Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH3:33])[N:27]=3)=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH3:33])[N:27]=3)=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)OC(C)(C)C)CC2CCCC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)O)CC2CCCC2)n1
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (368 mg, 0.81 mmol) in 1,4-dioxane (5.0 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (10.1 mL, 40 mmol) at room temperature. The reaction mixture was stirred for 4 hours. LCMS showed the reaction was complete. The solvent was then removed by reduced pressure to afford (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (323 mg, 100% yield), which was used directly in the next step. MS: 401 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=3[N:31]([CH3:33])[CH3:32])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[CH:34]([N:37]=[C:38]=[O:39])([CH3:36])[CH3:35]>ClCCl>[CH3:33][N:31]([CH3:32])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:23]=1[CH2:22][N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:38]([NH:37][CH:34]([CH3:36])[CH3:35])=[O:39])[N:14]=2)[CH2:17][CH2:18]1
Reactant: CC(C)N=C=O
Reactant: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(NCCN)nc3ccccc23)CC1
Solvent: ClCCl
Product: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(NCCNC(=O)NC(C)C)nc3ccccc23)CC1

Procedure:
A solution of Compound 125 (15 mg, 0.03 mmol) and isopropyl isocyanate (2.8 mg, 0.03 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 h. The product (Compound 126) was purified by Neutral alumina Prep TLC plate using 10% MeOH and 90% CH2Cl2 solution as eluent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[C:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:3][CH:2]=1.[OH-].[K+].[CH3:20][C:21]([CH3:23])=[O:22]>>[OH:9][C:8]1([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[CH2:23][C:21](=[O:22])[CH:20]=[C:7]1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: Cc1cccc(C(=O)C(=O)c2ccncc2)c1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Product: Cc1cccc(C2(O)CC(=O)C=C2c2ccncc2)c1
Reaction time: 1 h

Procedure:
To a solution of 1-pyridine-4-yl-2-m-tolyl-ethane-1,2-dione (1.8 g, 8.0 mmole) in acetone (20 mL) was added crushed KOH (448 mg, 8.0 mmole) in one portion at r.t. The reaction mixture was stirred at that temperature for 1 hr before quenching the reaction with aqueous NH4Cl. Standard aqueous work up, followed by chromatographic purification (silica gel, hexane/ethyl acetate) gave the a mixture of the title compound and the regiosiomer, 4-hydroxy-4-pyridine-4-yl-3-m-tolyl-cyclopent-2-en-1-one. MS (m/z): Calcd. C17H15NO2(M+): 265, found (M+H)+: 265.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:46][CH2:47][CH:48]([OH:59])[CH2:49][N:50]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](=[O:14])[NH:46][CH2:47][CH:48]([OH:59])[CH2:49][N:50]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:51]2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: NCC(O)CN1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(O)CN2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (300 mg, 1.3 mmol) in DCM (8 mL) was added EDCI (383 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), Et3N (263 mg, 2.6 mmol), 1-amino-3-(isoindolin-2-yl)propan-2-ol (499 mg, 2.6 mmol), and the mixture was stirred at 25° C. for 16 h. The crude reaction mixture was washed with water and extracted with DCM. The combined organic layers were concentrated, and the residue was purified by column chromatography to yield the desired product (DCM:MeOH=10:1). (260 mg, yield 49%) MS (ESI+) e/z: 412.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.87 (s, 1H), 7.58-7.50 (m, 1H), 7.45-7.38 (m, 1H), 7.34-7.28 (m, 1H), 7.25-7.14 (m, 4H), 4.08-3.96 (m, 5H), 3.63-3.53 (m, 1H), 3.45-3.37 (m, 1H), 2.94-2.80 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[C:10]([OH:12])[CH:11]=1)(=[O:4])[CH3:3].[C:14]([C:17]1[C:18](=[O:28])[O:19][C:20]([OH:27])=[C:21]([C:24](=O)[CH3:25])[C:22]=1[OH:23])(=[O:16])[CH3:15]>>[C:2]([NH:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([NH:13][C:24](=[C:21]2[C:22]([OH:23])=[C:17]([C:14](=[O:16])[CH3:15])[C:18](=[O:28])[O:19][C:20]2=[O:27])[CH3:25])[CH:7]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1cc(N)cc(O)c1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: Cl
Product: CC(=O)Nc1cc(O)cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)c1

