended in 50 ml of THF under nitrogen gas stream, and a solution prepared by dissolving 100 g of 4-n-propylbromobenzene in 300 ml of THF was added dropwise and stirred at room temperature for 1 hour. A solution prepared by dissolving 78 g of 1,4-cyclohexanedione-monoethylene ketal in 300 ml of THF was added dropwise thereto and stirred at room temperature for 1 hour. After finishing of the reaction, 500 ml of a saturated aqueous solution of ammonium chloride was added and extracted with 500 ml of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 98 g of 1,1-ethylenedioxy-4-hydroxy-4-(4-n-propylphenyl)cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29]([OH:31])=O)=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1.Cl.[CH3:33][NH2:34]>>[NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29]([NH:34][CH3:33])=[O:31])=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)n(-c2ccc(F)cc2F)n1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc2c(c1)OCCc1cc(-c3nc(N)nn3-c3ccc(F)cc3F)sc1-2

Procedure:
Similarly to as described in General Procedure D, 2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid was reacted with methylamine hydrochloride to give 127 as a colorless solid after reverse phase HPLC (140 mg). LCMS: 454.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:40])=[O:39])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2-fluorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 537.0 ([M+H]+)
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.F[C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])=[O:13]>CN(C)P(=O)(N(C)C)N(C)C>[N:3]1([C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[C:12]([C:14]2[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:13])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Cc1cc(C)c(C(=O)c2cccc(F)c2)c(C)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cc(C)c(C(=O)c2cccc(-n3ccnc3)c2)c(C)c1
Temperature: 40 °C
Yield: 80.4 %

Procedure:
To a suspension of 2.9 g of sodium hydride (60% dispersion in mineral oil) in 50 ml of hexamethylphosphoric triamide is added 5.3 g of imidazole over a 30 minute period under heating at 40° C. After the addition is complete, the mixture is stirred at room temperature for an hour. To the reaction mixture is added 16.6 g of 3-fluoro-2',4',6'-trimethylbenzophenone and the mixture is stirred at 70° C. for 24 hours. The reaction solution is poured into ice-cold water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated. The residue is recrystallized from a mixture of toluene and isopropyl ether to give 16 g of 3-(1-imidazolyl)-2',4',6'-trimethylbenzophenone as white crystals, melting at 134°-136° C.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([NH2:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[C:27](O)=[O:28])=[O:20])([CH3:17])([CH3:16])[CH3:15].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)C>[NH2:11][C:9](=[O:10])[C@@H:7]([NH:8][C:27]([C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:28])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
4-Iodo-(L)-phenylalaninamide (2 g), (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (2.4 g) and disopropylethylamine (3 mL) were dissolved in DMF (10 mL) and to the solution was added 2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.3 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (200 mL) then washed with water (250 mL) and brine (4×250 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Crude product was purified by flash silica chromatography eluting with ethyl acetate to give the sub-title compound (2.88 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[N:7]=[C:8]([NH:22][NH2:23])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=[O:4].C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43]C)=[O:41]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[N:7]=[C:8]([NH:22][NH:23][C:40]([O:42][CH3:43])=[O:41])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:10]=1[CH3:11])=[O:4]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(NN)=NC1c1ccc(C#N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NNC1=NC(c2ccc(C#N)cc2)C(C(=O)OC)=C(C)N1c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.9 %

Procedure:
Intermediate 2 (724 mg, 1.7 mmol) was dissolved in THF (20 mL) and cooled to 0° C. before addition of triethylamine (362 μl, 2.6 mmol) and ethyl chloroformate (191 μL, 2 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resultant residue was triturated with EtOAc, filtered and the solid collected to yield the title compound as a white solid (49 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([NH:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccccc2C)ccn1
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)C1CCN(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 112 %

Procedure:
A mixture of (R)-1-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)-piperidine-4-carboxylic acid (example 367, step 1; 100 mg, 226 μmol) triethylamine (68.6 mg, 94.5 μl, 678 μmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (79.8 mg, 249 μmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 15 min, then treated with methyl 2-aminoacetate hydrochloride (42.6 mg, 339 μmol). The reaction mixture was stirred for 20 h at room temperature, then partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to afford the crude title compound (130 mg), which was directly used in the next step. Yellow oil, MS (ESI+): m/z=514.6 ([M+H]+).