Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1.O>ClCCl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[C:15]([C:5](=[O:8])[CH2:6][CH3:7])[CH:16]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.1 %

Procedure:
Aluminium chloride (3.747 kg) was added to dichloromethane (7.0 l) at room temperature and propionyl chloride (1.297 kg) was then added over a 10 minute period. The mixture was stirred for 45 minutes and then a solution of 4-bromoanisole (1.312 kg) in dichloromethane (0.87 l) was added over a 15 minute period. The mixture was heated under reflux for 6.5 hours and then kept overnight at room temperature. The ice-cooled reaction mixture was quenched by the slow addition of ice (15 kg) over 1.5 hours. The mixture obtained was stirred for 15 minutes, the layers were separated and the aqueous layer extracted with dichloromethane (2×1.0 l). The organic layers were combined and washed with water (2×2.0 l), then two-thirds of the solvent removed by distillation at atmospheric pressure. Methanol (5.63 l) was then added slowly and the distillation continued until a pot temperature of 64° C. and a head temperature of 62° C. was achieved. Water (0.4 l) was added slowly and the mixture was cooled resulting in the precipitation of an off-white solid. Further water (0.4 l) was then added slowly and the precipitated solid granulated at about 10° C. for 2 hours. The solid was then filtered off, washed sparingly with a 6:1 methanol/water mixture and dried under reduced pressure at 50° C. to provide the title compound (1.464 kg).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2].[CH3:19]N(N=O)C(N)=O.[OH-].[K+].CC(O)=O>CCOCC>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2]
Reactant: CN(N=O)C(N)=O
Reactant: CC(=O)OCc1ccc2cc(C(=O)O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1ccc2cc(COC(C)=O)ccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 139.8 %

