Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:34]([CH2:40][CH2:41][CH3:42])=[N:33][C:27]=3[C:28]([NH2:32])=[N:29][C:30]=2[CH:31]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:32][C:28]1[C:27]2[N:33]=[C:34]([CH2:40][CH2:41][CH3:42])[N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][NH:17][S:13]([CH2:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)(=[O:15])=[O:14])=[CH:31][C:30]=2[N:29]=1
Reactant: O=S(=O)(Cl)CCc1cccc2ccccc12
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(OCCCNS(=O)(=O)CCc4cccc5ccccc45)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
2-(1-Naphthyl)ethanesulfonyl chloride (0.358 g, 1.40 mmol) was added in one portion to a suspension of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 30 minutes. Triethylamine (0.250 mL, 1.79 mmol) was then added. The reaction mixture was poured into saturated aqueous sodium carbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale yellow oil was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 94:6) and subsequent recrystallization from acetonitrile to yield 0.341 g of N-(3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-(1-naphthyl)ethanesulfonamide as white crystals, mp 164-168° C.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.[CH3:27][CH2:28][O:29][C:30]1[C:34](=O)[C:32](=[O:33])[C:31]=1[O:36]CC.O>C(O)C>[CH2:28]([O:29][C:30]1[C:31](=[O:36])[C:32](=[O:33])[C:34]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1)[CH3:27]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOc1c(N[C@H]2CC[C@H](CCN3C[C@H]4COc5ccc(C#N)cc5[C@@H]4C3)CC2)c(=O)c1=O

Procedure:
2 g of the compound of Example 1 (6.15 mmol) and 0.9 ml of diethyl squarate are stirred at ambient temperature for 2 hours in 15 ml of ethanol. After adding water, the crystals obtained are filtered off and dried in a desiccator to yield the title product in the form of a white powder.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:8]1=[O:17])[CH3:5])[CH3:2].C([Li])CCC.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCCCCC.C(=O)(O)[O-].[Na+]>[C:23]([N:9]1[C@H:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[C:8]1=[O:17])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(C)O[C@@H]1C(=O)N(C(=O)c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Yield: 101.7 %

Procedure:
To a solution of 2.35 g (10 mmol) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one in 40 mL of THF at -78° C. was added 6.1 mL (10.07 mmol) of a 1.65M solution of n-butyllithium in hexane. The mixture was stirred for 10 rain at -78° C. and a solution of 1.42 g (10.1 mmol) of benzoyl chloride in 10 mL of THF was added. The mixture was stirred at -78° C. for 1 h and diluted with 70 mL of saturated aqueous sodium bicarbonate and extracted with three 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and concentrated to give 3.45 g of an oil. Chromatography of the oil on silica gel eluted with ethyl acetate/hexane gave 3.22 g (95%) of cis-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (2) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:39](O)=[O:40])=[CH:34][CH:35]=[C:36]([CH3:38])[CH:37]=2)=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:39]([C:33]3[C:32]([C:29]4[CH:30]=[CH:31][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:27][CH:28]=4)=[CH:37][C:36]([CH3:38])=[CH:35][CH:34]=3)=[O:40])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Reactant: Cc1ccc(C(=O)O)c(-c2ccc(C(C)C)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(N3CCN(Cc4cccc(C#N)c4)CC3)cc2)c(-c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.6 %

Procedure:
To a stirred solution of 4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (150 mg), 4′-isopropyl-5-methyl-biphenyl-2-carboxylic acid (127 mg), HOBt (87 mg), and Et3N (64 mg) in CH2Cl2 (10 mL) was added at room temperature EDCl (124 mg) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the oily residue was crystallized from EtOH to give the title compound (160 mg) as white crystals.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][CH:12]=2)[C:8]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 56.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-ethynyl-phenyl)-propionic acid (121 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 24 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-ethynyl-phenyl)-N-thiazol-2-yl-propionamide (92 mg, 56.8%) as a white solid: mp 181-183° C.; EI-HRMS m/e calcd for C19H20N2OS (M+) 324.1296, found 324.1295.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]([O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17])([CH3:12])[CH3:11]>>[NH2:17][C:16]1[CH:15]=[C:14]([O:13][CH:10]([CH3:11])[CH3:12])[C:20]([O:21][CH3:22])=[CH:19][C:18]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(N)cc1OC(C)C
Product: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1OC(C)C

