Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].O>CS(C)=O>[N:29]([CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[4-(2-Tosyloxyethoxy)Benzyl]-2,4-Thiazolidinedione (12.5 g) in dry Dimethylsulphoxide (80 ml) was added sodium azide (2 g) in one portion. The mixture was stirred at ambient temperature for 18 hours and the resulting solution added to water (250 ml). The aqueous solution was extracted with dichloromethane (2×300 ml) and the combined organic phases were washed with water (3×300 ml), dried (MgSO4), filtered and evaporated to give the title compound as an oil which was used in the next stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][CH:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]([CH:9]([CH3:12])[CH2:10][OH:11])[C:24](=[O:25])[CH2:23][Br:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNC(C)CO)cc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)CBr)C(C)CO)cc1

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(4-methoxybenzylamino)propan-1-ol (11 g, 56.41 mmol, 1.00 equiv) in dichloromethane (100 mL). This was followed by the addition of triethylamine (5.7 g, 56.44 mmol, 1.00 equiv). To this was added a solution of 2-bromoacetyl bromide (11.4 g, 56.44 mmol, 1.00 equiv) in dichloromethane (50 mL) dropwise with stirring at −17˜−25° C. The resulting solution was stirred for 1 h at −17˜−25° C. in a liquid nitrogen bath. The resulting mixture was washed with 3×100 mL of water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. This resulted in 16 g (90%) of N-(4-methoxybenzyl)-2-bromo-N-(1-hydroxypropan-2-yl)acetamide as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:20])[N:8]2[CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:7](=[O:20])[N:8]2[CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccc(Cl)cc21)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccc(Cl)cc21)C(C)C
Yield: 69.4 %

Procedure:
By using 6-chloro-1-(2-diisopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-6-chloro-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 205°-208° C. (yield: 69.4%, recrystallizing solvent: aqueous methanol).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][CH:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CNC(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CNC(=O)C1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid methylamide, prepared following General Procedure B-3, was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine by General Procedure A. Purification on silica yielded 124. NMR (CDCl3): 1.85-1.87 (m, 4H, 2×CH2), 2.10-2.18 (m, 3H, CH2+CH), 2.85 (d, 3H, Ch3, J=4.8 Hz), 3.03-3.06 (m, 2H, CH2), 3.82 (s, 2H, CH2), 3.89-3.92 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 4.63 (sbr, 2H, NH2), 5.46 (sbr, H, NH), 6.58 (d, H, ArH, J=8.59 Hz), 7.26 (s, H, ArH), 8.48 (dd, H, ArH, J=2.2 Hz, 8.58 Hz), 9.17 (d, H, ArH, J=2.03 Hz). MS: (ESI+): MH+=468.37
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15].[Si:23](Cl)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[CH2:13]([O:17][C:18]([O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)C(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)=C(OCC(C)C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
Step 1 To a solution of diisopropylamine (2.94 mL, 20.8 mmol) in THF (20 mL) under nitrogen at 0° C. was added nBuLi (2.5M in hexanes, 8.32 mL, 20.8 mmol, 1 eq.) and the solution stirred at 0° C. for 30 min. The solution was cooled to −78° C. and then a solution of isobutylisobutyrate (3.49 mL, 20.8 mmol) in THF (6 mL) was added dropwise and then the reaction stirred at −78° C. for 1 h. TMS-Cl (3.19 mL, 25 mmol) was then added dropwise and the reaction allowed to warm to room temperature over 3 h. The reaction was quenched with ice-water (20 mL) and EtOAc (20 mL) was added. The organic phase was washed with water (10 mL) and then brine (10 mL) before it was dried (MgSO4), filtered and concentrated to give (1-isobutoxy-2-methyl-propenyloxy)-trimethyl-silane (3.5 g) used crude in the next reaction.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[F:10].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>CCO>[CH2:11]([N:13]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[F:10])[CH2:14][CH3:15])[CH3:12]
Reactant: Fc1cc(I)ccc1CBr
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)Cc1ccc(I)cc1F
Yield: 93.3 %