Procedure:
To a suspension of 1.08 g (4.43 mmol) of 6-acetoxymethyl-2-naphthoic acid in 150 mL of Et2O at 0° C. was added a cold solution of CH2N2 in Et2O which was prepared from 2.0 g (19 mmol) of N-methyl-N-nitrosourea and 30 mL of 40% aqueous KOH. The mixture was stirred at 0° C. for 10 min when all the solid went into solution. Excess CH2N2 was decomposed with HOAc. The reaction mixture was dried over Na2SO4 and concentrated to give 1.6 g of a white solid, which was purified on 100 g of silica gel (50% EtOAc/hexane) to give 1.04 g (91% yield) of the pure methyl ester. A portion was recrystallized from EtOAc/hexane to give white plates: mp 115°-116° C.; IR (mull) 1720, 1300, 1260, 1200, 1140, 1100, 1040, 980, 940, 900, 840, 820, 760 cm-1 ; 1 H NMR (CDCl3) δ2.15 (s, 3, CH3CO2), 3.98 (s, 3, CO2CH3), 5.28 (s, 2, CH2O), 7.3-8.7 (m, 6, ArH); MS calcd for C15H14O4 258.0892, found 258.0872.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)=[C:2]=S.[NH3:18].C[OH:20]>>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:4]([NH:1][C:2]([NH2:18])=[O:20])=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CO
Reactant: N
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Product: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-[2-(4-isothiocyanato-phenoxy)-ethyl]-pyrrolidine (0.355 g, 1.43 mmol), MeOH (2.75 mL) and a 2M solution of NH3 in MeOH (2.75 mL, 5.49 mmol, 3.84 equiv) is heated in a sealed tube at 60° C. for 1 h, under an argon atmosphere. The reaction mixture is allowed to cool to RT and concentrated in vacuo to afford the title compound as a dark brown solid: ES-MS: 266.0 [M+H]+; single peak at tR=3.99 min (System 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:8].[Br-:9].[K+].ClCl>O>[NH2:1][C:2]1[C:7]([Br:9])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: [Br-]
Reactant: Cl
Reactant: Nc1ccccn1
Agent: ClCl
Agent: [K+]
Solvent: O
Product: Nc1ncc(Cl)cc1Br
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To produce 2-amino-3-bromo-5-chloropyridine, 30 parts of chlorine are introduced in the course of 50 minutes, with slight cooling, into a solution of 37.6 parts of 2-aminopyridine in 160 parts of concentrated hydrochloric acid (36%). A solution of 53 parts of potassium bromide in 50 parts of water is then added, and a further 30 parts of chlorine are introduced within one hour at a temperature of about 35° C., whereby finally a light-yellow precipitate occurs. The mixture obtained is stirred for a further 30 minutes. The solution is afterwards poured on to ice, and the free halogen still present is removed by the addition of sodium bisulphite solution. There is now added, with ice-cooling, a solution of 95 parts of sodium hydroxide in 190 parts of water. The resulting beige-coloured precipitate is filtered off with suction, washed with ice-water and dried at 30° to 40° C. in a water-jet vacuum. There are obtained 74 parts (90% of theory) of 2-amino-3-bromo-5-chloropyridine, m.p. 78°-79° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:27][C@H:28]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:29][C:30](O)=[O:31])(=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:30](=[O:31])[CH2:29][C@H:28]([O:27][C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCCC
Solvent: ClCCCl
Solvent: CI
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCCCCCC
Yield: 91.5 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-undecanoyloxytetradecanoic acid (905 mg, 2.2 mmol) in the presence of EDC·MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 1.08 g (92%) of N-[(R)-3-undecanoyloxytetradecanoyl]-L-serine benzyl ester: mp 53-54° C.; 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.9 Hz), 1.1-1.7 (m, 44H), 2.30 (t, 2H, J=7.7 Hz), 2.49 (d, 2H, J=5.8 Hz), 3.99 (m, 2H), 4.65 (m, 1H), 5.19 (m, 3H), 6.58 (d, 1H, J=6.9 Hz), 7.35 (br s, 5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][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][C:23]([OH:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:40]1[C:45](=[O:46])[CH2:44][CH2:43][C:41]1=[O:42])=[N+](C)C)C.CCN(C(C)C)C(C)C.Cl>C1COCC1.C(#N)C>[O:42]=[C:41]1[CH2:43][CH2:44][C:45](=[O:46])[N:40]1[O:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)O
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Octadecanedioic acid mono-tert-butyl ester (4.2 g, 0.011 mol) was dissolved in THF (20 mL), TSTU (4 g, 0.013 mol) in acetonitrile (20 mL) was added and pH of the solution was adjusted to 8 with dropwise addition of DIPEA. The mixture was stirred at RT for 4 h, then acidified with HCl (2M) to pH 3 and evaporated in vacuo. The residual oil was subsequently partitioned between ethyl acetate and HCl (0.1 M). The organic layer was dried (MgSO4), filtered and evaporated to dryness in vacuo. This afforded 5.2 g of octadecanedioic acid tert-butyl ester 2,5-dioxopyrrolidin-1-yl ester as an oil, which could be used in the next step without further purification. LC-MS (electrospray): m/z=468 (M+1) and 412 (M+1-tBu).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=1)[C:7]#[N:8].CI.[CH2:25](Cl)Cl>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]([CH3:25])[C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=1)[C:7]#[N:8]
Reactant: Cn1cnc2ccc(Nc3ccc(C#N)cc3F)cc21
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(c1ccc2ncn(C)c2c1)c1ccc(C#N)cc1F
Reaction time: 0.5 h

Procedure:
NaH (7.14 mmol) was added to a solution of 3-fluoro-4-[(3-methylbenzimidazol-5-yl)amino]benzonitrile (2.38 mmol) in THF (10 mL) at 0° C. The mixture was stirred for 30 min. MeI (4.76 mmol) was added and the mixture was stirred at room temperature during 3 h. The mixture was diluted (DCM), washed (H2O) and concentrated. The residue was purified by prep HPLC to yield the desired product (Compound C).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[CH2:12][C:13]#N)(=[O:4])=[O:3].C[Si](Cl)(C)C.[OH2:21].[CH3:22][OH:23]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[CH2:12][C:13]([O:23][CH3:22])=[O:21])(=[O:4])=[O:3]
Reactant: CO
Reactant: O
Reactant: CS(=O)(=O)c1ccccc1C(=O)CC#N
Agent: C[Si](C)(C)Cl
Product: COC(=O)CC(=O)c1ccccc1S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-(methylsulfonyl)phenyl)-3-oxopropanenitrile (4.5 g, 20.25 mmol) in methanol (100 mL) was added trimethyl silyl chloride (11 mL, 100.58 mmol) at 25° C. The reaction mixture was stirred for overnight at 70° C. Water was added to the reaction mixture at 25° C. and extracted with EtOAc. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel using 0-30% EtOAc in hexane to give methyl 3-(2-(methylsulfonyl)phenyl)-3-oxopropanoate: 1H NMR (400 MHz, DMSO-d6): δ 3.294 (S, 3H), 3.645 (s, 3H), 4.12 (s, 2H), 7.762-7.874 (m, 3H), 7.979-7.984 (m, 1H); LC-MS (ESI) m/z 256.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:19])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O.C(Cl)Cl>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([Cl:23])=[O:19])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn(Cc2ccccc2)c2ccccc12
Yield: 100 %

