Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]=[C:44]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>C(Cl)(Cl)Cl>[CH3:58][C:56]([CH3:59])([O:55][C:54]([NH:53][C:44]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[N:45][C:46]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:52])=[O:60])[CH3:57]
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCN)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)NCCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
1.05 g (8.10-3 mol) of monoethyl malonate are dissolved in 15 ml of anhydrous chloroform, the solution is then cooled to 0° C. and 1.65 g (8.10-3 mol) of 1,3-dicyclohexylcarbodiimide and 0.108 g (0.8.10-3 mol) of 1-hydroxybenzotriazole hydrate are added. After stirring for 0.5 hour at 0° C., a solution of 1.5 g (4.19.10-3 mol) of bis(1,1-dimethylethyl) [[(6-aminohexyl)imino]methylene]biscarbamate in 5 ml of anhydrous chloroform is added. The mixture is then stirred for 48 hours at room temperature, after which the reaction medium is concentrated under reduced pressure. The crude product obtained is purified by medium pressure chromatography on silica using a hexane/ethyl acetate mixture (1/1 v/v) as the eluent to give 1.95 g (yield=99%) of the expected product in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.[C:13]([O-:16])([O-])=O.[K+].[K+].[Cl-].O>C(Cl)Cl>[OH:12][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[C:2]([NH:1][C:13](=[O:16])[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1)=[CH:11][CH:10]=[CH:9]2
Reactant: Nc1cccc2cc(O)ccc12
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc2cc(O)ccc12)c1ccccc1

Procedure:
To a round bottom flask containing 1.00 g (6.3 mmol) 5-amino-naphthalene-2-ol in 10 mL CH2Cl2, was added 2.61 g (0.0189 mmol) K2CO3, followed by 1.46 mL (0.0126 mmol) benzolyl chloride. The solution mixture was stirred under inert atmosphere until completion. After stirring for 18 h, water was added into the mixture and diluted with CH2Cl2. The organics were separated by sep. funnel, while extracting the organics 3× with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered and concentrated in-vacuo. The crude was purified by crystallization in CH2Cl2/Hexanes. A gray colored powder was collected, which was titled compound. MS (ESI pos. ion) m/z: 264 (M+H)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C-:32]#[N:33].[K+].O>CN(C)C=O>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:32]#[N:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 100 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Compound 67a (217 mg, 0.529 mmol) obtained in Example 67 was dissolved in N,N-dimethylformamide (4 mL), to the solution were added cesium carbonate (245 mg, 0.750 mmol, 1.5 equivalents) and potassium cyanide (39 mg, 0.600 mmol, 1.2 equivalents), and the mixture was stirred at 100° C. for 4 hours. To the reaction mixture was added water, and the deposited crystals were collected by filtration to obtain the title compound (125 mg, 73%) as a yellow solid.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5](S(OCCC#C)(=O)=O)=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)C=C[CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:16]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23]1)[CH2:17][C:18]#[CH:19]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCN1CCN(c2ccccc2)CC1

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (1.72 g), N-phenyl piperazine (1.17 mL) and diisoproylethylamine (1.45 mL) in 1,2-dichloroethane (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with sat. aq. NaHCO3 (5 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (3% Et3N in EtOAc) afforded 1-(but-3-ynyl)-4-phenylpiperazine (0.76 g)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]2=[CH:10][C:11]3[C:16]([N:8]2[CH2:7][CH2:6][C:5]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=[CH:13][CH:12]=3.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C=O)C>[CH2:20]([O:19][C:17]([C:5]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:6][CH2:7][N:8]2[C:16]3[C:11]([CH:10]=[C:9]2[C:4]1=[O:3])=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)OCC)CCn2c(cc3ccccc32)C1=O
Reaction time: 0.5 h
Yield: 95 %

Procedure:
1.3 g of sodium hydride were added over 0.5 hour to a stirred, ice-cold solution of 12.85 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate in 200 ml of DMF and the mixture was stirred for a further 0.5 hour. A solution of 9.2 g of ethyl bromoacetate in 50 ml of DMF was added dropwise to the cooled mixture. After a further 3 hours at room temperature the mixture was poured into 1.5 l of water and extracted with diethyl ether. The ethereal extracts were washed with water, dried and concentrated to give 16.3 g of ethyl 8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-acetate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.Cl.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]1([C:17]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:25]3[CH:21]([CH2:22][N:23]([C:7](=[O:9])[CH2:6][C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccsc3)CC12
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(3-thienyl)acetic acid (0.99 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.24 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 16 hours at 20° C., then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (40 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(3-thienyl)acetyl]-4-perhydroisoindolone (2.2 g) melting at 224° C. is obtained.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:7][O:6]1)[CH2:2][CH:3]=[CH2:4].[CH2:8]([O:11][CH2:12]C)[CH:9]=C>>[CH2:8]([O:11][CH2:12][CH:4]=[CH:3][CH2:2][CH2:1][CH:5]1[CH2:7][O:6]1)[CH3:9]
Reactant: C=CCOCC
Reactant: C=CCCC1CO1
Product: CCOCC=CCCC1CO1

