Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH3:27])[C:4](=[O:28])[C:3]=1[CH3:29].[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33].CCN(CC)CC>C1COCC1.CN(C=O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:5]([CH3:27])[C:4](=[O:28])[C:3]([CH3:29])=[C:2]3[NH:1][C:32](=[O:34])[CH3:33])=[CH:17][CH:16]=1
Reactant: Cc1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
To the product of EXAMPLE 40 (72 mg) in THF (3 mL) and DMF (0.2 mL) was added NaH (10 mg, 60% dispersion in mineral oil) followed by acetyl chloride (30 μL). After stirring 30 minutes at room temperature NEt3 (45 μL) was added. After an additional hour of reaction time TLC indicated incomplete reaction. Acetyl chloride (15 μL) and NEt3 (45 μL) was added to the reaction, however this generated the imide (N-acetyl-N-(7-(2,4-dichlorophenyl)-6-(4-chlorophenyl)-1,2-dihydro-1,3 dimethyl-2-oxo-1,8-naphthyridinyl)acetamide). The reaction was quenched with methanol and NaHCO3, diluted with EtOAc and washed with 2 M aqueous HCl followed by 1 M aqueous NaOH solution. The solution was concentrated and the residue in 8 mL of 2:1 THF:methanol was treated with CS2O3 (80 mg). TLC indicated conversion of the imide to the amide after about 10 minutes at room temperature. The reaction was concentrated, dissolved in EtOAc and washed with brine. The concentrated solution was then purified by flash chromatography (silica gel) gradient eluted with 0-90% EtOAc in hexane affording the title compound. HPLC/MS: 486.0 (M+1), 488.0 (M+3); Rt=4.24 min.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31](N(C)C)[CH:32]=[C:33](N=C=O)[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:40].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:6][C:5]([N:9]([CH3:10])[CH3:8])=[O:40])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N=C=O)cc(N(C)C)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc2ccc(NC(=O)N(C)C)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-6-dimethylamino-carbonylaminobenzimidazole and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[CH3:23][S:24]([OH:27])(=[O:26])=[O:25]>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1.[S:24]([O-:27])(=[O:26])(=[O:25])[CH3:23]
Reactant: CS(=O)(=O)O
Agent: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: CC(C)=O
Product: CS(=O)(=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 5.0 g of olanzapine base in 150 ml acetone was slowly added a solution of 1.53 g of methane sulfonic acid in 50 ml of acetone at room temperature. The mixture was stirred for 1 hour and then overnight at 4° C. Crystals were isolated by filtration, washed with 10 ml of acetone and 20 ml of ether and dried overnight at 40° C. in vacuo. Yield: 6.62 g (95%) as a hemi-acetonate.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[I:13]I>C(Cl)Cl>[I:13][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH2:1][CH2:2][CH3:3])[C:8]([OH:10])=[O:9]
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: II
Solvent: ClCCl
Product: CCCc1ccc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.3 %

Procedure:
A mixture of 4-propylbenzoic acid (0.3 g; 1.83 mmol), CF3SO3Ag (0.47 g; 1.83 mmol) and I2 (0.46 g; 1.83 mmol) in CH2Cl2 was stirred for 48 h at room temperature, then filtered through Celite pad, washed with fresh CH2Cl2 (2×15 ml). The combined filtrates were washed with 5% NaHSO3, H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated under reduced pressure to give the title compound (0.49 g; 92%) as creamy solid. 1H-NMR (CDCl3) 1.0 (tr, 3H, J=9 Hz); 1.57-1.7 (m, 2H); 1.72-1.77 (m, 2H); 7.28 (d, 1H, 9 Hz); 7.98 (dd, 1H, J=3, 6 Hz); 8.53 (d, 1H, J=3 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:37]/[O:38][C:39]([C:42]([OH:44])=[O:43])([CH3:41])[CH3:40])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:32]([O-:34])=[O:33])=[C:15]([CH2:18][N+:19]4[N:20]([CH3:31])[C:21]([NH:28]C=O)=[C:22]([CH2:24][NH:25]C=O)[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.Cl.C(=O)([O-])O.[Na+]>CO>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:37]/[O:38][C:39]([C:42]([OH:44])=[O:43])([CH3:41])[CH3:40])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:32]([O-:34])=[O:33])=[C:15]([CH2:18][N+:19]4[N:20]([CH3:31])[C:21]([NH2:28])=[C:22]([CH2:24][NH2:25])[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: Cn1c(NC=O)c(CNC=O)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1c(N)c(CN)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 2.2 %