Procedure:
A mixture of 1-benzyl-1H-indole-3-carboxylic acid (3.36 g, 13.37 mmol), oxalyl chloride (5.83 mL, 66.85 mmol), 100 mL methylene chloride and a catalytic amount of DMF was stirred at room temperature under nitrogen for 18 h (overnight). The solvent was removed under reduced pressure. To remove excess oxalyl chloride benzene was added and the solvent removed under reduced pressure to give 1-benzyl-1H-indole-3-carbonyl chloride as a brown oil (13.37 mmol) which was immediately used in step 2 without additional purification.
Reaction SMILES: [C:1]([N:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:24][CH3:25])=[C:17]([CH:23]=1)[C:18]([N:20]=[C:21]=[S:22])=[O:19].II.CO>O1CCCC1.N1C=CC=CC=1>[CH2:8]([C:7]1=[CH:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[S:22]/[C:21]/1=[N:20]\[C:18](=[O:19])[C:17]1[CH:23]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[O:24][CH3:25])[CH2:9][CH2:10][CH3:11]
Reactant: COc1ccc(Cl)cc1C(=O)N=C=S
Reactant: CCCCCC=NC(C)(C)C
Agent: II
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CO
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To the product of Example 1A (1.90 g, 12.2 mmol) in tetrahydrofuran (10 mL) at room temperature under N2 was added the product of Example 1C (2.30 g, 10.1 mmol). After 1 h at room temperature, the reaction was treated with I2 (2.59 g, 10.2 mmol), methanol (30 mL) and pyridine (3 mL) and stirred for 1 hour. The reaction was then partitioned between saturated NaHCO3/diethyl ether with continued stirring overnight. The reaction was diluted further with saturated NaHCO3/diethyl ether, the layers separated and the aqueous phase extracted again with diethyl ether (2×). The organics were combined, dried (MgSO4), filtered and solvent evaporated. Toluene/acetonitrile was added and evaporated 2× to remove excess pyridine and H2O. The crude was flash chromatographed, eluting with diethyl ether:CH2Cl2:hexane (7:3:3) to provide 2.68 g of the desired product with impurities running above and below. This material was dissolved in a minimum of CH2Cl2, hexane added until slightly cloudy and allowed to sit for 4 hours. A white crystalline solid was collected and washed with cold 1:1 CH2Cl2:hexane to provide 962.78 mg of the title compound. The mother liquor was recrystallized from methanol to provide 555 mg additional title compound. The second mother liquor was concentrated to dryness, dissolved in a minimum of CH2Cl2 and flash chromatographed on silica gel, eluting with diethyl ether:CH2Cl2:hexane (7:1:3) to provide an additional 600 mg of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.98 (t, 3H), 1.37-1.49 (m, 2H), 1.65 (s, 9H), 1.67-1.77 (m, 2H), 2.83 (t, 2H), 3.92 (s, 3H), 6.91 (d, 1H), 7.34 (dd, 1H), 7.95 (s, 1H), 8.11 (d, 1H). MS (DCI/NH4+) m/z 381 (M+H)+. Anal. calcd for C19H25ClN2O2S: C, 59.91; H, 6.61; N, 7.35. Found: C, 59.88; H, 6.67; N, 7.42.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(OCC)(=O)NN.[C:14](Cl)([Cl:16])=[O:15]>C(OCC)(=O)C>[CH3:6][O:5][C:1]([NH:2][NH:3][C:14]([Cl:16])=[O:15])=[O:4]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)NN
Agent: CCOC(=O)NN
Solvent: CCOC(C)=O
Product: COC(=O)NNC(=O)Cl
Yield: 91.8 %

