Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1/[CH:17]=[CH:18]/[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([CH:23]=[O:24])=[CH:25][CH:26]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1/C=C/c1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc3ccccc3c2)nc1/C=C/c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
A mixture of (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]benzyl alcohol (7.80 g), activated manganese dioxide (15.6 g) and chloroform (300 ml) was stirred at room temperature for 1 day. After the manganese dioxide was filtered off, the filtrate was concentrated under reduced pressure; the resulting crystal was recrystallized from dichloromethane-methanol to yield (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]benzaldehyde (6.56 g, 85%) as light yellow needles having a melting point of 162°-163° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][CH2:16][CH2:17][O:18][CH3:19].[I-].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: COCCCBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCn1ccc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of methyl 1H-indole-6-carboxylate (5.0 g) in N,N-dimethylformamide (40 mL) was added dropwise a solution of 1-bromo-3-methoxypropane (5.24 g) in N,N-dimethylformamide (10 mL) under ice-cooling, and then thereto was added potassium iodide (948 mg), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was sequentially added ethyl acetate and water under ice-cooling, and the organic layer was separated. The organic layer was washed with water twice and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1→4/1) to give methyl 1-(3-methoxypropyl)-1H-indole-6-carboxylate [REx(6-1)] (5.8 g) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[CH:5]=O.[CH2:11]([O:18][C:19]([NH:21][CH:22](P(OC)(OC)=O)[C:23]([O:25][CH3:26])=[O:24])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]([NH:21]/[C:22](=[CH:5]\[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1)/[C:23]([O:25][CH3:26])=[O:24])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.5 %

Procedure:
A well stirred solution of 3,5-difluorobenzaldehyde (1.92 g, 13.5 mmol) and methyl benzyloxycarbonylamino-(dimethoxyphosphoryl)acetate (5.37 g, 16.2 mmol) in dry THF (20 mL), under N2, was cooled to 0° C. and 1,1,3,3-tetramethylgaunidine (1.38 g, 16.2 mmol) added via syringe. The reaction was allowed to warm to rt and stir for 6 h, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration, the residue was chromatographed on silica gel (elution with 20% ethyl acetate/heptane) to give methyl (Z)-2-benzyloxycarbonylamino-3-phenyl-acrylate (3.55 g) as a white solid. MS (ESI+) for C18H15F2NO4 m/z 348.2 (M+H)+.
Reaction SMILES: [C:1](=[O:10])([O:6][CH2:7][CH:8]=[CH2:9])OCC=C.[H-].[Na+].[CH3:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15].Cl>C(OCC)C.O.O1CCCC1>[CH:16]1([C:14]([CH2:13][C:1]([O:6][CH2:7][CH:8]=[CH2:9])=[O:10])=[O:15])[CH2:18][CH2:17]1
Reactant: CC(=O)C1CC1
Reactant: C=CCOC(=O)OCC=C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOC(=O)CC(=O)C1CC1

Procedure:
Preparation of the β-ketoester. To a round bottom flask equipped with an addition funnel and cold water condenser was added, 21.3 grams (0.15 mol.) of diallyl carbonate and 50 mL of tetrahydrofuran and the mixture was stirred. Next, sodium hydride, 8.4 grams (0.21 mol.), was added portion-wise. To the reaction mixture was added, 12.6 grams (0.15 mol.) of cyclopropyl methyl ketone (dissolved in 25 mL of tetrabydrofuran) via the addition funnel. The mixture was heated to relux and heated for an additional 1 hour. Subsequently, the mixture was allowed to cool and the solvent was stripped. Next, cold water (50 mL) and 1N hydrochloric acid (50 mL) were added. The reaction mixture was transferred to a separatory funnel and diethyl ether was added. The organic layer was dried over MgSO4 and stripped under vacuum to yield the β-ketoester, carboallyloxymethyl cyclopropyl ketone. ##STR15## (B) Preparation of aryl β-triketone. To a round bottom flask was added 23.6 grams (0.14 mol.) of the β-ketoester, 16 grams (0.14 mol.) of magnesium ethoxide and 100 mL of tetrahydrofuran. The reaction mixture was then refluxed for 2 hours and the solvent stripped to insure complete removal of the ethanol by-product. The flask was then recharged with 100 mL of tetrahydrofuran and 29.3 grams (0.14 mol.) of the aryl acid chloride. The solution was refluxed for several hours, after which the mixture was stripped under vacuum, extracted with diethyl ether and washed with water. The 46.4 grams of β-triketone product, trifluoromethylbenzoylcarboallyloxy-methyl cyclopropyl ketone were confirmed by infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:12]([C:10]2[N:11]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][CH:29]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(C2CCCCC2)oc1C(F)(F)F
Product: COCCN(C)c1ccc(NC(=O)c2nc(C3CCCCC3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H25F3N4O3 (m/e) 426, obsd 427 (M+H).
Reaction SMILES: COC([N:5]1[N:12](C(OC)=O)[CH:11]2[CH:6]1[CH:7]1[CH:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]2[CH:9]=[CH:8]1)=O.[OH-].[K+].OO>CO>[C:19]([O:18][CH:17]1[CH:7]2[CH:8]=[CH:9][CH:10]1[CH:11]1[CH:6]2[N:5]=[N:12]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)N1C2C3C=CC(C3OC(C)(C)C)C2N1C(=O)OC
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC1C2C=CC1C1N=NC21
Temperature: 20 °C

