Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][C@H:13]([CH3:17])[C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:27])=O>CN(C)C=O.CCOCC>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][C@H:13]([CH3:17])[C:14]([Cl:27])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-[4-(4-trifluoromethylphenoxy)phenoxy]-propanoic acid (1.62 g., 4.96 mm), ether (20 ml) and dimethylformamide (about 2 drops) is added slowly oxalyl chloride (0.8 ml., 2 eq.). After addition of oxalyl chloride, the reaction mixture is stirred at room temperature for one hour. The mixture is then concentrated to give the acid chloride, (R)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propanoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[CH2:28][CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH2:28][CH3:29])=[CH:30][CH:31]=2)=[O:10])=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reaction time: 3 h
Yield: 21.2 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-ethylphenyl)acetate (10 mg, 0.0215 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.0429 ml, 0.215 mmol) and 5 drops of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl, and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with 10% MeOH/DCM to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-ethylphenyl)acetic acid (2 mg, 21.3% yield). (400 MHz, CD3Cl3, CD3OD) 7.65 (d, 2H), 7.30 (d, 2H), 7.10-7.25 (m, 4H), 6.90 (m, 3H), 3.62 (m, 2H), 3.40 (s, 1H), 2.90 (t, 2H), 2.55 (q, 2H), 1.15 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: NC1CCCCC1
Reactant: Clc1cc(Br)ccn1
Product: Brc1ccnc(NC2CCCCC2)c1
Yield: 12.8 %

Procedure:
A mixture of 4-bromo-2-chloropyridine (0.5 g, 2.6 mmol) and cyclohexylamine (0.26 g, 2.6 mmol) was heated in a CEM Microwave at 150 degrees for 15 minutes at 300 W. The resulting crude material was purified by flash chromatography (0% to 30% ethyl acetate/hexane) to give 85 mg of the title compound. MS m/z 256.8 (ESI: M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:17]23)[CH:22]=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][NH:29][CH2:30][C@@H:17]23)[CH:22]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: FC(F)(F)c1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 157. 1H NMR (CDCl3) δ: 7.69 (d, 1H, J=8.0 Hz), 7.64 (d, 1H, J=7.7 Hz), 7.52 (t, 1H, J=7.5 Hz), 7.38 (t, 1H, J=7.7 Hz), 6.31 (d, 1H, J=2.2 Hz), 6.22 (d, 1H, J=2.2 Hz), 4.48 (broad s, 2H), 3.67 (ABq, 2H, JAB=15.6 Hz), 3.57-3.50 (m, 1H), 3.40-3.30 (m, 2H), 3.15-2.90 (m, 6H), 2.60 (dd, 1H, J=13.2, 9.6 Hz), 2.20-1.97 (m, 2H). LRMS (ES)+: 420.4 (M+H)+.
Reaction SMILES: CN(CC[O:6][CH2:7]CN(C)C)C.C([Mg]Cl)(C)C.C1C[O:20]CC1.[CH2:22]([NH:29][C:30]1[N:35]2[N:36]=[CH:37][C:38](Br)=[C:34]2[N:33]=[CH:32][C:31]=1[C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:44][CH2:43]1)=[O:41])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([NH:29][C:30]1[N:35]2[N:36]=[CH:37][C:38]([C:7]([OH:6])=[O:20])=[C:34]2[N:33]=[CH:32][C:31]=1[C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:44][CH2:43]1)=[O:41])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(c2ccccc2)CC1
Reactant: CN(C)CCOCCN(C)C
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Product: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
Bis[2-(N,N-dimethylamino)ethyl]ether (4.1 mL, 25.7 mmol) was dissolved in THF (15 mL), 2 mol/L isopropylmagnesium chloride-THF solution (13.0 mL, 25.7 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 5 min. A suspension (5 mL) of 7-benzylamino-3-bromo-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (1.4 g, 2.9 mmol) obtained in step 4 in THF was added to this mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Carbon dioxide gas was bubbled into the reaction mixture for 30 min under ice-cooling, and the reaction mixture was added dropwise to ice-cooled 1 mol/L hydrochloric acid (100 mL). The mixture was stirred at room temperature for 1 hr, and the precipitate was collected by filtration, and washed with water (50 mL) to give the title compound (0.9 g, 67%).