Procedure:
Example 1 was repeated but substituting methyl carbazate (50 g, 0.55 mole) for the ethyl carbazate and using phosgene (75 ml, 1.13 mole) in dry ethyl acetate as solvent. Solvent was removed under reduced pressure at a bath temperature <60° C. and the product was re-dissolved in ethyl acetate, filtered to remove insoluble material and recovered by evaporation of the solvent in vacuo, giving 2-methoxycarbonylhydrazinecarbonyl chloride (77 g, 92%) mp 55°-58° C. The ir spectrum was similar to that of 2-ethoxycarbonylhydrazinecarbonyl chloride.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30](Cl)Cl)=[CH:25][CH:24]=1>>[C:26]1([NH:29][C:30]2[S:17][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]3[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:9]=3)=[N:18][N:19]=2)[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(Cl)=Nc1ccccc1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Product: c1ccc(Nc2nnc(NCCCOc3cccc(CN4CCCCC4)c3)s2)cc1

Procedure:
The compound is prepared by a method analogous to that of Example 29 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carbothioamide and phenyl isocyanide dichloride. The analytical values are summarized in Table II.
Reaction SMILES: C[N:2](C)[C:3]([CH3:24])=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[C:26]1([NH:32]N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:24][C:3]1[CH:4]=[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)[N:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:2]=1
Reactant: NNc1ccccc1
Reactant: CC(=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 15.7 %

Procedure:
A solution of 3-[3-(dimethylamino)but-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.270 g, 0.77 mmol) and phenyl hydrazine (0.200 mL, 2.0 mmol) in acetic acid (5.0 mL) was heated under microwave conditions at 120° C. for 10 min. After this time, the reaction was cooled to room temperature and concentrated onto silica gel. The crude product purified by column chromatography (silica gel, 50:50 ethyl acetate/hexanes to ethyl acetate) to separate the two isomers, followed by preparative reverse phase HPLC and crystallization from diethyl ether to give 3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.048 g, 16%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.42 (s, 3H), 6.73 (d, J=7.9 Hz, 1H), 6.99 (dd, J=1.7, 8.1 Hz, 1H), 7.18 (br s, 1H), 7.21 (s, 1H), 7.30-7.49 (m, 6H), 7.55 (d, J=7.8 Hz, 1H), 8.19 (d, J=7.9 Hz, 1H); APCI MS m/z 397 [M+H]+; mp 167-168° C.
Reaction SMILES: C([O-])(=O)/C=C/C([O-])=O.[NH4+].[NH4+].[NH2:11][C@H:12]([C:17]([O-:19])=[O:18])[CH2:13][C:14]([O-:16])=[O:15].C([O-])(=O)/C=C/C([O-])=O>>[NH3:11].[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=[O:15]
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: [NH4+]
Product: N
Product: N[C@@H](CC(=O)O)C(=O)O
Yield: 90 %

Procedure:
The enzyme L-aspartase, immobilized by the process of this invention, can be used to convert diammonium fumarate to L-aspartate in 90% yield at pH 7 and 25° C. The immobilized L-aspartase enzyme polymer can be used over and over again to convert fumarate to L-aspartate without significant loss in activity.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[CH3:10][C:11]([S:14]([NH:16][C@@H:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1)[C:18]#[CH:19])=[O:15])([CH3:13])[CH3:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C(O)CCC.O>O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:1]1[CH:19]=[C:18]([C@H:17]([NH:16][S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=2)[N:3]=[N:2]1)[CH3:9]
Reactant: C#C[C@@H](NS(=O)C(C)(C)C)c1ccc(OCC(F)(F)F)cn1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CCOC(=O)Cn1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To a 50 ml round bottom flask equipped with a magnetic stir bar were added ethyl azidoacetate (0.193 g, 1.495 mmol), 2-methyl-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]prop-2-yn-1-yl}propane-2-sulfinamide (0.500 g, 1.495 mmol), freshly made 1.0 N sodium ascorbate (0.150 ml, 0.150 mmol), and 1.0 N Cu2SO4 (0.150 ml, 0.150 mmol) into 6.0 ml of a mixed solvent BuOH/H2O (1:1). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by flash chromatography (SiO2, 50-80% ethyl acetate in hexanes, gradient) gave the title compound as a light yellow solid (0.365 g, 53%). 1H NMR (CDCl3, 400 MHz) δ 8.291 (d, J=2.93 Hz, 1H), 7.634 (s, 1H), 7.452 (d, J=8.79 Hz, 1H), 7.247 (ABq, J=3.03 Hz, 1H), 5.879 (d, J=5.50 Hz, 1H), 5.349 (d, J=5.31 Hz, 1H), 5.125 (ABq, J=7.49 Hz, 2H), 4.381 (q, J=7.87 Hz, 2H), 4.255 (q, J=7.14 Hz, 2H), 1.290 (t, J=7.14 Hz, 3H), 1.271 (s, 9H). ES-MS [M+1]+: 464.1.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH:5]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][NH:15][C:14]=2[N:13]=1.[OH-].[Na+]>CCO>[N:13]1[C:14]2[NH:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=[CH:21][C:12]=1[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)CC(CCCCNCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(CCCCNCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Reaction time: 1 h

