Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][O:22]C1C=CC(CCl)=CC=1.O>C1(C)C=CC=CC=1>[CH3:21][O:22][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[N:11]2)=[CH:9][CH:8]=1
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(CO)c3ccccc32)cc1
Temperature: 25 °C
Yield: 27.2 %

Procedure:
To a suspension of 60% NaH (2.7 g; 0.07 mol) in toluene (200 ml) was added 1-benzyl-3-hydroxymethylindazole (10 g; 0.07 mol). The mixture was brought to the boiling point and left stirring at reflux for 1 hour. 4-Methoxybenzyl chloride (14 g; 0.09 mol) was then added. The mixture was then stirred at reflux for 4 hours. The reaction was stopped by cooling the mixture to room temperature and adding water (50 ml). The organic phase was separated out and washed, respectively, with 2N HCl (50 ml) and water (5×50 ml). The solvent was evaporated off under reduced pressure. The crude residue thus obtained was purified by flash chromatography on silica gel, using as eluent a 3/2 hexane/ethyl acetate mixture. The product obtained was crystallized from a 5/1 hexane/ethyl acetate mixture to give 5.1 g of [1-(4-methoxybenzyl)-1H-indazol-3-yl]methanol with a melting point of 95-97° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[CH2:12]([O:14][C:15]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[C:16]#[CH:17])[CH3:13].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.ClCCl>[CH3:11][S:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:17]#[C:16][C:15]([O:18][CH2:19][CH3:20])([O:14][CH2:12][CH3:13])[O:21][CH2:22][CH3:23])[CH:7]=1)(=[O:10])=[O:9]
Reactant: C#CC(OCC)(OCC)OCC
Reactant: CS(=O)(=O)c1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C#Cc1cncc(S(C)(=O)=O)c1)(OCC)OCC
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 3-bromo-5-methanesulfonyl-pyridine (1.00 g, 4.20 mmol), 3,3,3-triethoxypropyne (1.75 g, 9.4 mmol), dichlorobis(triphenylphospine)palladium(II) (0.15 g, 0.21, mmol), copper(I)iodide (0.08 g, 0.42 mmol), triethylamine (1.80 mL, 12.7 mmol) and dichloromethane (40 mL) was heated at reflux for 48 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was chromatographed on silica (30% ethyl acetate/hexanes) to give the title compound (1.2 g, 87% yield) as yellow solid. 1H NMR (CDCl3) δ 9.08(d, 1H, J=2.4 Hz), 8.91 (d, 1H J=2.0), 8.28 (t, 1H, J=2.0 Hz), 3.75 (q, 6H, J=7.2), 3.13 (s, 3H), 1.29 (t, 9H, J=7.2).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.O>C1COCC1>[N:10]1[CH:11]=[CH:12][C:7]([C:20]2([OH:23])[CH2:21][CH2:22][C:17]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:18][CH2:19]2)=[CH:8][CH:9]=1
Reactant: Brc1ccncc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccncc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
n-BuLi (32 ml, 64.0 mmol, 2 eq, 2 M solution in hexane) was placed in THF (60 ml) and cooled to −78° C. A solution of 4-bromopyridine (6.3 g, 40.0 mmol, 1.25 eq) in THF (50 ml) was slowly added dropwise at that temperature, and stirring was carried out for 1.5 h. A solution of 1,4-dioxaspiro[4.5]decan-8-one (5.0 g, 32.0 mmol, 1 eq) in THF (50 ml) was added likewise at −78° C., and stirring was carried out for 2 h. After monitoring by thin-layer chromatography, the reaction solution was hydrolyzed with water (100 ml), while cooling, and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 2% MeOH in dichloromethane), the desired product was obtained in the form of a light-brown solid. Yield: 64% (6.0 g, 25.53 mmol).