Reaction SMILES: O1CCCC1.[CH3:6][Si:7]([CH3:14])([CH3:13])[NH:8][Si:9]([CH3:12])([CH3:11])[CH3:10].C([Li:19])CCC>CCCCCC>[CH3:6][Si:7]([CH3:14])([CH3:13])[N-:8][Si:9]([CH3:12])([CH3:11])[CH3:10].[Li+:19]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)[N-][Si](C)(C)C
Product: [Li+]
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran (hereinafter referred to simply as THF) (90 ml) solution of hexamethyldisilazane (6.84 ml), 19.1 ml of n-butyl lithium (a 1.56M hexane solution) was added at -78° C., and the mixture was stirred for 30 minutes to obtain a lithium hexamethyldisilazide solution. To this solution, a THF (20 ml) solution of 10 g of (1S,5R,6R,7R)-2-oxa-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methyl-bicyclo[3.3.0]octan-3-one (Compound 1) was dropwise added at -78° C., and the mixture was stirred for 60 minutes. Then, a THF (40 ml) solution of 9.37 g of N-fluorobenzenesulfonimide was added thereto at -78° C. The mixture was stirred at -78° C. for 60 minutes, then stirred at room temperature for 30 minutes. Then, it was poured into a saturated sodium hydrogen carbonate aqueous solution, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography (ethyl acetate:hexane=1:8 to 1:4) to obtain 9.46 g of the above-identified compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[N:12]=1)=[O:10].COC(C1C(C(F)(F)F)=NC(Br)=C(C2C=CC([Cl:56])=C(Cl)C=2)N=1)=O>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:18])[F:19])=[N:15][C:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([Cl:56])=[C:30]([Cl:34])[CH:29]=2)[N:12]=1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(Oc2ccccc2)nc1C(F)(F)F
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)c(Br)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)c(Cl)c2)c(Oc2ccccc2)nc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 8 (6-(3-chloro-phenyl)-5-phenoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) by substituting 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester with 5-bromo-6-(3,4-dichloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19]CN3C(=O)C4C(=CC=CC=4)C3=O)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:46]([NH:48][CH3:49])=[O:47])[N:8]([C:32]4C=C[C:35]([NH:38]C5C=CC(F)=CC=5)=[CH:34][CH:33]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH2:50]([NH2:54])[CH:51]([CH3:53])[CH3:52].O1CCOC[CH2:56]1>>[CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH3:19])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][C:10]3[C:6](=[C:7]([C:46]([NH:48][CH3:49])=[O:47])[N:8]([C:32]4[CH:56]=[N:38][C:35]([NH:54][CH2:50][CH:51]([CH3:53])[CH3:52])=[CH:34][CH:33]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)CN
Reactant: C1COCCO1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1
Product: CCN(c1cc2nn(-c3ccc(NCC(C)C)nc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To a solution of compound (iii) (4.7 mg, 0.0084 mmol) and isobutylamine (0.1 mL) in 1,4-dioxane (0.3 mL) was heated to 40° C. and stirred for 45 min. More isobutylamine (100 μL) was added and the mixture was heated at 70° C. for 1.5 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by preparative LCMS (5-30-50-100% acetonitrile in 0.1% aqueous formic acid) to give Compound (110) as a white solid. ESI-MS m/z calculated for [M+H]+: 485.2; found: 485.2; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=1.9 Hz, 1H), 7.86 (dd, J=9.3, 2.1 Hz, 1H), 7.68 (s, 1H), 7.32 (s, 1H), 6.82 (brs, 1H), 6.69 (d, J=9.3 Hz, 1H), 6.17 (brs, 1H), 3.88-3.71 (m, 2H), 3.24-3.13 (m, 2H), 3.08 (s, 3H), 3.03 (d, J=4.9 Hz, 3H), 2.39 (ddd, J=13.9, 8.4, 5.5 Hz, 1H), 2.04-1.89 (m, 1H), 1.23 (t, J=7.1 Hz, 3H), 1.11-0.97 (m, 9H), 0.66-0.45 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Product: O=C(Cl)c1c(F)cc(F)c(F)c1F

