Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:20][CH2:21][C:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[CH:28][C:27]=1[F:42])([CH3:25])[CH2:23][OH:24]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH2:21][OH:20])[CH2:23][OH:24])=[C:27]([F:42])[CH:28]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1F
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(CO)(CO)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (195 mg, 0.62 mmol, 1.0 eq) in DMF (10 mL) was added TEA (190 mg, 1.24 mmol, 2.0 eq) followed by phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)-3-fluorophenylcarbamate (200 mg, 0.62 mmol, 1.0 eq) at RT and the mixture was stirred for 16 h at 50° C. The reaction mixture was concentrated under vacuum and the residue purified by neutral alumina column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxy-2-methylpropan-2-yl)-3-fluorophenyl)urea (170 mg; 54%) as a white solid (TLC system: MeOH/CHCl3 (1:9); Rf: 0.45).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].[BH4-].[Na+]>ClCCl.CO>[N:5]1([CH2:4][CH2:3][CH2:2][NH:1][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: NCCCn1ccnc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: c1ccc(CNCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
A mixture of 1-(3-aminopropyl)imidazole (Aldrich, 37.1 g, 297 mmol), benzaldehyde (30 g, 283 mmol), 3 Å molecular sieves (50 g), sodium acetate (24.1 g, 283 mmol) and anhydrous methanol (700 mL) are stirred at room temperature under N2 overnight. The mixture is cooled to 0° C. and sodium borohydride (10.9 g, 288 mmol) is added portionwise over 1 hour. The mixture is stirred at room temperature for 3 hours. The mixture is filtered through celite, washed with methanol, and concentrated in vacuo to give a residue which is diluted with dichloromethane and washed with 10% aqueous sodium hydroxide. The organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (56.3 g, MH+=216).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].[C:13]([O:22][CH3:23])(=[O:21])[C:14]([CH2:16][C:17](OC)=[O:18])=[CH2:15]>>[CH3:23][O:22][C:13]([CH:14]1[CH2:16][C:17](=[O:18])[N:12]([CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)[CH2:15]1)=[O:21]
Reactant: NCC1COc2ccccc2O1
Reactant: C=C(CC(=O)OC)C(=O)OC
Product: COC(=O)C1CC(=O)N(CC2COc3ccccc3O2)C1

Procedure:
The title compound was prepared using 200 mg (1.21 mmol) of 2,3-dihydro-benzo[1,4]dioxin-2-ylmethylamine and 0.17 mL (1.21 mmol) of dimethyl itaconate according to the procedure for substituted pyrrolidines described in J. Org. Chem. 26 (1961) 1519-1524. Purification by column chromatography (silica gel, heptane/ethyl acetate, 1:2) afforded the pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[O:29]1[C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=[N:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:34]([C:33]3[O:29][N:30]=[CH:31][CH:32]=3)=[O:35])[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Reactant: O=C(Cl)c1ccno1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(C(=O)c3ccno3)CC2)C1

Procedure:
Compound 763 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and isoxazole-5-carbonyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%–20%–30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0268 g, 22% yield). HRMS (M+H) calcd for C23H26N5Cl2O5: 522.13111. found: 522.1312.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH3:13][NH:14][CH2:15][CH2:16][C:17]#[N:18].O>CN(C)C=O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([N:14]([CH2:15][CH2:16][C:17]#[N:18])[CH3:13])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CNCCC#N
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCC#N)C(=O)c1ccccc1N
Reaction time: 6 h