Procedure:
To a solution of 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-formamido-4-formamidomethyl-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (2.5 g) in methanol (25 ml) was added concentrated hydrochloric acid (2.5 ml) at room temperature. The mixture was stirred at room temperature for 17 hours. The reaction mixture was adjusted to about pH 7 with saturated aqueous sodium hydrogencarbonate solution and concentrated in vacuo to remove methanol. The resulting residue was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated to about 30 ml in vacuo. The concentrate was adjusted to about pH 1 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 20% aqueous 2-propanol. The eluate was concentrated in vacuo and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-amino-4-aminomethyl-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (50 mg) as an amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9](O)[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:15]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(O)NC(=O)OC(C)(C)C
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a stirred solution of the N-t-butyloxycarbonyl-aminopropanol (15.0 g, 65.6 mmol) in dichloromethane (260 mL) at 0° C. was slowly added Dess-Martin periodinane reagent (47.3 g, 111 mmol). The mixture was allowed to gradually warm to ambient temperature and stirred overnight. It was then partitioned between diethyl ether (600 ml) and 1N sodium hydroxide (300 mL) and shaken vigorously. The organic layer was dried and evaporated. The residue was chromatographed on silica, eluting with 25% ethyl acetate/hexane to afford the product as a thin, colorless oil (4.20 g, 28%). 1H NMR (300 MHz, CDCl3) δ 9.63 (s, 1 H), 5.17 (br s, 1 H), 3.30 (q, 2 H), 2.60 (t, 2 H), 1.33 (s, 9 H).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:11]([O:13][CH3:14])=[O:12].[C:22](=O)([O-])O.[Na+].C=O.Cl>O.C(O)=O.CC(C)=O.ClCCCl>[OH2:12].[ClH:21].[CH3:14][O:13][C:11](=[O:12])[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:9]1[CH2:8][CH2:7][C:3]2[S:2][CH:6]=[CH:5][C:4]=2[CH2:22]1
Reactant: O=C([O-])O
Reactant: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: CC(C)=O
Solvent: ClCCCl
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Yield: 86.6 %

Procedure:
To 28.4 g (0.082 mol) of methyl [2-(2-thienyl)ethylamino](2-chlorophenyl)acetate hydrochloride, prepared according to example 9. or 10., are added 50 ml of 1,2-dichloroethane and the solution of 7.5 g (0.09 mol) of sodium hydrogen carbonate in 100 ml of water. The mixture is stirred well, the phases are separated, the aqueous phase is washed with 2×30 ml of 1,2-dichloroethane, the combined organic layer is dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residual 25 g material (acetate base) is dissolved in 90 ml of formic acid, to the solution 4 g (0.13 mol) of paraformaldehyde is added and the mixture is stirred at 50° C. for 20 minutes. The majority of the formic acid is then distilled off in vacuo, the residue is dissolved in the mixture of 100 ml of water and 100 ml of 1,2-dichloroethane, the phases are separated, the aqueous phase is extracted again with 30 ml of 1,2-dichloroethane, the combined organic phase is shaken well with 100 ml of 5% sodium hydrogen carbonate solution, the phases are separated and the organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in 45 ml of acetone and to the solution 6.5 ml (0.077 mol) of conc. hydrochloric acid is added at 5-10° C., under cooling. The product slowly crystallizes. The mixture is stirred for 1 hour at 0-10° C. then the crystals are filtered off, washed with 2×10 ml of acetone and dried. Weight: 26.7 g (theoretical: 30.8 g) Yield: 86.6%, mp.:138-140° C. (literature mp: 130-140° C.).
Reaction SMILES: [Br-].OC1C=CC=CC=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:29]([O:39][C:40](=O)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=O)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]CC.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:41]([C:40]1[O:39][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[CH:35]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCC(=O)OC(=O)CCCCCCCC
Agent: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCc1cc2ccccc2o1
Yield: 76.6 %

Procedure:
112 g (249 mM) of (2-hydroxybenzyl)triphenylphosphonium bromide, 83 g (278 mM) of nonanoic anhydride, 104 g (1.03 mM) of triethylamine and 800 ml of toluene were placed in a 3 1-three-necked flask, followed by refluxing for 4.5 hours under stirring. After the reaction, the reaction mixture was left standing at room temperature to precipitate a crystal. The crystal was removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography (eluent:toluene/hexane=1/1) to obtain 44 g of liquid 2-octylbenzofuran (Yield: 76.6%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH2:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]1[N:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: NCc1ccc2ccccc2c1
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C1CCCC(=O)N1Cc1ccc2ccccc2c1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available naphthalen-2-ylmethanamine and commercially available 2-methoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions H): tR=1.35 min.; [M+H]+: 346.35 g/mol.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:5]2[C:16](=[O:32])[N:17]([CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[C:18](=[O:19])[C:4]2=[CH:3]1>C(O)(=O)C.[Zn]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[C:5]2[CH:16]([OH:32])[N:17]([CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[C:18](=[O:19])[C:4]2=[CH:3]1
Reactant: CN1CCN(c2c3c(cn(C)c2=O)C(=O)N(CCc2ccc4ccccc4n2)C3=O)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CN1CCN(c2c3c(cn(C)c2=O)C(=O)N(CCc2ccc4ccccc4n2)C3O)CC1
Temperature: 110 °C
Yield: 49.8 %

