Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27]C5CCNCC5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4]1.C1(NC([C:40]2[C:48]3[CH:47]=[C:46]([C:49]4C([Cl:55])=CN=[C:51](Cl)[N:50]=4)SC=3C=CC=2)=O)CC1.C(OC(N1CCCC(CCCN)C1)=O)(C)(C)C>>[ClH:24].[ClH:55].[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:40][CH:48]5[CH2:47][CH2:46][CH2:49][NH:50][CH2:51]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Cl)cc12
Agent: CC(C)(C)OC(=O)N1CCCC(CCCN)C1
Agent: Cl
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCCNC4)ncc3Cl)cc12

Procedure:
Using the method of 2-[5-chloro-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized as a di-hydrochloride salt from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and racemic 3-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester. ES+(m/z) 470 (35Cl) and 472 (37Cl) [M(free base)+H].
Reaction SMILES: [CH3:1]C1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C([O:21][CH2:22][CH2:23][C:24]1([C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH2:27][CH2:26][C:25]1=[O:29])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:29][C:25]12[CH2:26][CH2:27][CH2:28][C:24]1([C:30]([O:32][CH3:33])=[O:31])[CH2:23][CH2:22][O:21]2
Reactant: COC(=O)C1(CCOC(C)=O)CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)C12CCCC1(OC)OCC2
Temperature: 25 °C
Yield: 85 %

Procedure:
A reaction vessel was charged with 1,580 parts of methanol, 25 parts of PPTS, 228 parts of 2-(2-acetoxyethyl)-2-methoxycarbonylcyclopentanone (12) obtained in Preparation Example 2 at room temperature. The mixture was refluxed for three hours with stirring. After cooling the reaction solution to room temperature, 30 parts of potassium carbonate was added and the mixture was stirred for one hour at room temperature. Insoluble matters were removed by filtration, the filtrate was washed with a brine, and the solvent was evaporated. The residue was distilled under reduced pressure to obtain 167 parts of the target compound (13) (yield: 85%). Boiling point: 68° C./3.5 mmHg
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:20]([O-:22])=[O:21])[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 95 %

Procedure:
69.8 g (0.25 mol) of 6-chloro-1-(ethoxycarbonylmethyl)quinoxaline-2,3(1H,4H)-dione were dissolved in 625 ml of concentrated sulfuric acid and, at 0° C., 25 g (0.25 mol) of potassium nitrate were added in portions. The cooling was then removed and the mixture was stirred further. After reaction was complete, the mixture was poured into ice-water and the precipitate was filtered off with suction. 77.8 g (95%) of the product were obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[F:16])[C:10]([NH2:12])=O>C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[F:16])[C:10]#[N:12]
Reactant: NC(=O)c1cc(Br)c(F)c(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1cc(Br)c(F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.5 %

Procedure:
(I14B): Phosphoryl trichloride (8.0 ml, 86 mmol) was added to a suspension of 3,5-dibromo-4-fluorobenzamide (11.27 g, crude, ˜22.7 mmol) in acetonitrile (400 ml) at room temperature. The reaction mixture was heated to reflux for 30 minutes. Additional phosphoryl trichloride (8.0 ml, 86 mmol) was added and the mixture heated to reflux for an additional hour, then stirred at room temperature overnight, A precipitate had formed and was removed by filtration. (The product is well soluble in acetonitrile) The reaction mixture was evaporated to dryness, and then partitioned between EtOAc and aq. NaHCO3 solution. The organic layer was washed one more time with aq. NaHCO3 solution, once with brine, then dried over MgSO4, filtered and evaporated to dryness. Purification by column chromatography on silica (gradient 100% hexanes to 25% DCM in hexanes). 3,5-dibromo-4-fluorobenzonitrile (7.5 g) was obtained. The material is (by 1H NMR and 19F NMR) a 76:17:7 mixture of 3,5-dibromo-4-fluorobenzonitrile (desired product), 2,3,5-tribromo-4-fluorobenzonitrile (over-bromination) and 2,5-dibromo-4-fluorobenzonitrile (wrong regio-isomer). The material was used without further purification in the next reaction.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH3:21][N:22]=[C:23]=[S:24].Cl>C1C=CC=CC=1.CCOCC.O.C1C=CC=CC=1>[CH3:21][NH:22][C:23](=[S:24])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CN=C=S
Reactant: c1ccc(Cc2ccccn2)cc1
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CNC(=S)C(c1ccccc1)c1ccccn1
Reaction time: 0.5 h