Procedure:
38.8 g of 2,3,4,6-tetrafluorobenzoic acid, a known compound, was treated with thionyl chloride to give 36 g of 2,3,4,6-tetrafluorobenzoyl chloride as an oil. b.p. 87°-89° C. (36 mmHg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:14][C:15]([NH:17][CH3:18])=[O:16].C[N:20](C=O)C>CCOC(C)=O>[NH2:20][CH:4]1[CH2:5][CH2:6][N:1]([CH2:14][C:15]([NH:17][CH3:18])=[O:16])[CH2:2][CH2:3]1
Reactant: CN(C)C=O
Reactant: CNC(=O)CCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CNC(=O)CN1CCC(N)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2.0 g (10 mmoles) of piperidine, which as dissolved in DMF, anhydrous, 100 mL, was added 2.8 g (20 mmoles) K2CO3, and 1.2 g (11 mmoles) 2-chloro-N-methylacetamide. After stirring at 50° C. for overnight, the mixture was diluted with 500 mL of EtOAc, washed with brine (3×500 mL), dried over Na2SO4, and solvent was evaporated in vacuum. The resulting residue was treated with 50% TFA/DCM and was stirred at r.t. for 2 hrs, and solvent was evaporated in vacuum. The resulting mixture was purified by prep HPLC to give yellow oil, yield 1.5 g (88%). [M+H] calc'd for C8H17N3O, 172; found 172.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23]C(OC(C)(C)C)=O)[CH:17]=1)[CH2:5][P:6]([CH:11]([NH2:15])[CH:12]([CH3:14])[CH3:13])([O:8]CC)=[O:7].CCN(C(C)C)C(C)C.[C:41]1([S:47](Cl)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C[Si](Br)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:23][CH2:22][C:18]1[CH:17]=[C:16]([CH:4]([CH2:5][P:6]([CH:11]([NH:15][S:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:49])=[O:48])[CH:12]([CH3:13])[CH3:14])([OH:8])=[O:7])[C:3]([OH:2])=[O:31])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(N)C(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NS(=O)(=O)c1ccccc1)P(=O)(O)CC(C(=O)O)c1cccc(CN)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-amino-2-methylpropyl)(ethoxy)phosphinoyl)propanoic acid methyl ester (344 mg, 0.75 mmol) in methylene chloride (10 mL) was added DIEA (394 μL, 2.25 mmol) followed by DMAP (3.4 mg (cat.)). The reaction mixture was cooled to 0° C. and a solution of benzenesulfonylchloride (200 mg, 1.13 mmol) in methylene chloride was added dropwise over 15 minutes. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to warm to ambient temperature overnight. The reaction was diluted with methylene chloride and washed with 2 N aq NaHSO4, water, brine and dried over sodium sulfate. Evaporation gave a crude residue (425 mg) that was dissolved in 2.5 mL of methylene chloride and cooled to 0° C. under N2. TMSBr (1 mL) was added dropwise and the reaction was stirred at ambient temperature overnight, quenched with MeOH and evaporated. The resulting residue was dissolved in 5 mL of MeOH/H2O (1:1), neutralized with 0.25 M aq LiOH and 300 mg of LiOH and 10 mL of H2O. The reaction mixture was stirred at ambient temperature overnight. The solvents were evaporated and purification by preparative HPLC yielded 150 mg of 2-(3-(amino)methylphenyl)-3-((1-(phenylsulfonyl)amino-2-methylpropyl)(hydroxy)-phosphinoyl)propanoic acid, NMR (DMSO-d6) 0.5-0.8 (m, 6), 1.8 (m, 1), 1.92 (m, 1), 2.35 (m, 1) 3.25 (m, 1), 3.82 (m, 1), 4.0 (s, 2), 7.2 (dd, 1), 7.25-7.4 (m, 3), 7.4-7.6 (m, 3), 7.8 (m, 3), 8.18 (s, 3) ppm.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH2:7]1[C:3]2([CH2:2][O:1][C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[NH:8]2)[CH2:4][CH2:5][CH2:6]1