Procedure:
50 parts of 3,4-dimethoxycarbonyl-9-t-butoxy-3,4-diazatricyclo[4,2,1,02,5 ]non-7-ene, 50 parts of KOH and 250 parts of methanol were refluxed for 7 hours, after which 36 parts of 30 percent strength aqueous H2O2 were added dropwise at 60° C. and stirring was continued for a further hour at 60° C. The mixture was cooled to 20° C., and thereafter the solid product was filtered off under suction and washed with 50 parts of methanol, the combined filtrates were evaporated down in a rotary evaporator at from 20° to 40° C. and under 20 mbar, and the residue was extracted in a soxhlet for 12 hours with 300 parts of petroleum ether. The petroleum ether phase was evaporated down to give 28.5 parts (93 mole %) of 9-t-butoxy-3,4-diazatricyclo[4,2,1,02,5 ]nona-3,7-diene of melting point 78° C. (from naphtha). ##STR14##
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([CH2:18][C:19]#[N:20])[C:12]=1[O:21][CH3:22].Cl>CN(C)C=O.O>[C:19]([C:18]1([C:13]2[CH:14]=[C:15]([Br:17])[CH:16]=[C:11]([Br:10])[C:12]=2[O:21][CH3:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:20]
Reactant: BrCCCCCBr
Reactant: COc1c(Br)cc(Br)cc1CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Br)cc(Br)cc1C1(C#N)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (7 g) in dry dimethylformamide (200 ml) was added a solution of 1,5-dibromopentane (20 ml) and the product of stage (d) in dimethylformamide (40 ml), keeping the temperature at 20°-30° C. The mixture was stirred for 30 minutes, water was added cautiously, and was then poured into ice water. Hydrochloric acid was added and the mixture was extracted with dichloromethane, washed with water and brine, dried over magnesium sulphate and filtered, and the solvent was removed to give a pale brown oil which slowly crystallised. Recrystallisation from ethanol gave the title product as yellow crystalls, mp 100°-102° C.
Reaction SMILES: [CH:1]1[NH:8][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]=1[F:9].C(N(CC)CC)C.[C:17]([O:25][CH2:26]Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>CC(N(C)C)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([O:25][CH2:26][N:8]2[CH:1]=[C:2]([F:9])[C:3](=[O:4])[NH:5][C:6]2=[O:7])=[O:24])[CH:19]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(OCCl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(OCn1cc(F)c(=O)[nH]c1=O)c1cccnc1
Reaction time: 24 h

