Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=[O:9])(C)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[CH3:2][C:1]1([CH3:3])[O:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=2)=[CH:7][C:6](=[O:18])[O:5]1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)C=C(c2ccnc(C#N)c2)O1

Procedure:
Prepared from 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) by stirring in TFA/acetone with TFAA according to general procedure J (method b). Obtained as a brown solid (3.30 g).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.Cl.[CH:28]([NH:31][NH2:32])([CH3:30])[CH3:29].C(N(CC)CC)C.O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:10]=2[C:11]([NH:32][NH:31][CH:28]([CH3:30])[CH3:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)NN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc(C(=O)NNC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
A mixture of 0.60 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.29 g of isopropylhydrazine hydrochloride, 0.27 g of triethylamine and 6 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The combined organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 3-bromo-N-[4-chloro-2-(N′-isopropylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [F:1][N+]1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1S([O-])(=O)=O.[OH:20][C:21]1[C:31]2[CH2:30][CH2:29][N:28]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.C(O)(C(F)(F)F)C(F)(F)F>C(Cl)Cl>[F:1][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][CH2:27][N:28]([C:32](=[O:37])[C:33]([F:36])([F:34])[F:35])[CH2:29][CH2:30][C:31]=2[C:21]=1[OH:20]
Reactant: O=S(=O)([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)[n+]1F
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Solvent: ClCCl
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: O=C(N1CCc2ccc(F)c(O)c2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
Add N-fluoro-4,6-bis(trifluoromethyl)-pyridinium 2-sulfonate (3.02 g, 9.6 mmol) to a stirred mixture of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.5 g, 9.6 mmol) and hexafluoro-2-propanol (10 mL) in DCM (150 mL). Stir at ambient temperature for 16 h. Concentrate the reaction mixture and partition the residue between EtOAc and 1N aqueous HCl. Wash the organic fraction with saturated aqueous NaHCO3, brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 6:1, 5:1 and 3:1) to give 7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid (1.8 g, 68%). Dissolve 7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.5 g, 5.41 mmol) in a mixture of DCM (20 mL) and pyridine (2 mL) and cool in an ice bath. Add dropwise to the stirred solution a mixture of trifluoromethanesulfonic anhydride (1.64 mL, 9.74 mmol) in DCM and stir the reaction for 1.5 h at ambient temperature. Dilute the reaction with DCM (300 mL) and wash with 2.5N aqueous HCl. Dry the organic fraction over Na2SO4, filter and concentrate to give the title product as a white solid (2.2 g, 99%). MS (ES+) m/z: 410 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)C.C(=O)([O-])[O-].C([N:21](C(C)C)CC)(C)C>C(#N)C>[N:5]1[C:4]2[S:8][CH:9]=[CH:10][C:3]=2[C:2]([NH2:21])=[N:7][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ncnc2sccc12
Agent: *CC(*)C
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CC#N
Product: Nc1ncnc2sccc12

Procedure:
An amine (VIII) is added to a solution of the 4-chlorothieno[2,3-d]pyrimidine (VII) in either ethanol or a mixture of acetonitrile and a base (for example an alkaline carbonate or diisopropylethylamine) in a closable bottle. The bottle is closed with a polypropylene cap, and heated overnight in a conventional oven at a temperature comprised between 40° and 120° C., preferably between 60 and 85° C. After cooling, the solvent is removed under reduced pressure, and the residue is purified by flash chromatography to provide the final thieno[2,3-d]pyrimidin-4-ylamine (I).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:12][C:3]=12.[NH2:20][CH2:21][C:22]1[C:23]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[N:24][CH:25]=[CH:26][CH:27]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[C:8]([C:7]1[C:2]([NH:20][CH2:21][C:22]2[C:23]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:3]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:10][C:4]2=[N:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cnc2[nH]c(-c3ccc(F)cc3)cc2c1Cl
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(c1ncccc1CNc1c(C#N)cnc2[nH]c(-c3ccc(F)cc3)cc12)S(C)(=O)=O
Temperature: 170 °C