Reaction SMILES: [ClH:1].CO[C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1OC)[CH:8]([CH2:14][N:15](C)[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=C(OC)C(OC)=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.C1C[O:39][CH2:38]C1.[O:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[ClH:1].[CH3:43][O:44][C:45]1[C:46]([O:41][CH3:42])=[CH:30][C:23]2[CH2:22][CH2:21][N:20]([C:18](=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH:8]3[CH2:7][C:6]4[C:9]3=[C:10]([O:39][CH3:38])[CH:11]=[CH:4][CH:5]=4)[CH2:26][CH2:25][C:24]=2[CH:27]=1
Reactant: C1CCOC1
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Reactant: C1COCCO1
Agent: Cl
Product: COc1cc2c(cc1OC)CCN(C(=O)CCNCC1Cc3cccc(OC)c31)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by the product of Preparation 9 and of the THF by dioxane.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[OH:8].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:9][C:4]1([OH:8])[CH2:5][CH2:6][CH2:7][CH:3]1[CH2:2][O:1][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(O)CCCC1CO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 7a (1.78 g, crude), pyridine (5.5 mL, 68.0 mmol) and 4-dimethylaminopyridine (0.17 g, 1.37 mmol) in CH2Cl2 (40 mL) was added p-toluenesulfonyl chloride (3.13 g, 16.4 mmol) in one portion, and the mixture was left to stand at 4° C. overnight. The mixture was stirred at ambient temperature for 100 min. To the mixture was added ice and the mixture was stirred at ambient temperature and the organic layer was separated. The aqueous layer was extracted with EtOAc and ,he combined organic layers were washed with water, CuSO4 solution, water, NaHCO3 solution and NaCl solution, and dried over Na2SO4. Filtration and concentration gave 3.86 g of 8a, which was used in the next reaction without further purification.
Reaction SMILES: C(NC1CC2C(=CC=C(NC(C3C(C4C=CC(F)=CC=4)=CC=CC=3)=O)C=2)C1)(=O)C.Br[C:31]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:32]=1[C:33]([NH:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[CH2:41][CH2:40][CH2:39]2)=[O:34].[S:52]1[CH:56]=[CH:55][CH:54]=[C:53]1B(O)O>>[CH2:41]1[C:42]2[C:38](=[CH:37][C:36]([NH:35][C:33](=[O:34])[C:32]3[CH:45]=[C:46]([N+:49]([O-:51])=[O:50])[CH:47]=[CH:48][C:31]=3[C:53]3[S:52][CH:56]=[CH:55][CH:54]=3)=[CH:44][CH:43]=2)[CH2:39][CH2:40]1
Reactant: OB(O)c1cccs1
Reactant: O=C(Nc1ccc2c(c1)CCC2)c1cc([N+](=O)[O-])ccc1Br
Agent: CC(=O)NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(F)cc3)cc2C1
Product: O=C(Nc1ccc2c(c1)CCC2)c1cc([N+](=O)[O-])ccc1-c1cccs1

Procedure:
N-(Indan-5-yl)-5-nitro-2-(thiophen-2-yl)-benzamide is prepared similarly to the title compound of Example 3 using the title B compound, 2-bromo-N-(indan-5-yl)-5-nitro-benzamide (0.137 g, 0.380 mmol) and 2-thiopheneboronic acid (0.073 9, 0.570 mmol). 1H NMR (DMSO-d6, 300 MHz): δ 10.59 (1H, s), 8.38 (1H, dd), 8.30 (1H, d), 7.81 (1H, d), 7.73 (1H, d), 7.06 (1H, s), 7.46 (1H, d), 7.30 (1H, d), 7.18 (2H, m), 2.83 (4H, q), 2.01 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26](=[O:28])=[O:27]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:26]([OH:28])=[O:27])=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2cccc(C(=O)O)c12
Temperature: -70 °C

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (0.55 g) in tetrahydrofuran (30 ml) was added butyl lithium (3.0 ml, 1.6M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, and the mixture was then stirred at the same temperature for 15 minutes. Gaseous carbon dioxide was introduced to the reaction mixture over 10 minutes and the temperature was raised to 0° C. The reaction mixture was poured into ice water (40 ml) and washed with diethylether (twice each with 40 ml). The aqueous layer was separated, after pH was adjusted to 4 with potassium dihydrogen phosphate, then extracted with ethyl acetate (twice each with 40 ml). The combined extracts were dried over anhydous magnesium sulphate, filtered and the solvent was evaporated under reduced pressure, to give 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carboxy-1,2-benzisoxazole and 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-carboxyl-1,2-benzisoxazole as a colorless oily mixture (0.48 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:21]=3[C@H:20]3[C@H:15]([CH2:16][CH2:17][N:18]([CH3:31])[CH2:19]3)[N:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCOCC1.N1C=CC=CC=1>[CH3:30][O:29][C:24]1[C:25]([O:27][CH3:28])=[CH:26][C:21]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][N:18]([CH3:31])[CH2:19]3)[N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=3)[C:22]=2[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 0.6 ml methanesulphonyl chloride in 3 ml absolute dioxane is added dropwise to a solution of 2.1 g rac-cis-6-(4-aminophenyl)-8,9-dimethoxy-1,2,3,4,4a, 10b-hexahydro-2-methyl-benzo[c ][1,6]naphthyridine in 20 ml absolute pyridine, and the mixture is then stirred at 60° C. for a further 3 h. After cooling, the mixture is poured onto 100 ml of an ice/water mixture, rendered alkaline with dilute sodium hydroxide solution and extracted with n-butanol. After the n-butanol has been evaporated off, the residue which remains is extracted with methylene chloride and the organic phase is dried over sodium sulphate and then concentrated. 2.4 g of the title compound are obtained as the residue and are converted into the dihydrochloride with ethereal HCl, and the product is recrystallized from non-dried methanol. Yield: 2.3 g of the title compound as the dihydrochloride hydrate. M.p. 239°-240° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](ON1C(=O)CCC1=O)=[O:15])[N:10]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:9]=[CH:8]2.[NH2:33][C@H:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:33][C@H:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39])=[O:15])[N:10]([CH2:24][CH:25]([CH3:26])[CH3:27])[N:9]=[CH:8]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)ON3C(=O)CCC3=O)cc21
