Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[N:5]([CH2:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)[C:4]1=[O:26].C(N(CC)CC)C.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:43](Cl)=[O:44]>ClCCl>[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:43]([NH:2][C@H:3]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[N:5]([CH2:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)[C:4]1=[O:26])=[O:44]
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)c1cc2ccccc2[nH]1

Procedure:
On the other hand, to a suspension of (3S)-3-amino-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl) methyl]-2H-1,4-benzodiazepin-2-one hydrochloride in dry dichloromethane (50 ml) was added dropwise triethylamine (7.45 ml). To the mixture was added dropwise a solution of 2-indolylcarbonyl chloride obtained above under stirring and cooling below 10° C. After stirring under the same conditions for 2 hours, the mixture was washed with hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give (3S)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-1-[(1 H-tetrazol-5-yl)-methyl]-2H-1,4-benzodiazepin-2-one (5.3 g).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1.[CH3:14][C:15]([CH3:17])=O.C(O)(=O)C>CO.C(Cl)Cl>[CH:15]([NH:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=1)([CH3:17])[CH3:14]
Reactant: CC(C)=O
Reactant: COc1cccc(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(NC(C)C)c1

Procedure:
To a microwave tube charged with a stirring bar was added sodium cyanoborohydride (0.10 g, 1.6 mmol) and m-anisidine (0.075 mL, 0.8 mmol) in methanol (1 mL). To this solution was the added acetone (0.5 mL) and glacial acetic acid (0.5 mL). Once the gas evolution had subsided, the tube was crimped and subjected to microwave irradiation at 130° C. for 15 minutes. The solution was diluted with CH2Cl2, washed once with 1N NaOH, and the organic layer was dried (Na2SO4), filtered and concentrated to a yellow liquid. This was purified via silica gel chromatography with an ethyl acetate/hexanes gradient (Rf=0.60 in 4:1 Hex/EtOAc) to give N-isopropyl-3-methoxybenzenamine as a colorless oil. FIA MS 166 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:15][C:16]#[N:17]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1
Reactant: N#CCBr
Reactant: c1ccc(CN2CCNCC2)nc1
Product: N#CCN1CCN(Cc2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-2-ylmethyl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a brown solid; ES-MS: M+=217.2: 1HNMR(DMSO-d6) 8.45 (dd, 1H), 7.75 (td, 1H), 7.40 (d, 1H), 7.25-7.20 (m, 1H), 3.70 (s, 2H), 3.60 (s, 2H), 2.50-2.35 (m, 8H).
Reaction SMILES: O.[CH:2]1([O:7][C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][N:11]=[C:10](OC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:38](O)(=[O:40])C>>[CH:2]1([O:7][C:8]2[C:13]([O:14][CH:15]([F:16])[F:17])=[CH:12][N:11]=[C:10]([CH2:38][OH:40])[CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)O
Reactant: FC(F)Oc1cnc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1OC1CCCC1
Solvent: O
Product: OCc1cc(OC2CCCC2)c(OC(F)F)cn1
Temperature: 60 °C

Procedure:
Water (4 drops is added to a solution of 4-cyclopentyloxy-5-difluoromethoxy-2-trityloxypyridine (900 mg) in glacial acetic acid (20 mL) and the mixture heated at 60° C. for 18 hours. After cooling the mixture is evaporated to dryness and the residue partitioned between water and ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to give a pale yellow solid which is purified by flash chromatography (gradient elution using n-pentane/ethyl acetate 7:3 v/v to n-pentane/ethyl acetate 2:3 v/v on silica) to give 4-cyclopentyloxy-5-difluoromethoxy-2-hydroxymethylpyridine (250 mg) as a white solid, m.p. 85-6° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:4]1[C:3]2[C:2](=[CH:15][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][C:4]=1[C:3]1[C:2]2[C:11]([CH:10]=[C:9]3[C:8]=1[CH:7]=[CH:7][CH:6]=[CH:5]3)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc2cc(-c3c4ccccc4cc4ccccc34)ccc2c1
Yield: 173.5 %

