Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25](O)[CH:24]=1.C([N+]#[C-])(C)C>C(OCC)(=O)C>[N+:29]([C:28]1[CH:23]=[CH:24][C:25]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[CH:26][CH:27]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [C-]#[N+]C(C)C
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Yield: 53.4 %

Procedure:
A solution of 6.0 g (20 mM) N-carbobenzoxy-L-phenylalanine, 3.3 g (24 mM) p-nitrophenol, and 1.6 g (24 mM) isopropyl isonitrile in 50 ml ethyl acetate was held at 60°C for 40 hours, and then evaporated. The residue was dissolved in ethanol, and the solution stored in a refrigerator until crystals formed. The crystals were filtered out, washed with petroleum ether, and dried. 4.5 g N-Carbobenzoxy-L-phenylalanine p-nitrophenyl ester was obtained (53 percent yield). M.P. 125.5°-127°C. [α]D25 = - 8.0° (C = 2.2, in chloroform).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][C:32](Cl)=[O:33].Cl>ClCCl>[Br:30][CH2:31][C:32]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1)=[O:33]
Reactant: CCCCCCCCCCCCCCCc1ccc(NC)cc1
Reactant: O=C(Cl)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1ccc(N(C)C(=O)CBr)cc1
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
Compound 8 (1.5 g) was dissolved in dichloromethane (10 mL). Potassium carbonate (980 mg) and the solution of bromoacetyl chloride (890 mg) in dichloromethane (5 mL) was added thereto at 0° C., followed by stirring for 1.5 hours. The reaction solution cooled with ice was poured into 1N hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (1.7 g) having the following physical property values.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]1
Reactant: CC(C)Br
Reactant: COCC1(Nc2ccccc2)CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COCC1(Nc2ccccc2)CCN(C(C)C)CC1
Yield: 42.6 %

Procedure:
A mixture of 10 parts of 2-bromopropane, 9 parts of 4-(methoxymethyl)-N-phenyl-4-piperidinamine, 4.9 parts of N,N-diethylethanamine and 72 parts of N,N-dimethylacetamide is stirred and refluxed for 10.25 hours. After cooling, the formed N,N-diethylethanamine hydrobromide is filtered off and the filtrate is diluted with water. The product is extracted with methylbenzene. The extract is washed thoroughly with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5.7 parts (42.6%) of 4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidinamine as an oily residue.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:20])=[O:21]
Reactant: Cc1cc(O)cc(O)c1
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2,5-dimethylbenzenesulfonyl chloride (2.05 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.10 g, 72%). 1H-NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 7.29 (m, 1H), 7.25 (m, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 6.30 (s, 1H), 5.27 (br s, 1H), 2.30 (s, 3H), 2.18 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C[CH2:15][N:16]=[C:17]=NCCCN(C)C.Cl.CNC.C1COCC1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:16]([CH3:17])[CH3:15])=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1n[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-bromo-1H-indazole-3-carboxylic acid (1 g, 4.15 mmol) and EDC.HCl (1.2 g, 6.2 mmol) in DMF (5 mL) was added 2 M dimethylamine in THF (3.45 mL, 10.3 mmol). Mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo to remove the volatiles, then diluted with EtOAc (30 mL) and washed with water. The aqueous layer was extracted with more EtOAc (20 mL). The combined organics were washed with water (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid: 1H NMR (250 MHz, DMSO) delta 3.06 (3H, s), 7.34 (1H, dd, J=8.68, 1.52 Hz), 7.84 (1H, d, J=1.07 Hz), 7.92 (1H, d, J=8.68 Hz), 13.62 (1H, br. s.); LC-MS: m/z=+269.75 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)=[O:8])[CH2:2][CH2:3]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Reaction time: 3 h