Procedure:
The cross metathesis of (±)-2-(but-3-enyl)oxirane (3.80 g, 38.7 mmol) with ethyl allyl ether (10.0 g, 116 mmol) was performed as described previously in Example 9.2, Step A to give (±)-2-(5-ethoxypent-3-enyl)oxirane as an inseparable mixture of olefin isomers (trans:cis=10:1) after silica gel chromatography. 1H NMR (400 MHz, CDCl3): trans isomer: δ 5.73 (1H, m), 5.63 (1H, m), 3.91 (2H, m), 3.48 (2H, q, J=7.0 Hz), 2.93 (1H, m), 2.75 (1H, dd, J=5.0, 2.7 Hz), 2.22 (2H, m), 1.63 (2H, m), 1.21 (3H, t, J=7.0 Hz). cis isomer: δ 5.62 (2H, m), 4.04 (2H, m), 3.48 (2H, q, J=7.0 Hz), 2.93 (1H, m), 2.75 (1H, m), 2.49 (1H, m), 2.22 (2H, m), 1.63 (2H, m), 1.22 (3H, t, J=7.0 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:3])[CH3:2].[I:22]Cl.C([O-])(O)=O.[Na+]>CC(O)=O.O>[I:22][C:7]1[CH:6]=[C:5]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: ClI
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of 2-Isopropyl-4-methoxy-1-(toluene-4-sulfonyl)-benzene (10 g, 31.25 mmol) in HOAc (10 ml) was added a solution of ICl (9.6 g, 59.26 mmol) in HOAc (10 ml) and H2O (5 ml). The reaction mixture was stirred at room temperature for 16 hrs and basified by saturated NaHCO3 solution. The aqueous solution was extracted into EtOAc which was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1-Iodo-4-isopropyl-2-methoxy-5-(toluene-4-sulfonyl)-benzene (12.35 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a solution of the product of Example 308B (940 mg, 2.33 mmol) in ethyl acetate (50 mL) was added SnCl2.2H2O (1.85 g, 8.18 mmol) and the reaction was heated at reflux for 1 hour. The reaction mixture was cooled and basified to pH8 gradually with solid NaHCO3, stirred overnight, and extracted with ethyl acetate. The ethyl acetate extract was concentrated and the residue was purified by chromatography on silica gel (5% methanol-ethyl acetate) to give the aniline (450 mg, 52%) as an oil.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([C:21]4[CH:22]=[CH:23][C:18]([O:17][C:16]([F:15])([F:30])[F:31])=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)Oc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-trifluoromethoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. FDMS m/e=434 (M+ of free base). α[D]589=−13.45 (c=1.04, methanol).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]([CH3:28])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1>CS(C)=O>[CH3:28][C:10]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:2][O:9]1
Reactant: CC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(CN2CCN(C(=O)OCc3ccccc3)CC2)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
Trimethylsulfoxonium iodide (1.96 g, 8.91 mmol) was added to a suspension of sodium hydride (0.37 g, 9.32 mmol) in DMSO (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 30 minutes. To the mixture a solution of benzyl 4-(2-oxopropyl)piperazine-1-carboxylate (2.24 g, 8.10 mmol) in DMSO (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to afford benzyl 4-(2-methyl-2-oxiranylmethyl)piperazine-1-carboxylate (1.51 g, yield 64%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17]([CH3:19])=O)[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[O:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[CH3:19])=[O:21])[CH3:13]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1ccc(C(N)=O)cc1
Solvent: CCO
Product: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1C
Temperature: 50 °C

Procedure:
40.0 g 4-Methoxybenzamide was dissolved in 400 ml ethanol. The mixture was warmed to 50° C. and 48.8 ml ethyl-2-chloroacetoacetate was added in one portion. The resulting mixture was refluxed for four days. The reaction mixture was cooled and the solvent removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to obtain 23.5 g 2-(4-Methoxy-phenyl)-4-methyl-oxazole-5-carboxylic acid ethyl ester as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>CN(C)C=O.O1CCCC1>[CH3:1][O:2][C:3](=[O:9])[CH:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(=O)C(Cc1ccc(F)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Oxopentanoic acid methyl ester (7.5 g) was added to a stirred suspension of sodium hydride (60% in oil, 4.6 g) in N,N-dimethylformamide (20 mL) and tetrahydrofuran (80 mL) at 0° C. and the resulting mixture stirred at 0° C. for 30 minutes. A solution of 1-bromomethyl-4-fluorobenzene (7.0 mL) in tetrahydrofuran was added and the resulting mixture warmed to room temperature and then stirred at this temperature for 17 hours. The mixture was partitioned between ethyl acetate and water and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (19:1 by volume) to afford title compound, 1.0 g.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH2:7][CH:8]([NH:20][C:21](=[O:47])[C@H:22]([CH3:46])[NH:23][C:24](=[O:45])[C@H:25]([CH:42]([CH3:44])[CH3:43])[NH:26][C:27](=[O:41])[C@H:28]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[NH:29][C:30](=[O:32])[CH3:31])[C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.CO.[OH-].[Na+].Cl>O>[C:30]([NH:29][C@H:28]([C:27]([NH:26][C@H:25]([C:24]([NH:23][C@H:22]([C:21]([NH:20][CH:8]([C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:6]([OH:48])=[O:5])=[O:47])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CCCc1ccccc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)O)C(=O)CCCc1ccccc1)C(C)C
Yield: 72.8 %