Procedure:
22.5 g of 9-bromoanthracene, 15.8 g of 2-naphthelene boronic acid and 2.0 g of tetrakis(triphenylphophine)palladium were mixed, followed by argon displacement. After adding 150 ml of toluene and 140 ml of 2M sodiumcarbonate aqueous solution thereto, it was refluxed on heating for 7 hours. After standing to cool, the crystal precipitated was filtrated it was washed by ethanol and toluene. The crystal obtained was recrystallized in toluene, followed by filtering and drying, and then 23.1 g of 9-(naphthalene-2-yl)anthracene was obtained (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CC/C=C\c1cccc(Cl)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC/C=C\c1cccc(Cl)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A solution of cis-2-[4-(3-chlorophenyl)-but-3-enyl]-isoindole-1,3-dione (5.7 g) and hydrazine hydrate (1.8 mL) in ethanol (180 mL) was heated at reflux for 16 h. The solution was allowed to cool to rt and the volatiles were removed in vacuo. The resulting residue was dissolved in 2 M sodium hydroxide and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate and reduced in vacuo to yield cis-4-(3-chlorophenyl)-but-3-enylamine (2.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[N:23][N:24]([C@H:26]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)[CH:25]=1>CC(O)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)[CH:25]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(N)cn2)C1
Solvent: CC(C)O
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3cnn([C@H]4CCNC4)c3)ncc2Cl)[C@H]2C=C[C@@H]1C2
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
(+)-(1S,2S,3R,4R)-3-(2,5-Dichloropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (75 mg, 0.25 mmol) and (S)-tert-butyl 3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (63 mg, 0.25 mmol) were combined with 2-propanol (2.4 ml) in a sealed tube and the mixture was heated to 85° C. for 4 hours. The reaction mixture was concentrated to dryness, then treated with 5 mL TFA and stirred for 15 minutes. The mixture was again concentrated to dryness, the residue was dissolved in CH2Cl2, and the mixture was treated with aqueous saturated NaHCO3. The layers were separated and the aqueous layer was further extracted 3× with ethyl acetate. The extracts were dried (Na2SO4) and concentrated, then purified by flash chromatography yielding the desired product. 1H NMR (300 MHz, DMSO-D6) ppm 1.41 (d, J=7.8 Hz, 1H) 1.92-2.04 (m, 1H) 2.07-2.21 (m, 2H) 2.52-2.56 (m, 1H) 2.71-2.91 (m, 3H) 2.93 (d, J=5.4 Hz, 1H) 2.95-3.03 (m, 1H) 3.12 (dd, J=11.5, 7.12 Hz, 1H) 4.13 (t, J=7.5 Hz, 1H) 4.65-4.77 (m, 1H) 6.25-6.40 (m, 2H) 7.25 (s, 1H) 7.51 (s, 1H) 7.61-7.84 (m, 3H) 7.89 (s, 1H) 9.10 (s, 1H); MS (ESI(+)) m/e 415 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:11][C:10]=1[CH:24]([OH:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:34].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:11][C:10]=1[CH:24]([O:30][CH3:34])[CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C(O)CC(C)(C)C)c2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C(CC(C)(C)C)OC)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(benzyloxy)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-yl)-3,3-dimethylbutan-1-ol (425 mg) prepared in Example 14, step C, in DMF (3.0 mL) was added 60% sodium hydride (100 mg), and the mixture was stirred at room temperature for 30 min. Iodomethane (443 mg) was added dropwise and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crude product. This compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][N:13]3[C:18](=[O:19])[N:17]=[C:16]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[NH:15][C:14]3=[O:33])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:38](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][N:13]3[C:14]([O:33][CH3:38])=[N:15][C:16]([N:20]4[CH2:21][CH2:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[CH2:24][CH2:25]4)=[N:17][C:18]3=[O:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)n1Cc1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nc(N2CCN(c3ccc(F)cc3)CC2)nc(=O)n1Cc1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 7 %