Procedure:
(2-amino-5-methoxy-4-(1-methylethoxy)phenyl)-(2-chlorophenyl)-methanone (Xii) was prepared by reacting 2-chlorobenzaldehyde with 0.0252 moles of 3-isopropoxy-4-methoxy aniline in a manner analogous to Example 1. MH+/Z=320.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C:24]([S:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:7][P:8]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C:24]([S:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:43])=[O:25])[CH2:7][P:8]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(CP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)SCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CN(CP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)S(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl-N-[(benzylthio)carbonyl]-N-[bis(phenoxy)phosphinylmethyl]-glycinate (1.0 g.; 0.002 mol.) dissolved in 10 ml. of methylene chloride at 0° C. was slowly added a solution of metachloroperbenzoic acid (0.4 g.; B 0.002 mol.) dissolved in 100 ml. of methylene chloride. The reaction mixture was stirred for one hour and allowed to gradually warm to 25° C. The mixture was washed with 5% sodium hydroxide, dried, then concentrated in vacuo. The resulting oil was extracted into hot petroleum ether and allowed to crystallize for 16 hours to yield ethyl-N-[(benzylsulfinyl)carbonyl]-N-[bis-(phenoxy)phosphinylmethyl]-glycinate as a solid having a melting point of 106°-115° C. and the folloing analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:26][O:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][O:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH:30][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:23]
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(C)(C)OC)ccc21
Yield: 39.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide (73.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzo-imidazole-5-carboxylic acid (150.0 mg), 2-methoxy-2-methyl-propylamine (61.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 459; and 1H NMR (DMSO-d6, 400 MHz): δ 8.18-8.16 (1H, m), 8.08 (1H, m), 7.92-7.91 (1H, m), 7.79-7.77 (1H, m), 7.67-7.65 (1H, m), 7.54-7.52 (1H, m), 7.40-7.37 (1H, m), 4.21-4.20 (2H, m), 3.37-3.35 (2H, d), 3.18 (3H, s), 1.34-1.30 (3H, t), 1.14 (6H, s), —NH proton signal was not observed.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:9]([N+:24]([O-:26])=[O:25])[CH:8]=1.S(OC)(O[CH3:31])(=O)=O.O>CN(C=O)C>[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([N:11]([CH3:31])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[C:9]([N+:24]([O-:26])=[O:25])[CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: COCOc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(N(C)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a suspension of sodium hydride (60%, 0.40 g (10.0 mmol)) in 15.0 ml of DMF, 4′-methoxymethoxy-2′-nitro-p-toluenesulfonanilide (3.00 g (8.51 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (1.0 ml (10.6 mmol)) was added and the mixture was stirred for 15 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) to give 2.91 g (93%) of the title compound as yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[CH3:6])=[O:4].[CH2:22]([NH2:25])[CH2:23][NH2:24].C(N(CC)CC)C>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:7]2[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][N:24]3[CH2:23][CH2:22][NH:25][C:9]3([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:17]=1
Reactant: NCCN
Reactant: CN(C(=O)CCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1C(=O)CN2CCNC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 6.4 g. (20 mmole) of 2-(2-chloro-N-methylacetamido)-5-chlorobenzophenone, 12.0 g. (0.2 mole) of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol was heated at reflux for 20 hours. The reaction mixture was concentrated to a residue which was partitioned between ether and water. The ether layer was washed with water, dried and concentrated to a small amount of liquid which was treated with a small amount of ethanol to give upon standing the above-titled product as colorless crystals, m.p. 164°-167°.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:19]([NH:21][C@H:22]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.O>O1CCOCC1>[NH2:1][C@H:2]([C:19]([NH:21][C@H:22]([C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Yield: 86.3 %

Procedure:
5.0 g of Boc-His(Tos)-Lys(Z)-OBzl was added to 9.8 g of TosOH.H2O dissolved in 26 of dioxane, which was then left at room temperature for an hour with occasional shaking. Next, water was added to it and the mixture was extracted with ethyl acetate. The extract was washed with sodium bicarbonate aqueous solution and saturated saline, and dried over sodium sulfate anhydride. Thereafter, the solvent was distilled off to obtain 3.75 g of His(Tos)-Lys(Z)-OBzl as a pale brown oily matter.
Reaction SMILES: S([O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(C1C=CC(C)=CC=1)(=O)=O.C1(O)C=CC=CC=1.[OH:32][C@@H:33]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46](O)[CH:45]=1)[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].C([O-])(C)(C)C.[K+]>CN(C=O)C>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][C@H:33]([C:44]1[CH:49]=[C:48]([CH:47]=[CH:46][CH:45]=1)[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[OH:32])=[O:43])([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1

Procedure:
A mixture of (S)-tert-butyl 2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.6 g, 5.4 mmol), phenol (7, Intermediate I) (0.8 g, 2.9 mmol), t-BuO−K+ (0.5 g, 4.5 mmol) in anhydrous DMF (5 mL) was heated at +45° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, partitioned between EtOAc and 5% NaOH, organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure. Purification by column chromatography gave (S)-tert-butyl 2-((3-((R)-3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pyrrolidine-1-carboxylate as a light yellow oil. Yield (0.8 g, 59%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].C([Li])CCC.[O:15]=[C:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=2[N:19]=[C:18]([C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][CH3:32])[O:17]1>CCCCCC.O1CCCC1>[O:15]=[C:16]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=1[NH:19][C:18](=[O:17])[C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH3:32])[CH2:8][C:7](=[O:9])[NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nccs1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F