Procedure:
4-Chloro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (30 mg, 0.11 mmol), N-(3-aminomethylpyridin-2-yl)-N-methylmethanesulfonamide (159 mg, 0.552 mmol) and N-ethyldiisopropylamine (0.282 ml, 1.656 mmol) are suspended in 0.4 ml of 1-methyl-2-pyrrolidone and heated in a microwave at 170° C. for 40 min. The reaction is still not complete even after a further 40 min, so that a further equivalent of N-(3-aminomethylpyridin-2-yl)-N-methylmethanesulfonamide (31.8 mg, 0.110 mmol) is added, and the batch is heated at 170° C. for a further 60 min. For work-up, the batch is partitioned between water and ethyl acetate, the organic phase is dried (Na2SO4) and evaporated, giving a brown oil, which is purified by chromatography; yield: 17 mg (34%); LC-MS: 451 [M+H]+; HPLC: 3.07 (RT/min).
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2N)=[CH:12][CH:11]=1.[ClH:21]>C(#N)C>[Cl:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[CH:19]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12]2
Reactant: COc1ccc2cccc(N)c2c1
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COc1ccc2cccc(Cl)c2c1
Temperature: 25 °C
Yield: 41 %

Procedure:
CuCl2 (4.6 g, 24.6 mmol) and t-butyl nitrite (4.46 g, 43.3 mmol), were added to acetonitrile (125 mL) at 0° C. To this mixture was slowly added a solution of 7-methoxynaphthylamine (4.99 g, 28.8 mmol) in acetonitrile (25 mL). The reaction was allowed to warm to room temperature, stirred with HCl (400 mL of 2N solution) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with 2N HCl, dried over sodium sulfate, filtered, evaporation of the solvent, and purification on a silica column (hexanes) yielded 2.27 g (41%) of an orange liquid. An analytical sample was further purified by reverse phase preparative HPLC to yield the title compound as a yellow solid: mp 32–34° C.;1H NMR (CDCl3): δ 3.98 (3H, s), 7.20 (1H, dd, J=2.52 Hz, J=8.96 Hz), 7.22–7.27 (1H, m), 7.52 (1H, d, J=2.47 Hz), 7.55 (1 h, d, J=7.47 Hz), 7.69 (1H, d, J=8.15 Hz), 7.75 (1H, d, J=8.95 Hz); MS m/z 191/193 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=3)[CH:16]=1)[CH2:11]2.[CH2:29]([CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][C:35]([F:40])=[CH:36][CH:37]=2)[NH:32]1)[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:29]([CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][C:35]([F:40])=[CH:36][CH:37]=2)[N:32]1[C:26]([C:22]1[CH:21]=[C:20]([NH:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C:3]2([C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:10][C:2]2=[O:1])[CH2:18]3)[CH:25]=[CH:24][N:23]=1)=[O:27])[CH3:30]
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ccn1
Reactant: CCC1Cc2ccc(F)cc2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1Cc2ccc(F)cc2N1C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ccn1