Procedure:
2-Benzylpyridine (6.1 g.) dissolved in 25 ml. of dry benzene is added dropwise to 20 ml. of 2M phenyl lithium in benzene/ether with cooling. The mixture is stirred for 30 minutes, then 2.6 g. of methyl isothiocyanate, dissolved in 40 ml. of dry benzene, is added dropwise with cooling. The resulting solution is stirred overnight. An equal volume of water is added and the solution is cooled and made acidic with 10% aqueous hydrochloric acid. The phases are separated, the organic phase is washed with water and the combined aqueous phases are made basic to about pH 9, then extracted with chloroform. The chloroform extracts are washed with water and dried over magnesium sulfate. Filtration and removal of solvent gives a residue which is recrystallized from isopropyl ether/ethanol to give N-methyl-2-phenyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CCCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccccc1OCC(=O)OCC
Temperature: 0 °C
Yield: 103.9 %

Procedure:
2-Propylphenol (15.0 g, 110 mmol) was dissolved in DMF (70 mL), and stirred at 0° C. To the solution was added K2CO3 (30.43 g, 220.2 mmol) and ethyl 2-bromoacetate (13.43 mL, 121.1 mmol), and the reaction was stirred at room temperature for 3.5 h. The reaction was diluted with water, and the product was extracted with EtOAc twice. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give residue. The residue was purified using silica gel column chromatography (hexane/EtOAc=30/1) to give 4.2 (25.4 g). 1H NMR (400 MHz) (CDCl3) δ 7.18-7.08 (2H, m); 6.91 (1H, t, J=7.4 Hz); 6.71 (1H, d, J=8.1 Hz); 4.62 (2H, s); 4.25 (2H, q, J=7.1 Hz); 2.68-2.57 (2H, m); 1.70-1.60 (2H, m); 1.29 (3H, t, J=7.1 Hz); 0.95 (3H, t, J=7.4 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1.[OH:23][CH2:24][CH:25]([NH2:28])[CH2:26][OH:27]>C(O)(C)C>[F:20][C:16]1[CH:15]=[C:14]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[C:2]([NH:28][CH:25]([CH2:26][OH:27])[CH2:24][OH:23])=[N:3][C:4]=2[C:21]#[N:22])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Reactant: NC(CO)CO
Solvent: CC(C)O
Product: COc1ccc2c(NC(CO)CO)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
A suspension of 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile (50 mg) and [2-hydroxy-1-(hydroxymethyl)ethyl]amine (146 mg) in 2 mL isopropanol was heated at 160 C in a microwave reactor for 8 h. The reaction was concentrated and purified by flash chromatography (0% to 5% MeOH in EtOAc) to give a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:26])[C:11]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:26])[C:11]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1)(=[O:29])[CH3:28]
Reactant: Cn1c(-c2ccc(CN)cc2)nc(-c2ccccc2)c1-c1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCc1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
To a solution of 2-(4-aminomethylphenyl)-1-methyl -4-phenyl-5-(4-pyridyl)imidazole (30 mg, 0.09 mmol) [See Ex. 4 above] in pyridine (3 mL) was added acetic anhydride (0.30 mL, 3.18 mmol). The resulting solution was stirred at rt for 30 min, then concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 0-2% MeOH/CHCl3. The isolated material was triturated with Et2O to provide an off-white solid (10 mg, 28%) which was recrystallized from EtOAc to provide the title compound: mp 210-211° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].[NH:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][C:12]1=[O:13]>C(=S)=S>[Br:5][CH:6]([CH3:10])[C:7]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[NH:11][C:12](=[O:13])[CH2:14][CH2:15]2)=[O:8]
Reactant: O=C1CCc2ccccc2N1
Reactant: CC(Br)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2c(c1)CCC(=O)N2
Temperature: 0 °C
Yield: 92.6 %