Reactant: N[C@H]1CCNC1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (700 mg, 1.58 mmol) in dichloromethane (5 mL) was added (S)-3-aminopyrrolidin-2-one (prepared according to Example 2, 205 mg, 2.05 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with a gradient of 25-100% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ia) (520 mg, 77%). Mass spec: 429 (M+1). 1H NMR (CDCl3) δ 8.37 (s, 1H), 8.26 (d, 1H), 7.87 (s, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 6.03 (br, 1H), 4.59 (ddd, 1H), 4.22 (d, 2H), 3.46 (m, 2H), 2.87 (m, 1H), 2.36 (m, 1H), 2.10 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Brc1ccccn1
Reactant: COCC(=O)Nc1ccccc1
Product: COCC(=O)N(c1ccccc1)c1ccccn1
Yield: 58.6 %

Procedure:
Using 2-methoxy-acetanilide (5.0 g) and 2-bromopyridine (9.5 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate: hexane=1:1) produced 2-methoxy-N-(2-pyridyl)acetanilide (4.3 g, crude product) as a yellow oil.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][C:25]1=[O:30].C(N(CC)CC)C>O1CCCC1>[C:7]([NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][C:25]1=[O:30])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCNC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 45.3 %

Procedure:
Add triphenylmethyl chloride (35.11 g, 126.0 mmol) to a suspension of 3-amino-piperidin-2-one dihydrochloride (21.42 g, 114.5 mmol) in tetrahydrofuran (250 mL), follow by dropwise addition of triethylamine (55.9 mL, 400.8 mmol). Stir the reaction at room temperature under nitrogen overnight. Filter the mixture, wash with tetrahydrofuran, concentrate the filtrate to a yellow oil, and partition the material between 20% isopropanol/chloroform and water. Wash the organic layer with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1.25% methanol/chloroform) which gives 18.50 g of the title compound as a white foam, 45% yield. 1H NMR: consistent with structure. MS (ion spray) 113 (M+−1).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:36][O:37][C:38]1[CH:46]=[C:42]([C:43](O)=[O:44])[C:41]([OH:47])=[CH:40][CH:39]=1>ClCCl.O.C(N(CC)CC)C>[OH:47][C:41]1[CH:40]=[CH:39][C:38]([O:37][CH3:36])=[CH:46][C:42]=1[C:43]([NH:11][CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:13][CH:12]=1)=[O:44]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(O)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(O)c(C(=O)NCCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
4-nitrophenethylamine hydrochloride (1.81 g; 8.9 mmole), triethylamine (2.8 ml; 20=mole), hydroxybenzotriazole (1.45 g; 10.7 mmole) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (3.75 g; 19.62 mmole) are added to a solution of 1.5 g (8.9 mmole) of 5-methoxy-salicylic acid in dichloromethane (80 ml). The reaction medium is agitated overnight at 25° C. The mixture is diluted with 40 ml of water and agitated for ten minutes, then the product is extracted with dichloromethane. The organic solution is dried over sodium sulphate, filtered and concentrated under vacuum and the evaporation residue is purified on a silica column (eluent=ethyl acetate/heptane; 50/50) in order to produce a white solid which is obtained with a yield of 64%. Melting point: 200° C.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:17]I>CN(C)C=O.CCOCC.[Ag]=O>[C:1]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 35.6 ml of benzylchloroformate in 200 ml of dichloromethane was added dropwise to a mixture of 10 g of (racemic)-3-pyrrolidinol, 48.3 ml of triethylamine and 725 ml of dichloromethane which was cooled to 0° C. The mixture was stirred for 48 hours at room temperature. The dichloromethane solution was extracted with 5% hydrochloric acid and 5% aqueous sodium bicarbonate. The acid and bicarbonate washes were combined, salted with sodium chloride and extracted with 2×750 ml of ethyl acetate. The combined organic extracts were dried and concentrated, giving 22.7 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol. A mixture of 2.5 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol, 2.0 ml of methyl iodide and 5.1 g of silver oxide in 50 ml of dimethylformamide was stirred at room temperature for 2 days. The mixture was diluted with ether and then filtered. The filtrate was concentrated to a small volume. The ether solution was washed with water, dried and concentrated to dryness in vacuo. The residue was purified by chromatography (silica gel) to give 2.4 g of (racemic)-N-carbobenzyloxy-3-methoxypyrrolidine as a pale yellow oil.