Reactant: NC1(CO)CCCC1
Reactant: O=C1CCCC1
Solvent: Cc1ccccc1
Product: C1CCC2(C1)COC1(CCCC1)N2
Yield: 175.7 %

Procedure:
A solution of 1-hydroxymethylcyclopentanamine (Method B1c; 263 g, 2.3 mol) and cyclopentanone (220 mL, 1.3 mol, 1.1 equiv.) in toluene (2.7 L) was heated at the reflux temp. with azeotropic removal of water until the theoretical amount of water had been collected (41.4 mL). The reaction mixture was concentrated to 700 mL by simple distillation, then cooled to room temp. and concentrated to constant weight under reduced pressure to give 6-aza-12-oxadispiro[4.1.4.2]tridecane (414 g, 100%) as a pale yellow oil: 1H NMR (CDCl3) δ1.55-1.89 (m, 17H), 3.60 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CC)(CC)CC)C1C=CC=CC=1.[N+](C1C=CC([O:41][C:42](=O)[C@H:43]([CH2:55][C:56](=[O:58])[NH2:57])[NH:44][C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=CC=1)([O-])=O.N1C=CC=CC=1>CN(C)C=O>[CH2:48]([O:47][C:45]([NH:44][C@H:43]([C:42]([NH:14][C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:41])[CH2:55][C:56](=[O:58])[NH2:57])=[O:46])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
51 g Nε-tert.butyloxycarbonyl-L-lysine were converted in a conventional manner into the benzyltriethylammonium salt and then stirred in 700 ml dimethylformamide with 81 g benzyloxycarbonyl-L-asparagine-4-nitrophenyl ester with the addition of 1 equivalent of pyridine for 48 hours at 20°. The residue left after vacuum evaporation was treated with ethyl acetate and potassium hydrogen sulfate solutions simultaneously; the thick precipitate formed was filtered off and then recrystallised from ethanol/petroleum ether. F = 174° - 175° (Z);[α]D20 = + 13.8° (c = 1.0; in pyridine). Yield = 70 g (71 % of the theoretical amount).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9](Cl)=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:6][CH:5]=1.[CH3:16][O-:17].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([O:17][CH3:16])=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(C(=O)OC)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cncc(C(=O)OC)c1OC
Reaction time: 0.17 h

Procedure:
To a solution of 6.3 g (27.5 mmol) of methyl-4-chloro-5-methoxycarbonyl-nicotinate in 100 ml of THF is added 6.48 ml (35 mmol) of a 5.4 m solution of sodium methoxide in methanol. The mixture is stirred for 10 minutes and evaporated. 100 ml of a 0.25M aqueous HCl is added to the residue. The solution is made basic with K2CO3 and extracted with ethyl acetate. The organic phase is dried and evaporated to give an oil which crystallised on cooling. There is obtained 6,2 g (quantitative yield) of a solid (M+1=226).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:21]=[CH:20][O:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[N+]=[N-].C(Cl)[Cl:23].CO.C1COCC1.O>>[Cl-:23].[O:19]1[CH:20]=[CH:21][C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][NH3+:1])[O:9][C:8]3=[O:10])=[CH:12][CH:13]=2)=[N:18]1
Reactant: ClCCl
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(-c3ccon3)cc2)C(=O)O1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: [Cl-]
Product: [NH3+]C[C@H]1CN(c2ccc(-c3ccon3)cc2)C(=O)O1
Reaction time: 8 h

Procedure:
[(5R)-3-(4-Isoxazol-3-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (Intermediate 7,400 mg, 1.18 mmol), sodium azide (99 mg, 1.53 mmol), 18 crown-6 (23.6 mg, 0.089 mmol) and tetrabutylammonium iodide (28.2 mg, 0.076 mmol) were combined in DMF (5 ml) and heated to 60° C. for 4 hours. EtOAc (20 ml) was added and the organic layers were washed with brine (3×20 ml), dried over Na2SO4 and concentrated under vacuum to yield (5R)-5-(azidomethyl)-3-(4-isoxazol-3-ylphenyl)-1,3-oxazolidin-2-one. (5R)-5-(Azidomethyl)-3-(4-isoxazol-3-ylphenyl)-1,3-oxazolidin-2-one (300 mg, 1.045 mmol) was added to CH2Cl2:MeOH:THF:H2O 10:10:10:2 and then polystyrene triphenylphosphine resin (2650 mg, 4.18 mmol) was added. The reaction was allowed to stir overnight and then the resin was filtered and washed multiple times with dichloromethane and methanol. The filtrate was concentrated in vacuo and then dissolved in dichloromethane (10 ml) followed by addition of 2N HCl in ether (0.5 ml). The precipitate was collected and washed with ether (2×20 ml) and then dried under vacuum to yield the title product (300 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>C1COCC1.C(OCC)(=O)C>[F:16][CH:15]([F:17])[O:14][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-(difluoromethoxy)propanoic acid (780 mg, 3.05 mmol) and triethylamine (924 mg, 9.15 mmol) in THF (15 mL) at −78° C., isobutyl chloroformate (417.7 mg, 3.05 mmol) was added dropwise. After 30 minutes, (4-fluorobenzyl)amine (458 mg, 3.0 mmol) was added and the reaction mixture was allowed to warm up to room temperature. The mixture was then diluted with ethyl acetate and washed with water, 0.5N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated, and triturated with hexanes (1:3) to give tert-butyl {(1R)-1-[(difluoromethoxy)methyl]-2-[(4-fluorobenzyl)amino]-2-oxoethyl}carbamate (870 mg, 78.7%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.23 (dd, 2H), 7.03 (t, 2H), 6.60 (b, 1H), 6.23 (wt, 1H), 5.24 (w, 1H), 4.3-4.51 (m, 4H), 4.02 (dd, 1H) and 1.45 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:21][O:22][C:18]=2[CH:17]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([N:23]3[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[N:8]=[N:7]4)[CH2:25][CH2:24]3)=[N:21][O:22][C:18]=2[CH:17]=1
Reactant: Fc1ccc2c(N3CCNCC3)noc2c1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1ccc2c(N3CCN(CCCCn4nnc5ccccc54)CC3)noc2c1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 6-fluoro-3-(piperazine-1-yl)benzisoxazole (6.1 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.3 g compound (I-36) with a yield of 70.0%. ESI-MS [M+H]+: m/z 395.2.
Reaction SMILES: O=O.C[N:4]([CH3:21])[CH:5]=[CH:6][C:7]([C:9]1[CH:10]=[C:11]([N:15]([CH2:19][CH3:20])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)=O.N[C:23]1[C:27]([C:28]#[N:29])=C[NH:25][N:24]=1>O>[CH3:20][CH2:19][N:15]([C:16]([CH3:17])=[O:18])[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[N:25]3[N:24]=[CH:23][C:27]([C:28]#[N:29])=[C:21]3[N:4]=[CH:5][CH:6]=2)[CH:10]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: O=O
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Yield: 91 %

Procedure:
WO O2/100828 A2 discloses a further improvement in the '538 process by reacting the same intermediates, N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide and 3-amino-4-cyanopyrazole, in a liquid medium of water and a water-miscible organic compound under acidic conditions. Although the reaction is claimed to proceed through an imine intermediate that was prone to precipitate from water, the imine intermediate remained dissolved in the reaction media. It is stated in the '828 patent that the process proceeds rapidly at ambient temperature to produce zaleplon with a 91-97% yield having a purity ranging from 98.7 to 99.5% according the HPLC analysis. The method minimized the formation of a regioisomer by-product, N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide which is favored under excess acid conditions.