Procedure:
A mixture of 1-(bromomethyl)-2-fluoro-4-iodobenzene (1.89 g, 6.0 mmol) and a solution of diethylamine (2.19 g, 30 mmol) in EtOH (60 mL) was stirred at rt overnight under N2, then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), and washed with water (100 mL×3) followed by brine (100 mL). The organic phase was concentrated in vacuo to give the title compound as colorless oil (1.72 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:57]1([CH3:66])[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][CH2:64][NH2:65]>CN(C=O)C>[C:57]1([CH3:66])[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][CH2:64][NH:65][C:18]([C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[O:10][C:11]=2[CH:17]=1)=[O:20]
Reactant: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Reactant: Cc1ccccc1CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1CCNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-benzooxazole-6-carboxylic acid (8.9 mg) in anhydrous DMF (0.5 mL) was added BOP (17.4 mg), diisopropylethylamine (0.014 mL), and 2-o-tolyl-ethylamine (5.5 mg). The reaction mixture was stirred at 85° C. overnight, quenched with 1N NaOH aqueous solution at 0° C., extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was purified by silica SPE eluting with EtOAc/Hexane to give 2-(2,6-dichlorophenyl)-benzooxazole-6-carboxylic acid (2-o-tolyl-ethyl)-amide: MS (m/z) 425.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:10][O:9][C:8]=2[C:18]([NH:20][NH2:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:25][CH2:26][CH3:27])(=O)C>>[C:14]([C:13]1[CH:12]=[C:11]([CH:7]=[CH:27][C:26]=1[OH:25])[C:10]([NH:21][NH:20][C:18]([C:8]1[O:9][CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19])=[O:9])#[N:15]
Reactant: CCOC(C)=O
Reactant: NNC(=O)c1occ(-c2ccncc2)c1-c1ccccc1
Product: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccncc3)c2-c2ccccc2)ccc1O
Reaction time: 8 h

Procedure:
A mixture of 3-phenyl-4-(4-pyridyl)-2-furancarboxylic acid hydrazide (compound of Reference Example 11, 0.28 g) and the compound of Reference Example 63 (0.33 g in ethyl acetate (10 ml) was heated at reflux while stirring overnight. The thus-precipitated crystals were collected by filtration and recrystallized from ethyl acetate, thereby giving 0.02 g of the desired compound. Melting point: 179-181° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[C:15](Br)[CH:16]=1)[NH:13][C:12]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1)=[C:11]2[C@H:26]([CH3:29])[CH2:27][NH2:28])([CH3:7])[CH3:6])[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1)=[C:11]2[C@H:26]([CH3:29])[CH2:27][NH2:28])([CH3:7])[CH3:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)c1cc(Br)c2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CN)c2c1
Agent: [Pd]
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CN)c2c1
Temperature: 25 °C
Yield: 103.4 %

Procedure:
To a solution of (S)-2-[3-(2-amino-1-methylethyl)-7-bromo-2-(3,5-dimethylphenyl)-1H-indol -5-yl]-2-methyl propionic acid ethyl ester (79 mg in 1 mL methanol) was added 8 mg of 10% palladium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 7 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel (chloroform:methanol, 92:8) to provide the title compound (68 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[CH3:12])[C:2]([O:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:3][CH:4]=[CH:5]2
Reactant: COc1cc2ccnc(Cl)c2cc1C
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COc1cc2ccnc(Oc3ccccc3)c2cc1C
Yield: 19.6 %