Procedure:
To a solution of aluminum chloride (44 g) and α-bromopropionyl chloride (43 g) in carbon disulfide (150 ml) was added portionwise 3,4-dihydrocarbostyril (8 g) while refluxing with stirring. After completion of addition, the mixture was refluxed with stirring for 2 hours. After cooling, the mixture was poured into ice water and crystals which precipitated were collected by filtration and washed with water. Recrystallization from ethanol gave 14.2 g of 6-(α-bromopropionyl)-3,4-dihydrocarbostyril.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1F)[CH3:2].[CH3:15][S:16]([CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:18])=[O:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:22][CH2:23]1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1F
Reactant: CS(=O)(=O)CCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Temperature: 100 °C
Yield: 68 %

Procedure:
To 1-ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 187, Step C) (0.20 g, 1.0 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.23 g, 1.2 mmol), and K2CO3 (0.49 g, 3.5 mmol) was added DMSO (10 mL). The reaction was heated to 100° C. for two days. The reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step A (0.25 g, 0.68 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.56 (s, 1H), 3.92 (s, 3H), 3.22 (d, J=11.5 Hz, 2H), 3.00-3.14 (m, 2H), 2.92 (s, 3H), 2.69 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.76-1.97 (m, 4H), 1.35-1.70 (m, 3H), 1.24 (t, 3H).
Reaction SMILES: C(O)[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3]O.[Cl-].[K+].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.SCC[OH:19].C(O)C(N)(CO)CO.Cl>O.OCC(CO)O>[NH2:7][C@H:2]([C:5]([OH:19])=[O:6])[CH2:3][C:14]1[N:13]=[CH:12][NH:11][CH:15]=1
Reactant: OCCS
Reactant: c1c[nH]cn1
Reactant: NC(CO)(CO)CO
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: OCC(O)CO
Solvent: O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
Buffer C: 20 mM Tris-HCL (pH˜8.5), 100 mM KCl, 100 mM imidazole, 10 mM 2-mercaptoethanol, 10% (v/v) glycerol at 4° C., for example, 1 L (or 200 mL): 9 (1.8) mL 1 M Tris-HCl, 11 (2.2) mL 1 M Tris base, 50 (10 mL 2 M KCl, 100 (20) mL 1 M imidazole, 0.70 (0.14) mL 14.3 M 2-mercaptoethanol (add just before using), 100 (20) mL 100% glycerol (molecular biology grade), 729.30 (145.86) mL water.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc(NN)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a suspension of 4-methoxyphenylhydrazine hydrochloride (41 g, 230 mmol) in methylene chloride (1000 ml) under nitrogen were added diisopropylamine (79.8 g, 612 mmol), 4-chlorobenzylchloride (40.25 g, 250 mmol) and tetrabutylammonium bromide (22.8 g, 70 mmol). The resulting mixture was stirred at ambient temperature for 48 hours. The reaction mixture was then washed with water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2.5% methanol in methylene chloride) followed by washing of the solid with 10% ethyl ether in hexane and drying in vacuo to provide 43.5 g of 1-(4-chlorobenzyl)-1-(4methoxyphenyl)hydrazine, mp. 55° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:11]Br.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[C:8]([Br:11])=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Clc1nccc2occc12
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1nccc2occ(Br)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To the solution of 4-chloro-furo[3,2-c]pyridine (4.2 g, 0.03 mol) In CCl4 (77 ml) was added Br2 (2.4 ml, 0.046 mol) at 0° C. and the resultant reaction mixture was stirred for 4 hours at room temperature. The resultant suspension was poured into the mixture of ethyl acetate and 10% Na2SO3. The corresponding organic phase was separated and dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in THF (100 ml) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (5.6 ml) was added at 0° C. The resultant reaction mixture was stirred for 2 hours at room temperature and poured into NaHCO3 and ethyl acetate. The organic layers were separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on a silica gel column to afford the titled compound (5.4 g) 1H NMR (400 MHz, CDCl3) ppm 8.32 (d, J=5.8 Hz, 1H), 7.72 (s, 1H), 7.44 (d, J=5.8 Hz, 1H), 7.26 (s, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].FC(F)(F)C(O)=O.[C:17]1(=O)OC(=O)[CH2:20][C@@H:18]1O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(C)C>[CH:18]([O:8][C:1](=[O:9])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3])([CH3:20])[CH3:17]
Reactant: O=C1C[C@H](O)C(=O)O1
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)OC(=O)[C@@H](O)CC(=O)O
Yield: 97.7 %