Procedure:
186 mg (0.50 mmol) 4-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)picolinic acid, 220 mg (0.60 mmol) 2-ethyl-6-fluoro-2,3-dihydro-1H-indole, 0.26 mL (1.5 mmol) DIPEA and 0.18 g (0.55 mmol) TBTU in 5.0 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The aqueous residue was made alkaline with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: C(OC([NH:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)[CH2:10][NH:11][S:12]([NH:15]C(=O)OC(C)(C)C)(=[O:14])=[O:13])=O)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>ClCCl.O1CCOCC1.C(OCC)(=O)C>[NH2:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=1)[CH2:10][NH:11][S:12](=[O:13])(=[O:14])[NH2:15]
Reactant: CC(C)(C)OC(=O)NC(CNS(=O)(=O)NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(CNS(N)(=O)=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 100 mg (0.20 mmol) of the compound from Example 133A in 2 ml of dichloromethane was admixed with 2 ml of a 4M solution of hydrogen chloride in dioxane, and the mixture was stirred at RT for 2 h. It was diluted with ethyl acetate and admixed with 10% strength aqueous sodium hydrogen carbonate solution. The alkaline aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvents on a rotary evaporator. The residue was the title compound (53 mg, 92% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:24][CH:25]=1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
A stirred mixture of 3,4-difluoronitrobenzene (13.5 g, 0.85 mol), methyl 2-(4-hydroxyphenoxy)-propionate (23.1 g, 0.085 mol), and potassium carbonate (12.5 g, 0.09 mol) in DMSO (200 ml) was heated in an oil bath (120° bath temperature) for one hour. After cooling the reaction mixture was poured into ice water (1000 ml) and the resulting mixture was extracted with ether (3×200 ml). The ether extracts were combined, pentane (200 ml) added, and the resulting solution washed with 5% sodium hydroxide solution (200 ml), then with water. After drying (MgSO4), the solvent was evaporated to give 28 g (98%) of the desired product as a light-yellow oil which solidified upon standing. Recrystallization from hexane-ether gave an analytical sample: m.p.=67.5°-69° C.; Calc: C, 57.31; H, 4.21; N, 4.18. Found: C, 57.00; H, 4.13; N, 4.11.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.CCN(CC)CC.ClC([O:17][C:18](Cl)(Cl)Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([C:32]([F:35])([F:34])[F:33])[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1.ClC([O-])=O>C1(C)C=CC=CC=1>[N+:29]([C:27]1[CH:28]=[C:23]([NH:22][C:18](=[O:17])[O:1][C@H:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[CH:24]=[C:25]([C:32]([F:33])([F:34])[F:35])[CH:26]=1)([O-:31])=[O:30]
Reactant: O[C@H]1CCOC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: O=C([O-])Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1)O[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
3-(S)-Hydroxytetrahydrofuran (4.8 mL, 60.7 mmols, 5 eq) was dissolved in 60 mL of toluene. The solution was cooled to 0° C. and Et3N (5.1 mL, 36.4 mmols, 3 eq) was added. Trichloromethyl chloroformate (3.65 mL, 30.33 mmols, 2.5 eq) was added slowly. The solution was stirred at 0° C. for 45 min. 3-Amino-5-nitrobenzotrifluoride (2.5 g, 12.13 mmols, 1 eq) was added dropwise in 20 mL of toluene. The reaction was stirred at 0° C. for 1 h. An additional 5 eq of 3-(S)-hydroxytetrahydrofuran was converted to the chloroformate as described above, and added to the reaction mixture. After an additional h at 0° C., the reaction was heated to 60° C. for 1 h. The reaction was cooled to RT and concentrated. The residue was dissolved in EtOAc, washed twice with saturated NH4Cl and once with brine. After being dried over Na2SO4 the solution was filtered and the solvent removed in vacuo. The crude product was purified using a Biotage chromatography system eluting with a gradient of 5% to 35% EtOAc:hexane to yield the desired compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH3:26][Si:27](Cl)([CH3:29])[CH3:28]>ClCCl>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: C[Si](C)(C)Cl
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1(CO[Si](C)(C)C)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (4.2 mmol) was dissolved in 20 ml of dichloromethane. The solution was cooled in ice-water bath, and 0.7 ml of triethyl amine (5 mmol) was added thereto. After stirring for 5 minutes, 0.6 ml of trimethylsilyl chloride (4.6 mmol) was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.41 g of concentrate (yield 86%). MS(EI)m/e: 312(M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[O:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(N(CC)CC)C.[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[C:26]=1[C:27](Cl)=[O:28]>C1(C)C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([C:27](=[O:28])[C:26]3[C:25]([Br:24])=[CH:33][CH:32]=[CH:31][C:30]=3[Br:34])[C:12](=[O:16])[O:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: O=C(Cl)c1c(Br)cccc1Br
Reactant: O=c1[nH]c(=O)n(-c2cc(Cl)c(Cl)c(Cl)c2)o1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(Br)cccc1Br)n1c(=O)on(-c2cc(Cl)c(Cl)c(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3,4,5-Trichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dibromobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3,4,5-trichlorophenyl)-4-(2,6-dibromobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]C)(=[O:4])[CH2:2][CH3:3].[C:10]1([NH:16][C:17]2([C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-:36].[NH4+]>>[C:6]([OH:5])(=[O:9])[C:7]([OH:31])=[O:36].[CH2:33]([O:32][C:30]([C:17]1([N:16]([C:1](=[O:4])[CH2:2][CH3:3])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH2:22]1)=[O:31])[CH2:34][CH3:35]
Reactant: CCCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CCC(=O)OC(=O)CC
Reactant: [OH-]
Agent: [NH4+]
Product: CCCOC(=O)C1(N(C(=O)CC)c2ccccc2)CCN(Cc2ccccc2)CC1
Product: O=C(O)C(=O)O

Procedure:
260 parts of propanoic acid anhydride are added dropwise to 93 parts of propyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate while cooling in a water-bath. Upon completion, the whole is stirred and refluxed for 6 hours. After cooling, the reaction mixture is poured onto water, alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is dissolved in petroleumether. The solution is filtered and the filtrate is evaporated. The oily residue is converted into the ethanedioate salt in 2-propanone. The salt is filtered off and crystallized from a mixture of 2-propanone and ethanol (10:1 by volume), yielding propyl4-[N-(1-oxopropyl)-N-phenylamino]-1-(phenylmethyl)-4-piperidinecarboxylate ethanedioate; mp. 169.7° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]([CH:22]=1)=[N:19][O:20][N:21]=2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]2=[N:21][O:20][N:19]=[C:18]2[CH:22]=1)[CH3:2]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: Oc1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Oc1ccc2nonc2c1
Temperature: 90 °C
Yield: 26.2 %