Procedure:
A mixture of 1-chloro-6-methoxy-7-methyl-isoquinoline (9 g, 43.48 mol), phenol (16.3 g), potassium hydroxide (9.45 g) and xylene (100 ml) was refluxed for 4 days. The reaction mixture was poured out into aqueous sodium hydroxide (4 M) and the xylene layer separated. The aqueous layer was extracted twice with toluene. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give a residue. The residue was purified by flash chromatography using dichloromethane gave 6-methoxy-7-methyl-1-phenoxyisoquinoline (9 g, 33.96 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[Br:35][CH2:36][C:37](Cl)=[O:38]>C(Cl)Cl>[Br:35][CH2:36][C:37]([NH:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1)=[O:38]
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CBr)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of (2R)-2-[(4-aminobenzyl)-(4-chloro-benzenesulfonyl)amino]-4-methyl-pentanoic acid amide (248 mg, 0.56 mmol) and Et3N (176 mg, 1.74 mmol) in CH2Cl2 (3 mL) was added bromoacetylchloride (105 mg, 0.67 mmol). The reaction mixture was stirred overnight at rt. The reaction mixture was diluted with CH2Cl2 (5 mL), washed with 1 N HCl, brine, and dried through a cotton plug. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% acetone/CH2Cl2) afforded the title compound (124 mg) in 42% yield. MS (ESI), (M+H)+ 531.86, 1H NMR (CDCl3, 400 MHz) δ 8.78 (br s, NH), 7.95 (d, 2H, J=8.0), 7.82 (d, 2H, J=8.0), 7.42 (d, 2H, J=8.0), 7.33 (d, 2H, J=8.0), 6.20 (br s, 1H), 5.20 (br s, 1H), 4.30 (s, 2H), 4.22 (d, 1H, Jab=16), 4.14 (d, 1H, Jab=16), 3.25 (t, 1H, J=6.0), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.ClC1C=C(Cl)C(Cl)=CC=1O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:45]1[CH2:52][CH2:51][CH2:50][C@H:46]1[C:47]([OH:49])=[O:48].C(N(CC)CC)C>C(OCC)(=O)C>[N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([N:45]1[CH2:52][CH2:51][CH2:50][C@H:46]1[C:47]([OH:49])=[O:48])=[O:5]
Reactant: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cbz-D-hPro-OH (9.5 g, 36 mmol) was dissolved in ethyl acetate (100 mL) and the solution cooled to 0° C. Added to the solution was 2,4,5-trichlorophenol (7.1 g, 36 mmol) and 1,3-dicyclohexylcarbodiimide (7.4 g, 36 mmol). The reaction was stirred for 1 hour at 0° C. and 1 hour at room temperature. The precipitate was filtered and the filtrate concentrated in vacuo to an oil. The oil was dissolved in pyridine (100 mL), Pro-OH (4.2 g, 36 mmol), and triethylamine (5.0 mL, 36 mmol) were added. The reaction was stirred at room temperature (24 hours). The reaction solvent was removed in vacuo to an oil. The residue was dissolved in water (100 mL), diethyl ether (50 mL) was added and the pH adjusted to 9.5 with 2N sodium hydroxide. The aqueous layer extracted twice with diethyl ether. The aqueous layer separated, the pH adjusted to 2.8 with 3N hydrochloric acid and ethyl acetate (150 mL) was added. The organic layer was separated, dried (MgSO4), and the filtrate evaporated in vacuo to an amorphous solid (11.4 g, 88%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10]([C:12]1[C:13]([NH2:21])=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:11].N1C=CC=CC=1.Cl>ClCCl>[CH3:8][O:9][C:10]([C:12]1[C:13]([NH:21][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:11]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1ccc2c(c1N)CCC2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1NC(=O)OC(C)C)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
Add isopropyl chloroformate (2.22 mL, 2.22 mmol, 1.0 M in toluene) dropwise to a solution of 4-Amino-indan-5-carboxylic acid methyl ester (425 mg, 2.22 mmol) and pyridine (0.44 mL, 5.5 mmol) in dichloromethane (4.4 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 24 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure, to afford the title compound (576 mg, 93%): 1H NMR (MeOD) δ 1.37 (d, J=6.5 Hz, 6H), 2.16 (quintuplet, J=7.7 Hz, 2H), 2.97 (t, J=7.3 Hz, 2H), 3.05 (t, J=7.3 Hz, 2H), 3.94 (s, 3H), 4.97 (m, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H). MS (ES+): 278 (M+H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12])=[N+:2]=[N-:3].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15]>>[F:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[CH2:4][N:1]1[CH:15]=[C:14]([C:13]([O:17][CH3:18])=[O:16])[N:3]=[N:2]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C#CC(=O)OC
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
reacting 2-(azidomethyl)-1,3-difluorobenzene of formula III with methyl propiolate to obtain methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate of formula IV; and
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1B(O)O.[I:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1>[Cu]Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:16]1[CH:17]=[C:13]([I:12])[N:14]=[CH:15]1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Ic1c[nH]cn1
Agent: Cl[Cu]
Solvent: CO
Product: Fc1ccc(F)c(-n2cnc(I)c2)c1
Yield: 19.7 %