Procedure:
N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-7-phenyl heptanoic acid t-butyl ester (12 mg) was stirred with MeOH (0.5 mL), water(0.2 mL), and 2N NaOH (0.1 mL) overnight. The mixture was acidified with 2N HCl and was extracted with EtOAc (3×5 mL). The solvent was evaporated and the product was recrystilized from acetone/hexane to provide the title compound (8 mg).
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:4](=[O:6])[C:3]2[CH:2]=[CH:10][C:9]([CH:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:12])=[CH:8][CH:7]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(C(C)c2ccccc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)c3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
2-methyl-4-(1-phenylethyl)benzoic acid (150 mg, 0.6 mmol) was dissolved in 20 mL dichloromethane, and then N-hydroxybenzotriazole (0.9 mmol, 100 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9 mmol, 200 mg), triethylamine (10.48 mmol, 3 mL) was added to the mixture. After the mixture was stirred at room temperature for 10 minute, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.6 mmol, 90 mg) was added. The mixture was stirred at room temperature for 18 hours. Then washed with water (30 mL), extracted with dichloromethane (40 mL). The organic layer were concentrated and subjected to column chromatography (silica gel, dichloromethane/menthol=15/1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenylethyl)benzamide (150 mg, 90%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO.O>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccccc2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 72 %

Procedure:
To 5-Methyl-3-phenyl-isoxazole-4-carboxylic acid methyl ester (0.853 g, 3.69 mmol) in methanol (12 mL) was added 2N NaOH (8 mL) the reaction solution was stirred at ambient temperature for 60 hr. The solution was dilute with water and extracted twice with ethyl acetate. The combined extract was washed with brine and dried over MgSO4 and concentrated. Recrystallization (hexanes/ethyl acetate) afforded a white solid (0.540 g, 72% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:14]#[N:15])[C:7]([CH3:9])([CH3:8])[CH:6]1[C:10]([O:12][CH3:13])=[O:11])=[O:4].[OH-].[K+]>CO.O>[CH3:8][C:7]1([CH3:9])[C:5]([C:14]#[N:15])([C:3]([OH:4])=[O:2])[CH:6]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1C(C)(C)C1(C#N)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1C(C)(C)C1(C#N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A solution of 21.1 g (0.1 mol) of 3,3-dimethyl-1-cyano-cyclopropane-1,2-dicarboxylic acid dimethyl ester and 5.6 g of potassium hydroxide in a mixture of 50 ml of methanol and 25 ml of water was stirred at room temperature for 2 hours. The mixture was then filtered and the filtrate was acidified with dilute hydrochloric acid. An oil separated out and was taken up in methylene chloride. The methylene chloride phase was dried over sodium sulphate and then concentrated. 13 g (65% of theory) of 3,3-dimethyl-2-methoxycarbonyl-1-cyano-cyclopropane-1-carboxylic acid were obtained in the form of a partly crystalline mass, which could be further processed directly, without purification.
Reaction SMILES: Cl[C:2](=[N:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([C:16]1[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]2[C:28]=1[C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:21]=[C:20]2[N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl>[C:3]1([C:2]2[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][C:16]3[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]4[C:28]=3[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]4[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[O:10][N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#CCCCc1c2c(nn1CCC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCc1cc(-c2ccccc2)no1
Yield: 80 %

Procedure:
α-Chlorobenzaldoxime (0.64 g, 4.1 mmol) was added to a solution of di(tert-butyl) 1-pent4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (prepared as described in Parts A-E of Example 57, 1.36 g, 2.76 mmol) and triethylamine (0.60 mL, 4.14 mmol) in dichloromethane (10 mL). The solution was heated at 40° C. for 19 hours, during which time additional α-chlorobenzaldoxime (0.65 g) was added. The reaction was worked up as described in Part B of Example 595. The crude product was purified by chromatography (silica gel, sequential elution with 20% then 40% ethyl acetate in hexanes) to provide 1.35 g of di(tert-butyl) 1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:45]=[CH:46][CH:47]=1)[CH2:38][NH:39][C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:46]2[CH:47]=[CH:35][CH:36]=[C:37]([CH2:38][NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[CH:45]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1cccc(Br)c1)C1CC1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1)C1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), cyclopropanecarboxylic acid 3-bromo-benzylamide (41.7 mg, 0.16 mmol), and Pd[P(Ph)3]4 (15.1 mg, 8.0 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.0 mg. MS: 498.3 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.55-0.70 (m, 4H), 1.50-1.60 (m, 1H), 1.73-1.98 (m, 3H), 2.07-2.29 (m, 1H), 3.35-3.56 (m, 2H), 4.24-4.37 (m, 3H), 4.85-5.08 (m, 2H), 6.97-7.54 (m, 12H), 7.63-780 (m, 1H), 8.50-8.59 (m, 1H), 10.06-10.13 (s, 1H).