Procedure:
Zinc (0.38 g, 5.8 mmol) was added rapidly to a solution of 5-methyl-7-(4-methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (1 g, 2.318 mmol, see Example 2) in acetic acid (30 ml). The reaction was heated at about 110° C. for about 4 h. The solvent was removed. The residue was purified on a silica column (DCM/MeOH=10:1) to afford the title compound (0.5 g, 49.8% yield).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B(O)O.BrC1C=CC(N)=CC=1Cl.FC(F)(F)C1C=CC(B(O)O)=CC=1>>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(Br)cc1
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
The title compound was prepared as described in Example 159 substituting 4-bromoaniline and (2-chloro-4-(trifluoromethyl)phenyl)boronic acid for 4-bromo-3-chloroaniline and (4-(trifluoromethyl)phenyl)boronic acid, respectively.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:15]([NH:17][C@H:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:13][OH:14])=O)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:11][C@H:12]([C:15]([NH:17][C@H:18]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:13][OH:14]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CO)C(=O)OC(C)(C)C

Procedure:
A mixture of Z-Ser-Leu-OBut (11.36 g, 27.8 mmol, described in Example 3) and 5% palladium on carbon (1.1 g) in glacial acetic acid is subjected to hydrogenation. The mixture is filtered and the filtrate is evaporated under reduced pressure to give H-Ser-Leu-OBut in the form of its acetate salt. This product is suspended in toluene and the toluene is removed by distillation so that excess acetic acid is removed azeotropically.
Reaction SMILES: [ClH:1].C([O:6][CH:7](OCCCC)[C@H:8]([CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:38])[NH2:37])[NH:9][C:10](=[O:31])[CH2:11][NH:12][C:13](=[O:30])[C@@H:14]1[CH2:18][CH2:17][C:16](=[O:19])[N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])CCC.Cl.[OH-].[Na+]>C(#N)C>[ClH:1].[CH2:23]([O:22][C:20]([N:15]1[C:16](=[O:19])[CH2:17][CH2:18][C@H:14]1[C:13]([NH:12][CH2:11][C:10]([NH:9][C@H:8]([CH:7]=[O:6])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:38])=[O:31])=[O:30])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N=C(N)NCCC[C@@H](C=O)NC(=O)CNC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Yield: 65.8 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-pyroglutamyl-glycyl-L-argininal dibutylacetal hydrochloride (30 mg, 0.048 mmol) in acetonitrile (4.8 ml) was added 1N hydrochloric acid aqueous solution (2.4 ml). The mixture was reacted at 36° C. for an hour with stirring. After completion of the reaction, pH of the reaction mixture was adjusted to 4.8 with 1N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and chloroform was added to the residue. Insoluble matters were removed by filtration. After the filtrate was concentrated, the residue was recrystallized from chloroform-hexane to give 15.7 mg (66%) of N-benzyloxycarbonyl-L-pyroglutamyl-glycyl-L-argininal hydrochloride.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.[CH:15]1([CH2:27][CH2:28][N:29]=[C:30]=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:15]1([CH2:27][CH2:28][NH:29][C:30]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C=NCCC1CCCCCCCCCCC1
Reactant: O=C1COC(=O)C1
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCC1CCCCCCCCCCC1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry flask containing 40 mL of chloroform was added 1.87 g (18.7 mmol) of tetronic acid, 2.29 g (18.7 mmol) of 4-N,N-dimethylaminopyridine, 2.6 mL (18.7 mmol) of triethylamine followed by 4.4 g (18.7 mmol) of 2-cyclododecylethyl isocyanate. The reaction mixture was allowed to stir overnight at room temperature, after which time a small amount of starting materials was still evident by TLC. The reaction mixture was quenched with 1N HCl, the layers separated, the organic fraction dried over MgSO4, filtered, and stripped of solvent. The residue was flash chromatographed using acidic silica gel eluting with 25% EtOAc/hexane to give a yellow solid. M.P. 135°-137° C. Spectral data follow: 1H NMR (DMSO-d6) δ8.05 (bs, 1H), 4.6 (s, 2H), 4.2 (bs, 10 H), 3.25 (t, 2H), 2.5 (s, 3H), 1.2-1.4 (bm, >20 H); IR (KBr) 3340, 2920, 2850 (C--H), 1750, 1650 cm-1 (C=O);