Procedure:
1.5 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril and 1.5 g of triethylamine were suspended in 10 ml of dichloromethane. Under ice-cooled and stirring condition, 1.4 g of p-toluenesulfonylchloride in 10 ml of dichloromethane solution was added dropwise to the suspension and the reaction was continued for additionally 3 hours at a room temperature, further continued for 1 hour under ice-cooled condition. The crystals formed in the reaction mixture were collected by filtration and recrystallized from chloroform-ether to obtain 1.4 g of 6-[4-(p-toluenesulfonyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 280°-282° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: CS(=O)(=O)Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CS(=O)(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) with diethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol). Methane sulfonyl chloride (43 μL, 0.55 mmol) was added and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E72); MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[C:9]1([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH:16]=[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:19]=[N:18]2)=[N:3][CH:4]=1
Reactant: c1ccc(-c2cn[nH]c2)cc1
Reactant: Fc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccc(-n2cc(-c3ccccc3)cn2)nc1
Temperature: 85 °C
Yield: 93.7 %

Procedure:
A mixture of 2-fluoro-5-iodopyridine (368.3 mg, 1.652 mmol), 4-phenyl-1H-pyrazole (238.2 mg, 1.652 mmol), and potassium carbonate (457 mg, 3.30 mmol) in N,N-dimethylformamide (3.30 mL) was heated to 85° C. for 21 hours. The reaction was then concentrated and the crude residue diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted two more times with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated to give 5-iodo-2-(4-phenyl-1H-pyrazol-1-yl)pyridine (537.2 mg, 94%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.76 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.7, 2.2 Hz, 1H), 8.01 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.55-7.61 (m, 2H), 7.36-7.43 (m, 2H), 7.25-7.31 (m, 1H). MS (M+1): 348.0.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:4].[Br:11][CH2:12][C:13]([OH:15])=[O:14].[K].CCOCC>CN(C)C=O>[Br:11][CH2:12][C:13]([O:15][CH2:2][C:3]([O:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:4])=[O:14]
Reactant: O=C(O)CBr
Reactant: CCC(CC)OC(=O)CBr
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)OC(=O)COC(=O)CBr
Temperature: 0 °C

Procedure:
Bromoacetic acid, 3-pentyl ester (330 g, 1.6 mole) was dissolved in 300 ml of dimethylformamide. Bromoacetic acid, potassium salt (142 g) was added portionwise with stirring and the mixture was stirred overnight. It was then poured into 1 liter of ice-cold water and 500 ml of ether was added. After washing with water, NaHCO3 solution and drying with MgSO4, the ether was evaporated. On distillation 156 g of the starting ester was recovered and 103.5 g of the title compound (boiling point 160°-162° C. at 12 mm of Hg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[CH:19]=[N:18][NH:17][C:14]3=[CH:15][N:16]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[CH3:22]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[CH:19]=[N:18][N:17]([CH3:22])[C:14]3=[CH:15][N:16]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)ccc1Oc1cc2cn[nH]c2cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Oc3ccc(F)cc3C#N)ncc21
Temperature: 0 °C
Yield: 51.1 %

Procedure:
The intermediate (2u) (0.23 g) was dissolved in DMF (9 mL) and cooled to 0° C. Sodium hydride (60% in oil, 0.054 g, 1.36 mmol) and methyl iodide (0.28 mL, 642 mg, 4.52 mmol) were added to the solution at 0° C. and then the reaction mixture was stirred for an hour at 0° C. The mixture was quenched with 10 mL of water and extracted three times with 30 mL of ether. The combined organic layer was washed with 5 mL of water twice and brine once, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil residue was purified on silica gel with EtOAc/hexane (1:1) to afford colorless oil (3u) (0.124 g, 51% yield). 1HNMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.02 (s, 1H), 7.40-7.32 (m, 2H), 7.31-7.23 (m, 2H), 7.11-7.05 (m, 1H, 4.17 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[NH2:5].[As](=O)(O)(O)O.O[CH2:18][CH:19]([CH2:21]O)O>>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:4]2[C:3]=1[CH:18]=[CH:19][CH:21]=[N:5]2
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=[As](O)(O)O
Product: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Temperature: 140 °C