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C([Li])CCC.CN(C)CCN(C)C.Br[CH2:26][CH:27]=[CH:28][CH2:29][CH3:30]>O1CCCC1.O>[CH2:26]([C:2]1[CH2:4][C:3]=1[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:27]=[CH:28][CH2:29][CH3:30]
Reactant: CCC=CCBr
Reactant: CCCCCC1(Br)CC1(Br)Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC=CCC1=C(CCCCC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
A solution of 1.00 g (0.00287 mol) of 1,1,2-tribromo-2-pentyl-cyclopropane in 4 ml of tetrahydrofuran was placed under an inert atmosphere of nitrogen via a Firestone valve. To this mixture, cooling in an ice water bath, was added via syringe 3.58 ml (0.00861 mol) of 1.6M n-butyllithium in hexanes. After 30 minutes, 0.432 ml (0.00287 mol) of tetramethylethylene diamine and 0.339 ml (0.00287 mol) of 1-bromo-2-pentene were added by syringe. The reaction stirred for one hour while warming to room temperature, then for three hours at room temperature. To the resulting mixture was added 2 ml of water. This residue was extracted with diethyl ether. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 0.200 g (39.1% of theory) of 1-pent-2-enyl-2-pentyl-cyclopropene as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])=[O:3].[CH3:19][S:20]([N:23]([CH2:38][CH2:39][Cl:40])[N:24]([S:34]([CH3:37])(=[O:36])=[O:35])C(OC1C=CC=CC=1)=O)(=[O:22])=[O:21]>>[CH3:19][S:20]([N:23]([CH2:38][CH2:39][Cl:40])[N:24]([S:34]([CH3:37])(=[O:36])=[O:35])[C:2]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])=[O:3])(=[O:21])=[O:22]
Reactant: COc1cc(COC(=O)Cl)c([N+](=O)[O-])cc1OC
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Product: COc1cc(COC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)c([N+](=O)[O-])cc1OC

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4,5-dimethoxy-2-nitrobenzyloxy)carbonyl]hydrazine (compound 12) was prepared by reacting 4,5-dimethoxy-2-nitrobenzyl chloroformate with compound 2 using a procedure similar to that described for compound 10d. The product was recrystallized from ethanol, and the Mp was about 154° C. Yield was about 17.6% by weight. 1H NMR (acetone d6): δ 7.7 and 7.4 (2H, 2s, aromatic H), 5.8 (2H, d, ArCH2), 3.7-4.1 (4H, m, CH2CH2Cl), 3.9-4.0 (6H, 2s, 2 OCH3), and 3.5 and 3.2 (6H, 2s, 2 CH3SO2).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.[NH:21]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:22]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:23][CH2:24][C:25](=O)[OH:26].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:21]([C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[C@H:22]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:23][CH2:24][C:25]([NH:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:26]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
H-Val-Gly-OBzl.HCl and Z-Glu-OBzl (5.57 g, 15.0 mmol) described above was dissolved in methylene chloride (50 ml), and the solution was maintained at 0° C. Triethylamine (2.30 ml, 16.5 mmol), HOBt (1-hydroxybenzotriazole, 2.53 g, 16.5 mmol) and WSC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 3.16 g, 16.5 mmol) were added to the solution, and the mixture was stirred at room temperature overnight for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in heated ethyl acetate (1,500 ml). The solution was washed with water (200 ml), 5% of citric acid aqueous solution (200 ml×twice), saturated brine (150 ml), 5% sodium hydrogen carbonate aqueous solution (200 ml×twice) and saturated brine (150 ml) again. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The precipitated crystal was collected by filtration and dried under reduced pressure to obtain Z-Glu(Val-Gly-OBzl)-OBzl (6.51 g, 10.5 mmol) as a white crystal.