Procedure:
To Isatoic Anhydride (4.60 g, 28.2 mmol) in N,N-Dimethylformamide (30 mL) was added 3-Methylamino-propionitrile (3.00 mL, 32.1 mmol) and the reaction was stirred under an atmosphere of Nitrogen. After 6 h, the mixture was poured into 200 mL water, then extracted 3×100 mL DCM, washed with 100 mL satd. sodium bicarbonate, which was back extracted with 50 mL DCM. The combined organics were washed with brine (100 mL) and dried over sodium sulfate, then conc. in vacuo afforded 2-Amino-N-(2-cyano-ethyl)-N-methyl-benzamide as an oil in quantitative yield. 1H-NMR: 7.18 (dd, 1H, J=9.0, 9.0 Hz), 7.13 (d, 1H, J=7.3 Hz), 6.74 (m, 2H), 4.31 (br s, 2H), 3.76 (t, 2H, J=6.6 Hz), 3.15 (s, 3H), 2.75 (t, 2H, J=6.6 Hz).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:39][O:40][C:41]1[CH:42]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:45][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:43]4[CH:44]=[N:45][CH:46]=[C:41]([O:40][CH3:39])[CH:42]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc2nc(-c3ccnc(Cl)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cncc(-c2cc(-c3nc4cc(C)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(-c5ccc(Cl)cc5)c4s3)ccn2)c1
Temperature: 110 °C

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (40.0 mg, 0.070 mmol), 5-methoxy-3-pyridineboronic acid pinacol ester (19.7 mg, 0.084 mmol), potassium carbonate (29.0 mg, 0.210 mmol), and Pd(PPh3)4 (12.1 mg, 0.010 mmol) were placed in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (0.8 mL) and water (0.2 mL). The reaction mixture was heated at 110° C. for 1 h then cooled to rt. The aqueous layer was separated and extracted three times with ethyl acetate. All organic layers were combined, dried over Na2SO4, and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+: calc'd for C36H39ClN3O4S: 644.2 (M+H+); Found: 644.1 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.81 (d, J=4.9 Hz, 1H), 8.40 (d, J=2.7 Hz, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.83 (d, J=5.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 4.83 (dd, J=9.4, 2.7 Hz, 1H), 4.43 (dd, J=11.2, 9.5 Hz, 1H), 4.30 (dd, J=12.1, 2.9 Hz, 1H), 3.99 (s, 3H), 2.81 (s, 3H), 1.15 (s, 9H), 0.97 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12].ClC[CH:15]([O:18]C(CCl)CCl)CCl>ClCCl>[OH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:15]=[O:18])=[CH:11][C:2]=1[CH3:1]
Reactant: Cc1ccc2ccccc2c1O
Reactant: ClCC(CCl)OC(CCl)CCl
Solvent: ClCCl
Product: Cc1cc(C=O)c2ccccc2c1O
Reaction time: 0.75 h

Procedure:
2-Methyl-1-naphthol (7.0 g, 44.2 mmole) and 1,1-dichloromethyl-methyl ether (7.12 g, 61.9 mmol) were dissolved in dry dichloromethane (150 ml). To the stirred solution stannic chloride (20.72 g, 79.6 mmole) was added dropwise at -58°, the mixture stirred for 45 minutes, and warmed to +10°. It was poured onto ice-water (200 ml) and extracted with ethyl acetate (2×100 ml). The extract was washed with aqueous saturated sodium chloride solution, dried and evaporated. The residue solidified on trituration under diethyl ether:n-pentane (1:10) mixture, was filtered off and chromatographed on silica gel using dichloromethane as eluant to give 4-hydroxy-3-methyl-1-napthaldehyde as a buff coloured crystalline solid, (5.3 g, 64.4%), m.p. 160°-61°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:40][S:41]([NH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:43])=[O:42]
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNS(C)(=O)=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-[1-[2-[1-(2-aminoethyl) cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (synthesized in Example 18) (260 mg) in dichloromethane (3 mL) were added triethylamine (0.15 mL) and methanesulfonyl chloride (56 μL) successively. The solution was stirred at room temperature for 6 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3 to 1:1 to 1:2] to give the title compound (214 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][C:6]2=[O:13])[CH3:2].C(=O)(O)[O-].[Na+].O.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:8][CH2:7][C:6]2=[O:13])[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)CCN2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)C(=O)CCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of 6-ethyl-2,3-dihydroquinolin-4(1H)-one (1.25 g) in THF (15 mL) was added sodium bicarbonate (0.84 g). Water (5 mL) followed by benzyl chloroformate (1.58 g) were added to the mixture,and it was stirred at room temperature overnight. The reaction was not complete as determined by TLC, so an additional 0.60 g of NaHCO3 were added to the mixture and it was stirred at room temperature for two additional hours. The mixture was then concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated. Chromotography on silicia gel using 25% ethyl acetate in heptane solvent solution gave 1.84 g of the title compound. MS (ESI+) for C19H19NO3 m/z 310.03 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1Cl
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(F)c(Cl)c1