Procedure:
To an N,N-dimethylformamide solution (4 mL) of a crude product (0.69 mmol) of 3-{4-[(4-chlorobenzyl)oxy]benzyl}-6-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazine-2,4(1H,3H)-dione, potassium carbonate (332 mg, 2.40 mmol) and methyl iodide (137 μL, 2.20 mmol) were added at room temperature and the resultant mixture was stirred at room temperature for 1 day. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain the title compound (26 mg, two step yield: 7%).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[O:6]=[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13][C:14]([O:16][CH:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)=O>C(O)(=O)C>[C:20]1([C:18]2[N:5]=[C:14]([CH2:13][CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:7]3=[O:6])[O:16][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [NH4+]
Reactant: O=C(CC1CCCCC1=O)OC(C(=O)c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C1CCCCC1Cc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
A mixture of ammonium acetate (6.3 g), acetic acid (30 ml) and 1,2-diphenyl-2-oxoethyl (2-oxocyclohex-1-yl)acetate (15.0 g) was heated under reflux for 2.5 hours. After used workup, the crude product was purified by column chromatography (silica gel 100 g, eluent; hexane:ethyl acetate=20:1 then 9:1 then 6:1) to give 2-[(4,5-diphenyl-oxazol-2-yl)methyl]cyclohexanone as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:17][S:18][CH2:19][C@H:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[CH:11][N:22]2[C@H:20]([CH3:21])[CH2:19][S:18][CH3:17]
Reactant: CSC[C@@H](C)N
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Product: CSC[C@@H](C)n1ccc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized in a manner similar to Example 36 using 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) and (R)-1-(methylthio)propan-2-amine (Example 27C): MS (ESI): m/z 265 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.[CH3:24][C:25](O)=O>[Fe]>[CH3:24][C:25]1[NH:18][C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:11][C:2]=2[N:1]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: ClCCl
Product: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of methyl 3-amino-5-(4-morpholinyl)-2-nitrobenzoate (22 g) stirring at reflux in HOAc (400 mL) was added iron powder in portions (13 g). After the addition, the mixture was stirred at reflux for 5 h. It was cooled to room temperature and the solvent was removed in-vacuo. The residue was neutralized with aqueous Na2CO3 solution (1 L). It was extracted with EtOAc (500 mL×3). The combined organic layers were then concentrated in-vacuo and the residue was purified by silica gel chromatography eluted with MeOH:DCM=1:30 to afford the desired product as a solid (16.6 g, yield 77%). 1H NMR (300 MHz, CDCl3): δ ppm 2.67 (s, 3H), 3.17 (t, 4H, J=4.8 Hz), 3.90 (t, 4H, J=4.8 Hz), 3.98 (s, 3H), 7.44 (d, 1H, J=1.8 Hz), 7.54 (d, 1H, J=1.8 Hz); LC-MS: m/e=276 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][CH2:8][C:9](=[O:14])[NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.N1C2C(CCC3C=CC=CC=32)CC[C:18]1=O.[H-].[Na+].CI>C(OCC)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][CH2:8][C:9](=[O:14])[N:10]([CH3:18])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: O=C1CCC2CCc3ccccc3C2N1
Reactant: O=C1CCC2=C(CCc3cc(Br)ccc32)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CCC2=C1CCc1cc(Br)ccc12
Temperature: 25 °C

Procedure:
By substantially following the procedures described above in Example 1 5.17 g of 8-bromo-1,2,3,4,5,6-hexahydrobenzo[f]quinolin-3-one was obtained. The hexahydrobenzoquinolinone (5.17 g; 19.6 mmol) was dissolved in 60 ml of dry diethyl ether in a 250 ml round bottomed flask. To the solution was added 1.2 g of sodium hydride (60% dispersion in mineral oil). The flask was fitted to a reflux condenser with a stirring bar and the mixture refluxed for 2 hours. The mixture was then cooled to room temperature and 7.35 ml of methyl iodide was added. After addition, the reaction mixture was refluxed for an additional 3 hours. After cooling, the reaction mixture was quenched by the cautious addition of 5 ml of water. The mixture was then concentrated under vacuum affording a pale solid which was taken up in a ethyl acetate/water mixture and the resulting layers separated. The organic layer was washed twice with water and once with brine and then dried over MgSO4 and concentrated under vacuum to afford 5.22 g of a yellow crystalline solid. The solid was recrystallized from acetone to afford 3.55 g (62%) of the subtitle compound as a pale yellow solid. Melting point 126°-128° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH2:5]O)[CH3:2].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH2:5][Cl:16])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1CCl
Yield: 158.3 %

Procedure:
To a mixture of 138.41 g of 2,6-diethyl-4-methylbenzyl alcohol and 820 g of toluene was added dropwise 60.96 g of thionyl chloride at 25° C. over 4.5 hours. The resultant mixture was stirred for 15 hours. The reaction mixture was concentrated to obtain 159.58 g of 2,6-diethyl-4-methylbenzyl chloride (GC-area: 71%) as a brown oil.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7]2.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.C(OCC)(=O)C>[O:1]=[CH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7]2
Reactant: O=C(OCc1ccccc1)N1Cc2ccc(CC(O)CO)cc2C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=CCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reaction time: 0.33 h

Procedure:
To a solution of benzyl 5-(2,3-dihydroxypropyl)isoindoline-2-carboxylate (327 mg, 1 mmol) in THF (7 mL) and water (7 mL) was added sodium periodate (426 mg, 2 mmol). The resulting mixture was stirred for 20 min diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated to give the title compound a white solid. This material is used without further purification.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH2:16])(=[O:4])[CH3:3].[C:17]([O:20][CH2:21][C:22](O)=[O:23])(=[O:19])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O1CCOCC1>[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH:16][C:22](=[O:23])[CH2:21][O:20][C:17](=[O:19])[CH3:18])(=[O:4])[CH3:3]
Reactant: COC(=O)c1ccc(NC(C)=O)c(N)c1
Reactant: CC(=O)OCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C)=O)c(NC(=O)COC(C)=O)c1
Temperature: 0 °C
Yield: 678.9 %