Procedure:
A mixture of 5.5 g (29.4 mmol) 2-chloro nicotinic acid ethyl ester, 4.0 g (29.4 mmol) 5-hydroxybenzofurazan and 20.1 g (61.7 mmol) cesium carbonate in 125 ml dry dimethylformamide was heated at 90° C. for five days. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined; washed successively with sodium bicarbonate solution, water, and brine; then dried (Na2SO4); and concentrated in vacuo to give a solid. Recrystallization from diethyl ether/pentane gave 2.2 g (26%) solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7](=[O:19])[CH:6]=[CH:5]2.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:35][C@H:36]1[C@@H:43]2[N:39]([C:40](=[O:57])N(C3C4CCCCC=4C(C#N)=CC=3)[C:42]2=[O:44])[CH2:38][CH2:37]1>>[OH:35][C@H:36]1[C@@H:43]2[N:39]([C:40](=[O:57])[N:1]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7](=[O:19])[CH:6]=[CH:5]4)[C:42]2=[O:44])[CH2:38][CH2:37]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: Nc1ccc2c(ccc(=O)n2Cc2ccccc2)c1
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: O=C1[C@@H]2[C@H](O)CCN2C(=O)N1c1ccc2c(ccc(=O)n2Cc2ccccc2)c1

Procedure:
The title compound was prepared from compound 46D by procedures analogous to those described in Experiment 2E and 2F. LC/MS m/z 390 [M+H]+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH2:33][NH:34][CH:35]([CH3:37])[CH3:36])(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:1](=[O:2])[N:34]([CH2:33][CH2:32][S:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=1)(=[O:30])=[O:31])[CH:35]([CH3:37])[CH3:36])[CH3:14]
Reactant: COc1ccc(S(=O)(=O)CCNC(C)C)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CCN
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)N(CCS(=O)(=O)c1ccc(OC)cc1)C(C)C
Yield: 67.3 %

Procedure:
A solution of 4.54 g (0.28 mole) of 1,1'-carbonyldiimidazole and 2.90 g (0.025 mole) of N,N-diethylethylenediamine in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 5.89 g (0.0229 mole) of N-[2-[(4-methoxyphenyl)sulfonyl]ethyl]-2-propanamine in 50 ml of tetrahydrofuran was added, and the mixture was refluxed overnight. The solvent was removed in vacuo, and the residue was dissolved in 800 ml of a 50/50 mixture of methylene chloride-ether. The organic solution was extracted with water and was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. This was crystallized from ether-hexane to give 6.16 g (67.3%) of white crystalline solid; m.p. 39.5°-42° C.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:29][C:30]1[N:59]=[C:33]2[N:34]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=3)[C:35]([CH3:48])=[C:36]([C:46]#[N:47])[C@@H:37]([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=3)[N:32]2[N:31]=1>C1COCC1>[C:9]([O:8][C:6](=[O:7])[NH:1][CH2:2][C:3]([NH:29][C:30]1[N:59]=[C:33]2[N:34]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:57])([F:56])[F:58])[CH:50]=3)[C:35]([CH3:48])=[C:36]([C:46]#[N:47])[C@@H:37]([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=3)[N:32]2[N:31]=1)=[O:5])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CNC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, N-Boc-Gly-OH (5 mg, 28 μmol) and NMM (5.3 mg, 52 μmol, 2.4 eq.) were dissolved in abs. THF (1 ml), and isobutyl chloroformate (4.2 mg, 31 μmol, 1.4 eq.) was added at −15° C. (solution A). At −78° C., (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (10 mg, 22 μmol) and NMM (2.2 mg, 22 μmol, 1 eq.) were added, and the mixture was stirred overnight, during which time it slowly warmed to RT. Since the conversion was still incomplete, more solution A consisting of in each case 285 μmol of N-Boc-Gly-OH, isobutyl chloroformate and NMM in abs. THF was added at −15° C., and the mixture was stirred for 3 d, warming to RT. The reaction mixture was then directly purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (6.3 mg, 50% of theory).