Procedure:
The title compound, off-white solid, m.p. 119° C. and MS: m/e=374.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:33])[CH2:17][C:18]4[CH:32]=[CH:31][C:21]5[N:22](C6CCCCO6)[CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[NH:22]1[C:21]2[CH:31]=[CH:32][C:18]([CH2:17][N:16]([CH3:33])[C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)=[CH:19][C:20]=2[N:24]=[CH:23]1
Reactant: CN(Cc1ccc2c(c1)ncn2C1CCCCO1)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CN(Cc1ccc2[nH]cnc2c1)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 80 °C

Procedure:
A tube was charged with a solution of 70 (444 mg, 1.0 mmol) in MeOH (5 mL) and water (1 mL) then TsOH.H2O (190 mg, 1.0 mmol) was added. The tube was sealed and heated at 80° C. overnight. The solvent was evaporated in vacuo and the residue was purified by preparative HPLC to afford 240 mg (66%) of I-12 as a white solid.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2][C:3]([OH:5])=O.[CH3:23][O:24][NH:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])[CH2:2][C:3]([N:25]([O:24][CH3:23])[CH3:26])=[O:5]
Reactant: CNOC
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Fmoc-Gly-OH, 1 g (3.36 mmol), 361.0 mg (3.70 mmol) of CH3ONHCH3 and 447.3 mg (3.53 mmol) of HOBt were dissolved in DMF. Under ice cooling, 677 mg (3.53 mmol) of WSCI.HCl and 1.94 mL (11.1 mmol) of DIEA were added to the solution, followed by stirring overnight. After the reaction solution was concentrated, 10% aqueous citric acid solution was added and the precipitated solid was extracted with AcOEt. The organic layer was washed with 10% aqueous citric acid solution, 5% NaHCO3 aqueous solution and satd. sodium chloride aqueous solution, and dried over anhydrous Na2SO4. The oily Fmoc-Gly-N(CH3)OCH3 product obtained by concentrating the solvent was dissolved in THF. Under ice cooling, 332 mg (0.726 mmol) of LiAlH4 was added by small portions to the solution over 15 minutes. After stirring at 0° C. for 30 minutes, 150 mL of diethyl ether and 150 mL of 20% citric acid aqueous solution were sequentially added to the reaction solution, which was then vigorously stirred for an hour. The organic layers were collected and the aqueous layer was again extracted with 150 mL of diethyl ether. The pooled organic layer was washed sequentially with 5% NaHCO3 aqueous solution, water, 10% citric acid aqueous solution, water and then satd. sodium chloride aqueous solution, and dried over anhydrous Na2SO4. The organic layer obtained was concentrated to give Fmoc-Gly-al as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([O:15][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH3:20])[C:11]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:10]=3[S:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
A mixture of 1.6 g of (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.69 g of benzoyl chloride, 5 ml of pyridine and 2 ml of benzene is stirred at room temperature for 2 hours. The mixture is poured into ice-water, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated under reduced pressure to remove solvent. 2.14 g of (±)-cis-2-(4-methylphenyl)-3-benzoyloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]1[C:11](=[O:12])O[C:8](=[O:9])[CH2:7]1)=[O:4].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17]>O1CCCC1>[CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:7][C:8](=[O:9])[N:17]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:20]=[C:19]([Cl:21])[CH:18]=2)[C:11]1=[O:12])=[O:4]
Reactant: COC(=O)N[C@H]1CC(=O)OC1=O
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
12.9 g of N-methoxycarbonylaspartic anhydride are dissolved in 100 ml of tetrahydrofurane, and to this solution is added a solution of 12 g of 3,5-dichloroaniline in 50 ml of tetrahydrofurane. The reaction solution is stirred for 4 hours at 50° C. and then evaporated to dryness in vacuo. The residue is dissolved in 80 ml of acetic anhydride and then 2.5 g of sodium acetate are added and the solution is stirred for 11/2 hours at 80° C. After cooling to room temperature, the reaction mixture is poured into water and stirred vigorously for 1/2 hour. The mixture is extracted with ethyl acetate and the extracts are washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over sodium sulfate, filtered and concentrated. Recrystallisation of the residue affords colourless crystals of the above compound with a melting point of 136°-138° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)(=[O:21])[CH3:20]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:19](=[O:21])[CH3:20])=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OCCCCBr
Reactant: CCCCOc1c(O)c2cc(O)ccc2oc1=O
Product: CCCCOc1c(O)c2cc(OCCCCOC(C)=O)ccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-butoxy-4,6-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 4-bromobutyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-butoxy-4-hydroxy-6-(4-acetoxybutoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.[CH3:14][O-:15].[Na+].CO>C(#N)C>[CH3:14][O:15][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[C:5]([O:12][CH3:13])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)n2nc(N)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1cnc(OC)n2nc(N)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
5-Chloro-8-methoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (4; 100 mg, 0.50 mmol) was suspended in acetonitrile (5 mL) at room temperature and treated with 25% sodium methoxide in methanol (200 mg, 2 eq). The resulting slurry was stirred at room temperature for 1.5 hours and then filtered. The solids were washed with water and dried to afford the title compound as a chalk-colored solid (87 mg, 88%) that was identical in HPLC retention to authentic 5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (5): mp 185-186° C.; 1H NMR (DMSO-d6) δ 7.48 (s, 1H), 6.38 (br s, 2H), 4.04 (s, 3H), 3.88 (s, 3H); EIMS m/z 195.
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](OCCCC)=[C:12](F)[CH:11]=2)=[CH:6][C:5]=1F)C.C([Li])CCC.[C:28](=[O:33])(OC)OC.Cl>CCCCCC.O1CCCC1>[C:28]1(=[O:33])[C:6]2[C:7]([C:10]3[C:11]([CH:5]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][CH:9]=[CH:4]1
Reactant: CCCCOc1ccc(-c2ccc(OCC)c(F)c2)cc1F
Reactant: COC(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: -70 °C
Reaction time: 2 h