Procedure:
5-FU (1.31 g, 0.01 mol) was dissolved in 5 mL of dimethylacetamide and treated with triethylamine (2.78 mL, 0.02 mol). Chloromethyl nicotinate (2.95 g. 0.012 mol) in 5 mL of dimethylacetamide was added in one portion, and the mixture was stirred for 24 hours, filtered, washed with ethyl acetate and evaporated. The residue was chromatographed on a column of silica gel, using as eluent first benzene, then 3:1 benzene/chloroform, then 1:1 benzene/chloroform, then 3:1 chloroform/benzene, then chloroform and finally 99:1 chloroform/methanol. Unreacted nicotinate was eluted initially, followed by the 1,3-bis-isomer and finally the 1-isomer. The 1-isomer (1.3 g, 50%) melted at 190°-192° C. and had the formula ##STR158## as confirmed by NMR analysis.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][N:7]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[N+:22]([O-:24])=[O:23])=[N:10][N:9]=[N:8]1)(=O)C.[ClH:25]>C(O)C>[ClH:25].[NH2:4][CH2:5][CH2:6][N:7]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[N+:22]([O-:24])=[O:23])=[N:10][N:9]=[N:8]1
Reactant: CC(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A mixture of 6.5 g. (0.02 mol) of 1-(2-acetamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, 100 ml. of 12 N hydrochloric acid and 100 ml. of 95% ethanol was refluxed for 4.5 hours. The mixture was evaporated to dryness to give a gummy residue which crystallized upon addition of ethanol to give 1-(2-aminoethyl)-5-(2,4-dinitrophenylthio)tetrazole hydrochloride, mp 217°-219° C. (d).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH2:12])[CH:7]=[CH:8]2)=[N:3]1.C[Al](C)C.C[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:29]=1.C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:19](=[O:18])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([N:37]([CH3:38])[CH3:39])=[O:36])[CH:29]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1c2ccc(N)cc2nn1C
Reactant: COC(=O)c1ccccc1NCc1ccnc(NC(=O)N(C)C)c1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1c2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N(C)C)c3)cc2nn1C
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 14.8 %

Procedure:
To a stirred solution of 2,3-dimethyl-2H-indazol-6-ylamine (60 mg, 0.34 mmol) in DCE (1.5 mL) at 0° C., under nitrogen, was added trimethylaluminium (2M in toluene, 0.35 mL, 0.7 mmol), followed by a solution of 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoic acid methyl ester (111 mg, 0.34 mmol) in DCE (1.5 mL). The reaction was heated at 100° C. (bath temperature) for 5 hours. On cooling the reaction was poured onto saturated aqueous sodium hydrogencarbonate solution and diluted with dichloromethane. The mixture was stirred for 15 minutes before filtering through Celite®. The organic phase was washed with water and brine, dried, and concentrated in vacuo. The residue was purified by repeated chromatography on Isolute® flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 95:5) to give N-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide (23 mg, 15%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.10 (1H, s), 8.79 (1H, s), 8.15 (1H, d), 8.00 (1H, s), 7.95 (1H, t), 7.82 (1H, s), 7.70-7.73 (1H, m), 7.60 (1H, d), 7.22-7.29 (2H, m), 6.93-6.95 (1H, m), 6.67 (1H, t), 6.53 (1H, d), 4.45 (2H, d), 4.01 (3H, s), 2.91 (6H, s), 2.59 (3H, s); m/z (ES+) 458 [M+H]+, 230.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[CH3:13][O:12][C:10]([C:5]1[C:4]2[CH:3]=[CH:2][N:1]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:15]4[CH:16]=[CH:17][C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:14]=4)=[CH:33][CH:32]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:11]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Product: COC(=O)c1cccc2c1ccn2Cc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
This compound was prepared from methyl 4-indole carboxylate and 4-(quinolin-2-ylmethoxy)benzyl chloride (Example 1a by the method described in Example 1b part i), m.p. 128°-131° C.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>O1CCCC1.CCCCCC.O>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:26][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: ClCc1cccc(Cl)c1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(Cl)c1
Temperature: -40 °C
Yield: 92 %