Procedure:
Following a procedure similar to that outlined in Chem. Comm. 2004, 188-189: A solution of 2,5-difluorophenylboronic acid (47 mg, 0.30 mmol), 4-iodo-1H-imidazole (46 mg, 0.24 mmol), copper(I) chloride (1.8 mg, 0.018 mmol), and 1 mL of methanol was stirred under air at 60° C. for 3 h, then concentrated. Column chromatography (0-33% EtOAc/hexanes) afforded 14.5 mg (20%) of 1-(2,5-difluorophenyl)-4-iodo-1H-imidazole as a white solid.
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: Cc1ccccc1C
Solvent: O
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: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22]Br.O>CN(C=O)C>[F:17][C:18]([F:31])([F:32])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH2:22][O:4][CH2:3][C@@H:2]([NH:1][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
D-serine (25 g, 238 mmol) and triethylamine (35 mL, 250 mmol) were dissolved in water (400 mL), and Boc2O (50 g, 230 mmol) was added thereto and stirred at room temperature for 20 hours. The reaction mixture was washed with ethyl acetate (200 mL×2). The aqueous layer was acidified with 2 mol/L HCl to pH 2 and extracted with ethyl acetate (200 mL×5). The organic extract was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation under reduced pressure to give Boc-D-Ser (44.4 g, 91%) as a colorless oil. Resulting Boc-D-Ser (44.4 g, 216 mmol) was dissolved in DMF (500 mL) and the mixture was cooled in an ice bath to 0° C. and then, NaH (18.4 g, 460 mmol) was added thereto in several portions. The mixture was stirred at 0° C. for 2 hours, and a solution of 3,5-bis(trifluoromethyl)benzyl bromide (42 mL, 230 mmol) in DMF (100 mL) was added dropwise thereto for a period of 30 min. After stirring at 0° C. for 2 hours and at room temperature for 20 hours, the reaction was stopped by adding water (1 L) thereto. The mixture was washed with hexane (250 mL×2) and acidified with 2 mol/L HCl to pH 2. After extracting with ethyl acetate (250 mL×4), the organic extract was washed with water and saturated brine in order and dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation under reduced pressure to give (2R)-3-(3,5-bis(trifluoromethyl)benzyloxy)-2-tert-butoxycarbonylaminopropionic acid (76.6 g, 82%) as a pale brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].IC.[C:13](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(F)ccc1O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(F)cc1C=O

Procedure:
20.0 g (0.143 mol) of 5-fluoro-2-hydroxybenzaldehyde are dissolved in 250 ml of acetonitrile. 81.04 g (0.57 mol) of iodomethane and 39.5 g (285 mol) of potassium carbonate are added, and the suspension is heated at reflux for 3 hours. The suspension is filtered and the mother liquor is diluted with ethyl acetate, washed twice with water, dried over magnesium sulphate and filtered, and the solvents are evaporated under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:16][CH:13]1[CH2:15][CH2:14]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: NC1CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2cnccc2nc1NC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (3.55 g, 17.75 mmol) in dioxane (71.0 mL) at room temperature was treated with cyclopropanamine (1.63 mL, 23.07 mmol), followed by dropwise addition of DIPEA (6.51 mL, 37.3 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. Purification by flash silica gel chromatography using a gradient of 25% to 100% EtOAc in hexanes gave the title compound (3.15 g, 80%) as an orange solid. ESI-MS m/z [M+H]+ 221.1.
Reaction SMILES: C1(CC(N[C@H](C(=O)N)CCC(O)=O)=O)C=CC=CC=1.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35]>>[C:20]1([CH2:26][C:27]([NH:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: NC(=O)[C@H](CCC(=O)O)NC(=O)Cc1ccccc1
Product: NC(=O)CC[C@H](NC(=O)Cc1ccccc1)C(=O)O

Procedure:
Phenylacetylisoglutamine can be synthesized by the reaction of phenylacetyl chloride with L-glutamine to yield phenylacetylglutamine, with subsequent heating under vacuum at 160° C. to yield 3-phenylacetylamino-2,6-piperidinedione, which can then be treated with sodium hydroxide. Also, phenylacetylisoglutamine can be prepared by treatment of phenylacetic acid with N,N′-disuccinimidyl carbonate in acetonitrile followed by reaction with L-isoglutamine in the presence of NaHCO3 in a 1:1 acetonitrile/water mixture. However, the second synthesis requires L-isoglutamine, which is expensive, so the former route of synthesis is preferred on economic grounds. In either synthetic pathway, D-glutamine or a racemic mixture of glutamine stereoisomers can be used in place of L-glutamine, or D-isoglutamine or a racemic mixture of isoglutamine stereoisomers can be used in place of L-isoglutamine, yielding the corresponding optical isomer of phenylacetylglutamine. Either optical isomer of phenylacetylisoglutamine, or a mixture thereof in any proportion, can be used in the present invention.