Procedure:
By the use of the procedures and conditions described by Example 3A, L-malic acid was converted to L-malic anhydride trifluoroacetate with trifluoroacetic anhydride, and the anhydride allowed to react with isopropyl alcohol to provide in 97.7% yield L-malic acid monoisopropyl ester as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][OH:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][OH:26])=[O:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
N-(benzyloxysuccinyl)-L-proline (152.5 g, 0.5 mol), L-prolinol (50.5 g, 0.5 mol) and triethylamine (200 ml) are dissolved in methylene chloride (2 l), and a solution of DMC (127 g, 0.75 mol) in methylene chloride (500 ml) is added dropwise thereto over a period of 40 minutes under water-cooling. The mixture is stirred for a further three hours at room temperature. The reaction liquid is washed successively with water (1 l), a saturated aqueous solution of sodium hydrogen carbonate (1 l), 1N hydrochloric acid (1 l) and water (1 l), and the organic layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure and the residue is purified by column chromatography on silica gel (chloroform:methanol) to give N-(benzyloxysuccinyl)-L-prolyl-prolinol (90 g, 46.4%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17](N)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=CC=C[CH:31]=1.C[OH:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:39][C:29](=[O:36])[CH:30]([CH3:35])[CH3:31])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Reactant: CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OC(=O)C(C)C)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 67 %

Procedure:
A solution of 39 (0.10 g, 0.26 mmol), benzoyl chloride (0.11 g, 0.78 mmol) and DMAP (0.08 g, 0.78 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 2 h. Absolute MeOH (15 mL) was added and the solvent was removed under reduced pressure. CH2Cl2 (25 mL) was added to the residue and the solution was washed with 10% HCl (2×20 mL), H2O (3×20 mL), and saturated NaCl (3×20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded 0.09 g (67%) of 10 as a white crystalline solid, mp 155-157° C. (EtOAc/n-hexanes); 1H NMR (CDCl3): δ 1.44 (3H, s); 1.50 (3H, s); 1.63 (3H, m); 1.82 (1H, dd, J=2.1, 10.5); 2.0 (1H, m); 2.12 (1H, dd, J=2.7, 8.4); 2.17 (1H, m); 2.32 (1H, s); 2.48 (1H, dd, J=5.4, 13.2); 2.79 (1H, dd, J=3.3, 6.9); 2.87 (1H, dd, J=2.7, 13.5); 3.71 (3H, s); 4.69 (1H, m); 5.55 (1H, dd, J=5.1, 11.4); 6.37 (1H, dd, J=0.9, 1.8); 7.1 (1H, d, J=6.0); 7.39 (1H, t, J=1.8); 7.41 (1H, dd, J=0.9, 1.8); 7.46 (1H, m); 7.53 (1H, tt, J=1.5, 2.7, 7.2); 7.80 (1H, t, J=2.4); 7.82 (1H, t, J=1.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:13])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1