Procedure:
Similarly reaction of 5-acetamido-3-aminophenol hydrochloride with 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one as described above furnishes 3-[1-(5-acetamido-3-hydroxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH:13]=O)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc(N)c(Cl)cc1CCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cc(N)c(Cl)cc1CCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of 5-amino-4-chloro-2-(4-oxobutyl)benzonitrile (35 mg, 0.157 mmol) in THF (0.5 mL) at room temperature was added morpholine (24.65 mg, 0.283 mmol), sodium cyanoborohydride (19.76 mg, 0.314 mmol), and a drop of acetic acid. The reaction was stirred at room temperature for 1 h at which point LCMS indicated full conversion. The reaction was quenched with aq. Na2CO3, extracted w/ DCM, concentrated and purified by flash column chromatography (0-10% MeOH/DCM) to give 5-amino-4-chloro-2-(4-morpholinobutyl)benzonitrile (29 mg) as a yellow oil.
Reaction SMILES: N1C=CC=C([C:7]([C:9]2[C:10]([C:15](OC)=O)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])C=1.O.[NH2:20][NH2:21]>C(O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=1[C:15]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:7](=[O:8])[NH:21][N:20]=1
Reactant: COC(=O)c1ncccc1C(=O)c1cccnc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccn2)c2ncccc12
Temperature: 75 °C
Yield: 135.4 %

Procedure:
A mixture of methyl 3-picolinoylpicolinate 7, (240 mg, 0.99 mmol), hydrazine hydrate (63 μL, 1.3 mmol) and 12 mL of absolute ethanol was heated to 75° C. in a sealed tube for 1 h. After cooling, the solid was collected by vacuum filtration and dried under air suction. The mother liquor was concentrated to dryness under reduced pressure and purified by normal phase flash chromatography eluting with 0-10% methanol in dichloromethane over approximately 20 minutes. Like fractions were combined and concentrated under reduced pressure and combined with the solid collected by filtration to give 8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one 9 (150 mg, 0.67 mmol). 1H NMR (400 MHz, Methanol-d4) δ 9.07 (dd, J=4.5, 1.6 Hz, 1H), 8.98 (dd, J=8.4, 1.6 Hz, 1H), 8.72 (ddd, J=4.9, 1.7, 1.0 Hz, 1H), 8.00 (ddd, J=7.9, 7.3, 1.7 Hz, 1H), 7.99-7.92 (m, 1H), 7.97-7.84 (m, 1H), 7.53 (ddd, J=7.3, 4.9, 1.5 Hz, 1H). LCMS: (M+H)+, 225.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C@@H:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:9](O)=[O:10]>C1COCC1>[NH2:7][C@@H:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH2:9][OH:10]
Reactant: N[C@H](C(=O)O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 150 mL flame dry round bottom flask was added LiAlH4 (1.14 g, 29.9 mmol) and 70 mL THF. The solution was cooled to 0° C. and (S)-2-amino-2-(4-fluorophenyl)acetic acid (2.53 g, 15.0 mmol) was added portionwise. Following the addition, the reaction mixture was heated to reflux under N2 for 20 h. The resulting mixture was then cooled to 0° C. and quenched slowly with 5% NaHCO3. The solvents were removed and the residue was suspended in EtOAc. After 2 h, the white precipitate was filtered and the filtrate concentrated to give the title compound. MS (m/z): 156.3 (M+H) (Calc'd for C8H10FNO: 155.17).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.[C:22]([O:26][C:27]([N:29]1[C@H:34]([C:35](O)=O)[CH2:33][C@@H:32]2[C@H:30]1[CH2:31]2)=[O:28])([CH3:25])([CH3:24])[CH3:23].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:35]([C@@H:34]3[CH2:33][C@@H:32]4[C@@H:30]([CH2:31]4)[N:29]3[C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[NH:21][C:16]=2[CH:15]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(Br)cc2[nH]1
Temperature: 75 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
EDCI.HCl (2.65 g, 13.8 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine 2.35 g, 12.6 mmol), (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3.00 g, 13.2 mmol) and 1-hydroxybenzotriazole (1.93 g, 12.6 mmol) in CH2Cl2 (80 mL) and stirred at ambient conditions for 16 h. The mixture was then diluted with CH2Cl2, washed with water, dried (brine; MgSO4), filtered and concentrated in vacuo to provide a brown foam. Acetic acid (80 mL) was added to the foam and the mixture was heated at 75° C. (bath temperature) for 5 h. The volatile component was removed in vacuo and the residue was dissolved in EtOAc, washed with saturated NaHCO3 solution and the organic phase was dried (brine; MgSO4), filtered and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; 50-100% EtOAc/hexanes) to provide (1R,3S,5R)-tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (3.01 g, 7.96 mmol, 63.3% yield) as a light orange foam, which was used without further purification. The reaction also yielded 847 mg of same product with lower purity. An aliquot of the collected material was purified further by preparative HPLC (C-18/30-100% CH3CN-water+0.1% NH4OAc) to achieve an analytical sample. LC-MS retention time 1.248 min; calcd. for C17H21BrN3O2: 378.08. found m/z 380.05 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.67 (br s, 1H), 7.43 (br s, 1H), 7.34 (d, J=8.6 Hz, 1H), 4.75 (br s, 1H), 3.62 (br s, 1H), 2.50-2.57-2.31 (m, 1H), 2.31 (dt, J=13.2, 6.7 Hz, 1H), 1.66-1.85 (m, 1H), 1.45 (br s, 3H), 1.11 (br s, 6H), 0.87 (dt, J=8.6, 5.8 Hz, 1H), 0.66 (br s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A mixture of 2.8 g of 4-diphenylmethyl-1-(3-phthalimidopropyl)piperidine (prepared as described in Preparation 44') and 0.90 g of hydrazine hydrate in 100 ml of ethanol was heated under reflux for 2 hours. At the end of this time, the mixture was cooled to room temperature and filtered. The mixture was concentrated by evaporation under reduced pressure, to give 0.93 g (yield 47%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].Cl>CN(C)C=O>[CH2:18]([C:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([C:12]#[N:13])[C:10]#[N:11])[CH:17]=[CH2:16]
Reactant: N#CC(C#N)Cc1ccc(Cl)nc1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cc1ccc(Cl)nc1