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([N:65]1[CH2:64][CH2:63][N:62]([C:45](=[O:44])[CH2:46][NH:47][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[O:49])[CH2:67][CH2:66]1)=[O:15]
Reactant: O=C(O)c1cc(F)c(Cl)cc1Cl
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)c(Cl)cc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2,4-dichloro-5-fluoro-benzoic acid (53.8 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 45 mg (33.9% yield) of biphenyl-4-carboxylicacid {2-[4-(2,4-dichloro-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.74%, 1H NMR: (DMSO) δ 8.7-8.62 (t, 1H), 8.02-7.92 (d, 3H), 7.82-7.7 (q, 4H), 7.7-7.64 (q, 1H), 7.52-7.45 (t, 2H), 7.45-7.36 (m, 1H), 4.26-4.12 (dd, 2H), 3.76-3.56 (m, 4H), 3.54-3.44 (m, 2H), 3.28-3.14 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14]Br.[H-].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CN(C)C=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14][O:8][CH2:7][CH:3]1[C:4]([CH3:6])([CH3:5])[C:2]1([CH3:9])[CH3:1]
Reactant: CC1(C)C(CO)C1(C)C
Reactant: Fc1ccc(CBr)cc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)C(COCc2ccc(F)c(Br)c2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 20 g of 2,2,3,3-tetramethylcyclopropylmethanol and 41.9 g of 3-bromo-4-fluorobenzyl bromide in 100 ml of a 1:1 mixture of toluene/dimethylformamide is added dropwise at 0°-10° C. to 8.2 g of sodium hydride (50% dispersion in mineral oil) in 200 ml of a 1:1 mixture of toluene/dimethylformamide. When the reaction has subsided, the batch is stirred for 16 hours at room temperature and, after the dropwise addition of a saturated solution of ammonium chloride, extracted with toluene. The combined toluene extracts are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The crude product is chromatographed through a column of silica gel (elution with a 5:1 mixture of hexane/ether), affording the title compound in the form of a clear oil with a refractive index of nD24 =1.5128.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]1[CH2:8][C@@H:7]1[C:9]([OH:11])=O.C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]1[CH2:8][C@@H:7]1[C:9]([Cl:15])=[O:11]
Reactant: O=C(O)[C@H]1C[C@@H]1c1cccs1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (0.110 g, 0.66 mmol) in dichloromethane (10 ml) in an ice-bath was added oxalyl chloride (0.58 ml, 6.60 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 50 ml round-bottom flask was charged with (R)-2-Amino-2-[4-(2-methyl-pentyloxy)-phenyl]-ethanol HCl (0.47 mmol), dichloromethane (6 ml) and triethylamine (0.31 ml, 2.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×10 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (0.088 g, 48% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (m, 2H), 6.99 (dd, J=5.2, 1.1 Hz, 1H), 6.81 (m, 3 H), 6.72 (d, J=3.3 Hz, 1H), 6.14 (d, J=6.3 Hz, 1H), 4.95 (m, 1H), 3.80 (m, 2H), 3.67 (m, 2H), 2.72 (dd, J=7.1, 4.8 Hz, 1H), 2.62 (m, 1H), 1.85 (m, 1H), 1.60 (m, 2H), 1.27 (m, 5H), 0.92 (d, J=6.8 Hz, 3H), 0.83 (m, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C22H30NO3S 374.5].
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([CH:13]=O)[N:12]=2)[C:8]=1[CH3:9])[CH3:2].[NH2:17]OS(O)(=O)=O>O>[CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]#[N:17])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: NOS(=O)(=O)O
Reactant: CCc1c(OC)nc2nc(C=O)cn2c1C
Solvent: O
Product: CCc1c(OC)nc2nc(C#N)cn2c1C
Yield: 82.7 %

Procedure:
To a rapidly stirred suspension of 19.84 g of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxaldehyde in 300 ml of water at room temperature was added all at once a solution of 13.30 g of hydroxylamine-o-sulfonic acid in 250 ml of water. After 40 minutes when the intermediate had precipitated, 8 g of solid sodium hydroxide were added and the intermediate dissolved. After 1 hour when the product had precipitated, the mixture was filtered and the solid was washed with water, dried, then crystallized from ethyl acetate to obtain 16.18 g of 6-ethyl-7-methoxy-5-methylimidazo [1,2-a]pyrimidine-2-carbonitrile (83% yield) as a pale yellow solid melting at 166°-168° C.