Procedure:
31.5 g of N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (e.g., as prepared in step A of Example I above) is dissolved in 600 mL of dry tetrahydrofuran and the resulting solution is cooled to -40° C. Two equivalents of n-butyllithium in hexane are added while the temperature is maintained at -40° C. The solution turned deep purple-red. 1.6 g of sodium bromide is added and the mixture is stirred. A solution of 26.5 g (0.174 mole) m-chlorobenzylchloride in 125 mL of tetrahydrofuran is added while the temperature is maintained at -40° C. The reaction mixture is stirred until the reaction is complete as determined by thin layer chromatography. Water is added to the reaction until the color is dissipated. The reaction mixture is extracted with ethyl acetate, washed with water, and concentrated to a residue. A yield of 92% for the product is shown by chromatography.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[O:11])[N:5]=[CH:4]1>CO>[S:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[N:5]=[CH:4]1
Reactant: O=CCCc1cscn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCCc1cscn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
NaBH4 (1.68 g, 44.4 mmol) was added to a sol. of 3-thiazol-4-yl-propionaldehyde (4.35 g, 29.3 mmol) in MeOH (80 mL) at 0° C. The mixture was stirred for 30 min at 0° C., then for 1 h at rt. The mixture was cooled to 0° C., and ice was added. The mixture was partially evaporated under reduced pressure, and the residue was diluted with EtOAc. This mixture was washed with water and brine. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:1→EtOAc→CH2Cl2/EtOAc 1:9) yielded the title compound (4.01 g, 93%). LC-MS: tR=0.34, ES+: 144.16.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:34](O)=[O:35])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:59][CH2:60][CH2:61][C:62]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[NH:64][CH:63]=1>CN(C=O)C>[NH:64]1[C:65]2[C:70](=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:62]([CH2:61][CH2:60][NH:59][C:34](=[O:35])[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[NH:18][C:1]([O:3][CH2:4][CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17]2=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:2])=[CH:63]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1c[nH]c2ccccc12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Commercially available Nα-Fmoc-Nδ-Cbz-L-ornithine (528.0 mg) was dissolved in DMF (10.6 ml), and HOBt (235 mg), WSCI hydrochloride (334 mg), and tryptamine (0.165 ml) were added to the solution. The mixture was stirred for 16 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform and extracted with 1 mol/l aqueous solution of hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate. The solvent was removed by distillation and the residue was purified by silica gel column chromatography (50 g, chloroform/ethyl acetate=1/1) to obtain the title compound (690 mg) as a white solid.
Reaction SMILES: [C:1]1([CH:11]([NH:14]C(=O)C(Cl)(Cl)Cl)[CH:12]=[CH2:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH:11]([NH2:14])[CH:12]=[CH2:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(NC(=O)C(Cl)(Cl)Cl)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CC(N)c1cccc2ccccc12
Temperature: 20 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
Amide 11 (3.0 g, 9.1 mmol) was dissolved in 50 ml of distillated ethanol and 50 ml of 3 M aqueous solution of NaOH was added. All was stirred at 20° C. for 24 h and evaporated to aqueous residue and 32 ml of 5 M HCl was added. It was extracted twice with 40 ml of dichloromethane. The aqueous layer was alkalified with sodium carbonate to pH=8 and extracted three times with 50 ml of diethyl-ether. Organic layers were combined and dried over anhydrous sodium sulphate. Filtration and evaporation yields 1.20 g (72%) of yellow oil; 1H NMR (CDCl3) δ: 1.72 (2H, bs, NH2), 5.18-5.24 (1H, m, CH2), 5.30-5.38 (1H+1H, m, CHCH2+ArCHNH2), 6.15-6.27 (1H, m, CHCH2), 7.42-7.60 (4H, m, ArH), 7.74-7.78 (m, 1H, ArH), 7.84-7.89 (m, 1H, ArH), 8.20 (d, 1H, J=8.3 Hz, ArH) ppm; 13C NMR (CDCl3) δ: 53.92 (CNH2), 114.28 (CH2), 123.41 (CH), 123.51 (CH), 125.55 (CH), 125.56 (CH), 126.05 (CH), 127.80 (CH), 128.92 (CH), 131.40 (C), 134.00 (C), 141.71 (CH) ppm.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.N(CCO)CCO.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: OCCNCCO
Solvent: CS(C)=O
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 83.2 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of diethanolamine and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 g of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.5 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:24]([NH:26][C@@H:27]([C:29](O)=[O:30])[CH3:28])=[O:25])[CH:13](CC1C=CC=CC=1)[C:14](=[O:16])[OH:15])=O)C1C=CC=CC=1.Cl.[CH3:33][O:34][CH2:35][C@H:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH3:33][O:34][CH2:35][C@H:36]([NH:43][C:29](=[O:30])[C@@H:27]([CH3:28])[NH:26][C:24](=[O:25])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH2:11])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC[C@H](N)c1ccccc1
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Agent: Cl
Product: COC[C@H](NC(=O)[C@@H](C)NC(=O)[C@@H](N)CC(=O)O)c1ccccc1
Yield: 57.3 %

Procedure:
The same process as in Example 15 was repeated, except that N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-alanine was used in place of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-valine and that (R)-α-methoxymethylbenzylamine hydrochloride was used in place of (R)-α-ethoxymethyl benzylamine hydrochloride, and α-L-aspartyl-D-alanine-(R)-α-methoxymethylbenzylamide was obtained as a solid product. The total yield was 57.3%.