Procedure:
60 mmol of 4-ethoxy-3,3′-difluoro-4′-butoxybiphenyl (5) are introduced into 200 ml of tetrahydrofuran, and the mixture is cooled to −70° C. 120 mmol of a 1.6 M solution of n-butyllithium in hexane are added dropwise, and the mixture is stirred at this temperature for 2 hours. 60 mmol of dimethyl carbonate are subsequently added rapidly with vigorous stirring, the mixture is stirred at −70° C. for a further hour, allowed to warm to 0° C., hydrolysed with dilute hydrochloric acid and subjected to conventional work-up.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:19]([CH:23]=2)[C:20](Cl)=[O:21])=[CH:3][CH:2]=1.[NH:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(OCC)(=O)C.CCCCCC>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:20](=[O:21])[C:19]1[CH:23]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:4]2[CH:5]=[CH:6][C:1]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:2][CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:44]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: O=C(Cl)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Yield: 74 %

Procedure:
The reaction of 5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2-(phenylmethoxy)benzoic acid chloride with diethyl iminodiacetate under conditions described in Example 80 gave, after purification by HPLC using 25% ethyl acetate-hexane, N-(2-ethoxy-2-oxoethyl)-N-[5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2-(phenylmethoxy) benzoyl]glycine ethyl ester (74% yield, mp 60°-62° ). The structure was confirmed by nmr and mass spectra.