Procedure:
Using the procedure of Step B of Example 3, 7.78 g of N-(2-thiazolyl)-acetamide, 240 ml of tetrahydrofuran and 78.3 ml of a solution of n-butyllithium in hexane and 10.2 g of the product of Step A in 75 ml of tetrahydrofuran were reacted to obtain 8.3 g of 1,1-dimethylethyl N-[(S) 2-[[2-[1,3-dioxo-3-(1,1-dimethylethyl N-[(S) 2-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-(trifluoromethyl)-phenyl]-amino]-1-ethyl-2-oxoethyl]-carbamate melting at 190° C. and having a specific rotation of [α]D =-36.5°±2° (c=0.5% in CH3COOH).
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[OH:17])[CH3:13])=[C:8]([Cl:27])[CH:7]=1)=O.[NH3:28]>CO>[C:3]([CH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[OH:17])[CH3:13])=[C:8]([Cl:27])[CH:7]=1)(=[O:2])[NH2:28]
Reactant: N
Reactant: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(Cl)c1
Solvent: CO
Product: CC(COc1ccc(CC(N)=O)cc1Cl)NCC(O)c1cccc(Cl)c1

Procedure:
A solution of 2 g of 2-[2-(4-methoxycarbonylmethyl-2-chlorophenoxy) -1-methylethyl]amino-1-(3-chlorophenyl)ethanol (prepared as described in Example 22) dissolved in 50 ml of methanol was saturated with gaseous ammonia in a reaction vessel, whilst ice-cooling, after which the reaction vessel was tightly stoppered and allowed to stand at room temperature for one week. At the end of this time, the solvent (methanol) was removed by distillation under reduced pressure, and the residue was recrystallized from ethyl acetate, to give 0.55 g of the title compound as crystals, melting at 99°-101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:21]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([OH:28])=[O:27])=[CH:35][CH:36]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Yield: 82 %

Procedure:
7.09 g (14.00 mmol) of the compound from Example 3-1 and 35 ml of trifluoroacetic acid are stirred at room temperature in 35 ml of dichloromethane for 2 hours. The solvent is distilled off and the residue is then dissolved in ethyl acetate, washed with water, 20 percent strength sodium acetate solution and saturated sodium chloride solution and then dried over magnesium sulphate. The solvent is removed and the residue is then purified by flash chromatography on silica gel (dichloromethane→dichloromethane/ethyl acetate 5:1→2:1→1:1): The gives the target compound in a yield of 82%.
Reaction SMILES: B(F)(F)F.CCOCC.Cl[C:11](Cl)(Cl)[C:12](=N)[O:13][C@H:14]1[S:31][CH2:30][C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18].OC1C=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:17]([O:16][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[CH2:30][S:31][C@H:14]1[O:13][C:12]1[CH:37]=[CH:38][C:39]([C:40]#[N:41])=[CH:42][CH:11]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Reactant: N#Cc1ccc(O)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C#N)cc1
Yield: 80 %

Procedure:
1 ml of a 0.1M solution of boron trifluoride etherate in methylene chloride is added at -15° C., under an inert atmosphere, to a suspension of 250 mg (0.57.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 57 mg (0.48.10-3 mol) of 4-hydroxybenzonitrile and a molecular sieve (1 nm) in 10 ml of methylene chloride. The reaction medium is allowed to return gradually to 0° C. and, after a reaction time of 3 h, is neutralized with sodium bicarbonate. The reaction mixture is then washed with water and dried over magnesium sulfate, MgSO4, and the solvent is evaporated off under reduced pressure. 150 mg (yield: 80%) of the expected product are obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (2/1 v/v) as the eluent.
Reaction SMILES: [C:1](OCC)(=[O:4])[CH2:2][CH3:3].[C:8]([I:12])(=[O:11])[CH2:9][CH3:10].C(I)C.C(I)(=[O:18])C.CI>>[C:8]([O:11][C:1](=[O:4])[CH2:2][CH3:3])(=[O:18])[CH2:9][CH3:10].[C:8]([I:12])(=[O:11])[CH2:9][CH3:10]
Reactant: CCOC(=O)CC
Reactant: CC(=O)I
Agent: CCC(=O)I
Solvent: CI
Solvent: CCI
Product: CCC(=O)OC(=O)CC

Procedure:
Examples 1-5 are repeated but using ethyl propionate, propionyl iodide and ethyl iodide in place of methyl acetate, acetyl iodide and methyl iodide, respectively. Propionic anhydride is produced in corresponding manner, with propionyl iodide also being produced in the procedures of runs 2-5.