Procedure:
Example 71 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.39–7.34 (m, 6H), 7.26 (t, 1H, J=7.2 Hz), 6.96 (d, 1H, J=7.6 Hz), 5.68 (br s, 1H), 3.26 (dd, 2H, J=6.8, 12.8 Hz), 2.88 (d, 2H, J=13.2 Hz), 2.45 (m, 1H), 2.30 (t, 2H, J=7.2 Hz), 2.19 (s, 3H), 1.96 (t, 2H, J=11.6 Hz), 1.78 (d, 2H, J=12.8 Hz), 1.65–1.58 (m, 6H), 1.02 (dd, 2H, J=3.6, 6.8 Hz); ESMS m/e: 454.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](C=O)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:23](=[O:26])[CH2:24][CH3:25])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].[OH-].[Na+].Cl.[CH3:30]O>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:25]=[C:24](\[CH3:30])/[C:23]([C:15]2[CH:16]=[C:17]([O:21][CH3:22])[C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)=[O:26])=[CH:5][CH:4]=1
Reactant: CO
Reactant: COc1ccc(C=O)cc1
Reactant: CCC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(/C=C(\C)C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-methoxybenzaldehyde (1.0 g, 7.3 mmol) and 1-(3,4,5-trimethoxyphenyl)propan-1-one (1.64 g, 7.3 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (1 ml). The mixture was stirred for 24 hours at room temperature, acidified with 2N HCl and extracted with ethyl acetate (3×30 ml). The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The product was purified by column chromatography using hexane/ethylacetate (4:1) as eluant, followed by recrystallisation from ethanol to afford the title compound as a pale yellow solid, 0.36 g (14%). 1H-NMR (CDCl3) δ 7.8 (1H, s), 7.6 (2H, m), 7.3 (2H, d), 7.0 (2H, d), 3.9 (9H, s), 3.8 (3H, s), 2.3 (3H, s). Mass Spectrum (FAB) m/e 343 (M+1).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8]([OH:10])=O)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH2:27]([NH2:32])[CH2:28][CH2:29][CH2:30][CH3:31].CCOCC>C(OCC)(=O)C>[CH2:27]([NH:32][C:8](=[O:10])[CH2:7][CH:6]([N:5]1[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]2[C:4]1=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: CCCCCN
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCNC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
By following the procedure of Example 46 utilizing 3-phthalimido-3-(3,4'-dimethoxyphenyl)propionic acid and amylamine (1.0 equiv) to afford 2.15 g (84%) of crude product. The crude product was dissolved in 150 mL of ethyl acetate and then 50 mL of ether was added and the mixture stirred for 1 hour. The resulting slurry was filtered and the solid dried in vacuo to afford 1.28 g (50%) yield of 3-phthalimido-3-(3',4'-dimethoxyphenyl)propionic amylamide as a white powder: mp 140.5°-142.1° C.; 1H NMR (DMSO-d6, 250 MHz), d 8.05 (t, 1 H, J=5 Hz), 7.85 (m, 4 H), 7.03 (br s, 1 H), 6.90 (m, 3 H), 5.68 (t, 1 H, J=8 Hz), 3.73 (s, 3 H), 3.71 (s, 3 H), 3.19 (d, 2 H, J=8 Hz), 2.8-3.1 (m, 2 H), 0.9-1.3 (m, 6 H), 0.74 (m, 3 H); 13C NMR (DMSO-d6) δ 168.8, 167.7, 148.5, 148.3, 134.5, 131.5, 131.2, 123.1, 119.5, 111.6, 111.1, 55.4, 50.6, 38.2, 37.4, 28.7, 28.3, 21.7, 13.7; Anal. Calcd. for C24H28N2O5. Theoretical: C, 67.9; H, 6.65; N, 6.60. Found: C, 67.84; H, 6.70; N, 6.57.