Procedure:
A mixture of 25.2 g of 3-chloro-6-nitro-aniline, 21 g of arsenic acid and 35.1 ml of glycerine was heated to reflux and after cooling the mixture to 20°~30° C., 25.5 ml of 66° Be sulfuric acid were added thereto. The mixture was heated at 140° C. for 8 hours and was poured over ice. The mixture was filtered and the solid product was dissolved in methylene chloride. The solution was neutralized and extracted with methylene chloride. The combined organic phases were dried, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The 10 g of residue were chromatographed over silica gel and eluted with methylene chloride to obtain 8.61 g of 5-chloro-8-nitro-quinoline melting at 136°-138° C. which was reacted with N-hydroxyphthalimide to obtain 0-(8-nitro-5-quinolyl)-phthalimide melting at 226°-228° C. The latter was reacted to obtain 0-(8-nitro-5-quinolyl)-hydroxylamine melting at 186°-188° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1SC(C(Cl)=O)=C(C)N=1)C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:42][CH:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:44]#[N:45]>C(N(CC)CC)C>[C:44]([CH:43]([NH:42][C:15]([C:11]1[S:10][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:13][C:12]=1[CH3:14])=[O:17])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)#[N:45]
Reactant: N#CC(N)c1ccccc1
Reactant: Cc1nc(NCc2ccccc2)sc1C(=O)O
Agent: Cc1nc(NCc2ccccc2)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(NCc2ccccc2)sc1C(=O)NC(C#N)c1ccccc1
Yield: 38.8 %

Procedure:
1.2g of 2-benzylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-benzylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.1g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 0.89g of amino-phenylacetonitrile hydrochloride and 2.3ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.68g (Yield 39%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.C(Cl)CCl.[CH3:58][C:59]1[O:60][C:61]([CH3:67])=[C:62]([C:64](O)=[O:65])[N:63]=1>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([C@@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:7]=[CH:8][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:10][CH:11]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:64]([C:62]5[N:63]=[C:59]([CH3:58])[O:60][C:61]=5[CH3:67])=[O:65])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:38][CH:39]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(C(=O)O)c(C)o1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.67 h

Procedure:
(S)-2-({(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (35 mg) was dissolved in 2 mL DCM. In a separate vial EDC (5 equiv) and 2,5-dimethyl-oxazole-4-carboxylic acid (10 equiv) were dissolved in DCM and stirred 40 min. This solution was added to the above mixture stirred 4 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+2% MeOH). The resulting compound was hydrolyzed according to General Procedures B to give the title compound (10 mg). LCMS (m/z): 862.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][C:54]=1[C:63]1[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=1>CN(C=O)C>[CH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][C:54]=1[C:63]1[CH:64]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:66]=[CH:67][CH:68]=1
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3ccccc3c2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 74.2 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.068 mmol) and HATU (0.029 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-naphthalen-2-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 63% yield: LCMS (ESI) m/z 476 (MH+).
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[S:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:13]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[CH:21][CH:20]=1)[C:14]([OH:16])=[O:15]>>[C:3]([S:10][CH:13]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[CH:21][CH:20]=1)[C:14]([OH:16])=[O:15])(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: OC(=S)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(SC(CCc1ccc(-c2ccccc2Cl)cc1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To 17.4 ml. of 2N alcoholic potassium hydroxide solution (0.035 mole) is added 4.84 g. (0.035 mole) of thiobenzoic acid. The solution is cooled to room temperature and to this is added in small portions 0.035 mole of α-chloro-γ-(2'-chloro-4-biphenylyl)butyric acid. The reaction mixture is stirred at room temperature for 25 hours, then the solvent is removed, the residue dissolved in ether, filtered and washed with cold water. The ethereal solution is then dried over magnesium sulfate and evaporated to dryness to obtain α-benzoylthio-γ-(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:19][C:20](Cl)=[O:21])=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([OH:25])[CH3:24].N1C=CC=CC=1>C1C=CC=CC=1>[CH2:23]([O:25][C:20](=[O:21])[CH2:19][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:9]=1)[CH3:24]
Reactant: Cc1ccc(-n2cc(-c3ccccc3)c(CC(=O)Cl)n2)cc1
Reactant: CCO
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nn(-c2ccc(C)cc2)cc1-c1ccccc1
Reaction time: 16 h