Procedure:
Compound 16 (0.20 g, 0.96 mmol) was dissolved in a mixture of anhydrous DMF (2 mL) and anhydrous dioxane (5 mL), and the solution was cooled to 0°-5° C. in an ice bath. To this were added acetoxy acetic acid (0.124 g, 0.129 mmol) and DCC (0.198 g, 0.210 mL, 0.960 mmol). The reaction mixture was stirred for a few minutes at 0° C., the ice bath was removed, and the mixture was stirred at room temperature for 4 hours. The solid which separated was filtered and the filtrate was concentrated to dryness on a rotary evaporator. The solid residue was triturated with 5% HCl, filtered, and washed on the filter with water. The collected solid was then triturated with 5% NaHCO3, filtered, washed with water, and dried under vacuum to give 17 (270 mg, 70.9% yield) as a white solid: mp 182°-186° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH2:12][N:13](C)[C:14](=O)OCC3C=CC=CC=3)[O:11][C:7]=2[C:6]([F:25])=[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]=1[CH3:32])#[N:2]>[C].[Pd].C(O)C>[F:25][C:6]1[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([CH3:32])[C:3]([C:1]#[N:2])=[C:8]2[C:7]=1[O:11][C:10]([CH2:12][NH:13][CH3:14])=[N:9]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(CN(C)C(=O)OCc3ccccc3)nc2c1C#N
Agent: [Pd]
Solvent: CCO
Product: CNCc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
A catalyst 10% palladium-carbon (100 mg) was added to an ethanol (6 ml) solution of benzyl [(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)methyl]methylcarbamate (I-272) (242 mg, 0.564 mmol), followed by stirring under hydrogen atmosphere at room temperature for 6 hours. The insoluble matter was separated by filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (115 mg, 69%) as a colorless oily substance.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[CH3:49][N-:50][CH3:51].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:49][N-:50][CH3:51]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[N-]C
Agent: On1nnc2ccccc21
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 162 mg of Z-Phe-His-OH, 95 mg of H-Leu-Val-dimethyl amide, 57 mg of HOBt and 99 mg of DCCI, the title compound is obtained after flash chromatography (100 g of silica gel 60, 40-63 μm, system B3). Rf (B2)=0.57, Rf (S10)=0.74.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=O)[C:4]([O:6]CC)=O.[C:12]1([C@@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C(C)=CC=CC=1>[CH3:11][C:2]([CH3:1])([CH3:10])[C:3](=[N:20][C@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])[C:4]([NH:20][C@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])=[O:6]
Reactant: CCOC(=O)C(=O)C(C)(C)C
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: C[C@H](N=C(C(=O)N[C@@H](C)c1ccccc1)C(C)(C)C)c1ccccc1
Yield: 44.7 %

Procedure:
A solution of 15 g (95 mmol) of ethyl trimethyl-pyruvate and 50 g (413 mmol) of (S)-1-phenylethylamine in 50 ml of xylene was boiled under reflux on a water separator for 18 hours. Subsequently, the solvent was distilled off and excess amine was removed at 120° C. in a vacuum. After crystallization of the distillation residue from 125 ml of hexane there were obtained 14.3 g (45%) of (S)-3,3-dimethyl-N-[(S)-1-phenylethyl]-2-(1-phenylethylimino)-butyramide of melting point 96°-97° C. [α]=-58.9 (c=1.0, CHCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])[C:3]=1[N+:15]([O-:17])=[O:16].C(N(C(C)C)CC)(C)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:38][CH:37]=[N:36][N:35]=2)=[CH:30][C:29]=1[NH2:39]>CCCCO>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:8]([CH3:9])[C:4]1[C:3]([N+:15]([O-:17])=[O:16])=[C:2]([NH:39][C:29]2[CH:30]=[C:31]([C:34]3[NH:38][CH:37]=[N:36][N:35]=3)[CH:32]=[CH:33][C:28]=2[CH3:27])[N:7]=[CH:6][N:5]=1
Reactant: Cc1ccc(-c2nnc[nH]2)cc1N
Reactant: CN(CC(C)(C)C)c1ncnc(Cl)c1[N+](=O)[O-]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nnc[nH]2)cc1Nc1ncnc(N(C)CC(C)(C)C)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
A solution of (6-Chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-methyl-amine (185 mg, 0.72 mmol), diisopropylethylamine (0.13 mL, 0.72 mmol) and 2-Methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamine (126 mg, 0.72 mmol) in 3 mL of n-BuOH was heated with stirring at 80° C. for 18 h. The solvent was then evaporated in vacuo and the crude product was purified by flash chromatography to afford 87 mg of the product (30%). MS (m/z) calcd for C19H24N8O2 (MH+), 397.2, found, 397.3.