Procedure:
To a solution of 21-7 (0.8255 mmol) in EtOH (5 mL) was added 1N NaOH (1.0 ml, 1.0 mmol). After stirring for 1 hour, the solvents were evaporated and the residue was chromatographed (silica gel, 20:10:1:1 followed by 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 21-8 as a white solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:46])([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)/[CH:15]=[CH:16]/[C@@H:17]1[C@@H:29]2[C@@H:20]([O:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH2:28]2)[CH2:19][C@H:18]1[O:31]C1CCCCO1>CO>[F:46][C:14]([F:13])([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)/[CH:15]=[CH:16]/[C@@H:17]1[C@@H:29]2[C@@H:20]([O:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH2:28]2)[CH2:19][C@H:18]1[OH:31]
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: O
Solvent: CO
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-toluenesulfonic acid monohydrate (10.37 g, 54.5 mmol) was add to a stirred solution of (8aR,9R,10R,11aS,Z)-9-((E)-3,3-difluoro-4-phenoxybut-1-en-1-yl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-4,5,8,8a,9,10,11,11a-octahydrocyclopenta[b]oxecin-2(3H)-one (26.0 g from example 33) in methanol (200 mL). The mixture was stirred for 2 hr at room temperature (TLC monitoring). Then, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (300 mL), and the methanol was removed under reduced pressure. The residue was extracted with ethyl acetate (200 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 30.0 g of crude product. The crude product was purified by column chromatography providing 20.0 g of the titled compound (90.0% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]([NH:5][C@@H:6]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([NH:9][C@H:10]([B:16]1[O:20][C@@H:19]2[CH2:21][C@@H:22]3[CH2:25][C@H:24]([C@:18]2([CH3:28])[O:17]1)[C:23]3([CH3:27])[CH3:26])[CH2:11][CH:12]1[CH2:15][CH2:14][CH2:13]1)=[O:8])=[O:4].Cl.C(#N)C.[C:48](OC(=O)C)(=[O:50])[CH3:49].C(N(CC)C(C)C)(C)C>>[C:48]([NH:1][C@@H:2]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]([NH:5][C@@H:6]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([NH:9][C@H:10]([B:16]1[O:20][C@@H:19]2[CH2:21][C@@H:22]3[CH2:25][C@H:24]([C@:18]2([CH3:28])[O:17]1)[C:23]3([CH3:26])[CH3:27])[CH2:11][CH:12]1[CH2:15][CH2:14][CH2:13]1)=[O:8])=[O:4])(=[O:50])[CH3:49]
Reactant: CC1(C)[C@@H]2C[C@H]3OB([C@H](CC4CCC4)NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@@H](N)CCc4ccccc4)O[C@@]3(C)[C@H]1C2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC1CCC1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 8 h
Yield: 53 %

Procedure:
Into a 20 mL scintillation vial was added (2S)-2-amino-N-[(1S)-1-benzyl-2-({(1R)-2-cyclobutyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}amino)-2-oxoethyl]-4-phenylbutanamide.HCl (52.0 mg, 0.0836 mmol), acetonitrile (5.20 mL, 0.0996 mol), acetic anhydride (8.68 μL, 0.092 mmol), N,N-diisopropylethylamine (36.4 μL, 0.209 mmol) and N,N-dimethylaminopyridine (0.0005 g, 0.004 mmol). The mixture was stirred overnight and the precipitate was filtered and washed with Et2O to give 0.028 g (53% yield) of product as a white solid.