Procedure:
2.2 g. of [4-phenyl-1-(4-tolyl)-3-pyrazolyl]-acetyl chloride crude product are reacted with 5 ml. of absolute benzene and 5 ml. of absolute ethanol. 0.2 ml. of pyridine are added dropwise to this mixture, which is allowed to stand at room temperature for 16 hours, and then diluted with 20 ml. of benzene. The reaction mixture then is washed in turn with water, diluted hydrochloric acid and water; dried and concentrated in vacuum. The residue is recrystallized from acetone/hexane. 1.7 g. of [4-phenyl-1-(4-tolyl)-3-pyrazolyl]-acetic acid ethyl ester with a melting point of 76°-79° C., is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:8]2[CH:18]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:20]=[C:7]2[NH:6][C:5]=1[CH3:26])(=[O:3])[NH2:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([C:4]1[C:5]([CH3:26])=[N:6][C:7]2[N:8]([CH:18]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:20]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])(=[O:3])[NH2:2]
Reactant: COC(=O)Cc1cn2c(n1)NC(C)=C(C(N)=O)C2c1ccc(Cl)cc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)Cc1cn2c(-c3ccc(Cl)cc3Cl)c(C(N)=O)c(C)nc2n1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a slurry of methyl 2-(6-carbamoyl-5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidin-2-yl)acetate (1.05 g, 2.66 mmol) in THF (30 mL was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (604 mg, 2.66 mmol). After 30 min, CH2Cl2 (100 mL) and satd aq NaHCO3 (50 mL) were added. The layers were separated, the aqueous layer extracted with an additional 50 mL of CH2Cl2, and the combined CH2Cl2 extracts were washed with satd aq NaHCO3 (3×50 mL). The organic solution was dried with MgSO4, filtered, and concentrated under reduced pressure to yield methyl 2-(6-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)acetate (816 mg, 2.08 mmol, 78%) as a pale grey-green solid contaminated with 11% (by HPLC analysis) of the starting material. This material was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[C@H:10]1([NH2:17])[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]1.O>C(O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([NH2:17])[CH2:11][CH2:12]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Solvent: CCO
Product: N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 180 °C

Procedure:
A mixture of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) and trans-cyclohexane-1,4-diamine (2 g, 18 mmol) in ethanol (2 mL) was heated in a Biotage Initiator microwave reactor at 180° C. for 4 h. After cooling, the mixture was poured into water and the solid collected by filtration and washed with water to give the title compound. Yield: 1.02 g (79%). MS (DCI/NH3) m/z 352 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][NH:3]1.[CH2:17]([N:20]=[C:21]=[O:22])[CH:18]=[CH2:19]>O1CCCC1.O>[CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[CH2:4][N:3]1[C:21]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:22]
Reactant: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Reactant: C=CCN=C=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1C[C@@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 16 h
Yield: 8.5 %

Procedure:
A solution of 6 g (0.015 mole) of crude trans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine (56.6%) in 50 ml of tetrahydrofuran was treated with 1.54 g (0.0165 mole) of 2-propenyl isocyanate all at once and stirred under a blanket of nitrogen for 16 hr. The reaction mixture was diluted with water until an oil separated. The oil failed to crystallize and after 7 weeks it was triturated with isopropyl ether (3×25 ml). The combined triturates gave 400 mg of white granular crystals (8.5%), m.p. 55°-57° C.