Procedure:
((6-Chloro-3-pyridyl)methyl)malononitrile (58 mg) was dissolved in N,N-dimethylformamide (2 ml), and sodium hydride (60% in oil, 14 mg) was added to the solution with stirring under ice-cooling. Then allyl bromide (0.13 ml) was added dropwise thereto, and the mixture was stirred overnight at room temperature. To the reaction mixture was added 10% hydrochloric acid, and extracted with diethyl ether. The organic layer was washed successively with 10% hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 26 mg of 2-allyl-2-((6-Chloro-3-pyridyl)methyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (1)).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:38]([OH:40])=[O:39])[CH2:22][CH2:23][C:24]([N:26]1[CH:34]2[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH:27]1[C:35]([OH:37])=[O:36])=[O:25])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:47][O:48][C:49]1[CH:63]=[CH:62][CH:61]=[CH:60][C:50]=1[CH2:51][O:52]N1C(=O)CCC1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:38]([OH:40])=[O:39])[CH2:22][CH2:23][C:24]([N:26]1[C@@H:34]2[C@@H:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][C@H:27]1[C:35]([OH:37])=[O:36])=[O:25])=[O:19])[NH:17][C:51](=[O:52])[C:50]1[CH:60]=[CH:61][CH:62]=[CH:63][C:49]=1[O:48][CH3:47])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1CON1C(=O)CCC1=O
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@H](CCC(=O)N1C(C(=O)O)CC2CCCCC21)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@H](CCC(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2S,3aS,7aS)-1-(N6 -benzyloxycarbonyl-L-lysyl-gamma-D-glutamyloctahydro-1H-indole-2carboxylic acid was dissolved in 6 ml of water, and sodium carbonate and 10 ml of THF were added. With vigorous stirring, N-(2-methoxybenzyloxy)succinimide was added. The mixture was stirred overnight at room temperature. The reaction mixture was acidified with 10% citric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was chromatographed on a column of CHP20P using acetonitrile/water (30%→70% gradient) as an eluent. Fractions containing the desired product were concentrated to dryness under reduced pressure to give 1.0 g of (2S,3aS,7aS)-1-[N6 -benzyloxycarbonyl-N2 -(2-methoxybenzoyl)-L-lysyl-gamma-D-glutamyl]octahydro-1H-indole-2-carboxylic acid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])(=[O:9])[CH:6]([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[C:5]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([Cl:3])=[O:14])(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(=O)c1cccc(C(=O)O)c1
Solvent: Cc1ccccc1
Product: CC(C)C(=O)c1cccc(C(=O)Cl)c1

Procedure:
100 ml of toluene and 5 g of thionyl chloride were added to the crude product of m-isobutyrylbenzoic acid obtained in the above step (1), and the mixture was reacted under refluxing for 1 hour. After completion of the reaction, excess thionyl chloride was distilled off to obtain a toluene solution of crude m-isobutyrylbenzoic acid chloride.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[H-].[Na+].[CH3:10][C:11]1([CH3:25])[C:20]2([CH3:22])[O:21][CH:19]2[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:23]#[N:24])[CH:17]=2)[O:12]1.B(F)(F)F>C1COCC1>[CH3:10][C:11]1([CH3:25])[C:20]([CH3:22])([OH:21])[CH:19]([O:6][C:3]2[CH2:4][CH2:5][C:1](=[O:7])[CH:2]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:23]#[N:24])[CH:17]=2)[O:12]1
Reactant: O=C1CCC(=O)C1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21C
Agent: FB(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2C(OC2=CC(=O)CC2)C1(C)O
Reaction time: 1 h

Procedure:
2.1 g of 1,3-cyclopentanedione are dissolved in 200 ml of THF under N2, 650 mg of NaH (80% in mineral oil) are added, the mixture is stirred for 1 hour, a solution of 4.6 g of 2,2,3-trimethyl-3,4-epoxy-6-cyanochroman ("IIa") in 20 ml of THF, then 2.4 ml of BF3 etherate are added successively and the mixture is stirred overnight at 20°. The mixture is evaporated and the 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-cyano-3-chromanol ("A") obtained is purified by chromatography on silica gel (ethyl acetate/methanol 100:1); m.p. 204°-206° (from isopropanol).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])=[CH:8][CH:7]=1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>C(O)C>[CH2:29]([N:31]([CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])=[CH:8][CH:7]=1)[CH3:30]
Reactant: CCNCC
Reactant: O=C(c1ccc(OCCCBr)cc1)c1oc2ccccc2c1-c1ccccc1
Solvent: CCO
Product: CCN(CC)CCCOc1ccc(C(=O)c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
2-[4-(3-Bromopropoxy)benzoyl]-3-phenylbenzofuran (2.5 g., 5.7 mmol.) is refluxed for 6 hours in 50 ml. of ethanol containing 20 ml. of diethylamine. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in chloroform. The chloroform solution is washed with water, saturated aqueous sodium chloride solution and water, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19]O.C(N(CC)CC)C.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>C(Cl)Cl>[CH3:45][S:42]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][S:42]([CH3:45])(=[O:44])=[O:43])(=[O:44])=[O:43]
Reactant: CC(C)(C)OC(=O)N(CCCCO)CCCCCCCCN(CCCCO)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCCCCCCCN(CCCCS(C)(=O)=O)C(=O)OC(C)(C)C)CCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cool to 0° C. a mixture containing 3.0 gm of the product of Step F, 3.3 ml of triethylamine and 70 ml of CH2Cl2. In a dropwise fashion add 1.22 ml of mesylchloride in 10 ml of CH2Cl2, and stir the resulting mixture at 0° C. for 11/2 hours. Pour the mixture into 100 ml of CH2Cl2, wash with 200 ml of 1N AcOH, 100 ml of water, 100 ml of sat'd sodium bicarbonate, dry over MgSO4 and remove the solvent in vacuo. Flash chromatograph the residue, eluting from silica gel with 60% EtOAc/hexane to obtain 3.5 gm of the desired product. Rf is 0.39.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].[CH3:27][C:28]([CH3:32])([CH3:31])[CH:29]=[O:30].C([N-]C(C)C)(C)C.[Li+].O1CCCC1.C1CCCCC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[C:12]([CH:29]([OH:30])[C:28]([CH3:32])([CH3:31])[CH3:27])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: O=C(NCc1cccc(Cl)c1)c1occc(=O)c1OCc1ccccc1
Reactant: CC(C)(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)C(O)c1coc(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (300 mg) obtained in Example 10, Step 1 and 2,2-dimethylpropionaldehyde (9 ml) in tetrahydrofuran (9 ml) was added dropwise 1.5 M lithium diisopropylamide-tetrahydrofuran/cyclohexane solution (4.5 ml) under nitrogen at −78° C. After stirring at the same temperature for 2 hr, the cooling bath was removed and 1N aqueous hydrochloric acid (15 ml) and ethyl acetate (25 ml) were added, and the mixture was warmed to room temperature. The organic layer was separated from the aqueous layer and extracted with ethyl acetate (25 ml). The combined organic layer was dried, concentrated and purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (0.22 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[O:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].ClS([N:27]=[C:28]=[O:29])(=O)=O>C1(C)C=CC=CC=1>[C:28]([N:11]1[C:10](=[O:14])[C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:13][CH2:12]1)(=[O:29])[NH2:27]
Reactant: CC(C)(C)c1cc(C=C2OCNC2=O)cc(C(C)(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=C2OCN(C(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 90 °C
Yield: 63.9 %

Procedure:
To a suspension of 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)oxazolidin-4-one (100 mg, 0.33 mmole) suspended in dried toluene (0.5 ml), 32 μl of chlorosulfonyl isocyanate (0.363 mmole) was added under nitrogen atmosphere with stirring and the mixture was dissolved for 2 min. After the solution colored to brown, it was heated at 90° C. for 10 min. and toluene was evaporated under reduced pressure. A mixed solution (0.8 ml) of acetic acid and water (2:1) was added thereto, and the mixture was heated at 90° C. under nitrogen atmosphere for 10 min. The resulting mixture was poured into ice-water, which was subjected to extraction with dichloromethane, then the organic layer was washed with water, dried over sodium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (toluene:ethyl acetate=1:1), and recrystallized from ether-n-hexane, whereby 73 mg of the objective compound was obtained in 64% yield. The physical constants are described on Table 1.