Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]1[NH:17][CH:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[C:15]2[C:14](=[O:26])[CH2:13][CH2:12][CH2:11][C:10]=2[N:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.Br[CH2:38][CH:39]1[CH2:43][CH2:42][O:41][CH2:40]1>CN(C)C=O>[F:35][C:33]([F:36])([F:34])[C:29]1[CH:28]=[C:27]([N:9]2[C:10]3[CH2:11][CH2:12][CH2:13][C:14](=[O:26])[C:15]=3[CH:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=3)[N:17]([CH2:38][CH:39]3[CH2:43][CH2:42][O:41][CH2:40]3)[C:8]2=[O:7])[CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: BrCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (67 mg, 0.486 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 100 mg, 0.243 mmol) in N,N-dimethylformamide (3 mL). 3-(Bromomethyl)tetrahydrofuran (60 mg, 0.365 mmol) is added, and the mixture is stirred at room temperature for 1 h and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 12 mg; ESI mass spectrum [M+H]+=496; Retention time HPLC: 0.91 min (Z011_S03).
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:19])[CH2:8]/[CH:9]=[CH:10]/[C@H:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni].C(OCC)(=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][CH:11]([CH3:18])[CH2:10][CH2:9][CH2:8][CH:7]([CH3:19])[CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17]
Reactant: [H][H]
Reactant: CCOC(=O)C[C@@H](C)/C=C/C[C@@H](C)COC(C)(C)C
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)CCCC(C)COC(C)(C)C

Procedure:
A mixture of 1.104 g. (4.084 mmoles) of (3R,7R)-E-Ethyl 8-tert. butoxy-3,7-dimethyl-4-octenoate, a small amount of Raney nickel, and 30 ml. of ethyl acetate was stirred in an atmosphere of hydrogen, at room temperture, for 2 hours during which time approximately one equivalent of hydrogen was taken up. The catalyst was filtered off and washed with ethyl acetate. Concentration of the combined filtrate and washes in vacuo followed by evaporative distillation afforded 1.045 g. (95%) of saturated ester (3S,7R)-Ethyl 8-tert. butoxy-3,7-dimethyloloctanoate as a colorless oil, b.p. 80°-83° C. (bath temperature) (0.15 mm Hg.).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH3:24])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 5.18 (2H, s), 5.77 (1H, d, J=2.0 Hz), 7.18-7.22 (2H, m), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=1.2 Hz, J=5.2 Hz), 7.58 (1H, d, J=2.0 Hz), 8.00 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13ClN4O, 325. Found, 325.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1>>[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]4[CH2:24][C:23]5[CH:22]=[CH:21][N:20]=[CH:19][C:18]=5[CH2:17]4)=[O:15])=[CH:9][CH:8]=3)[CH2:5][CH2:6]2)[CH2:27][CH2:26]1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Reactant: O=CC1CCOCC1
Product: O=C(Nc1ccc(C2CCN(CC3CCOCC3)CC2)cc1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 926, substituting N-(4-(piperidin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide and tetrahydro-2H-pyran-4-carbaldehyde for isobutraldehyde. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.33 (s, 1H), 7.44 (m, 3H), 7.12 (m, 2H), 4.79 (m, 4H), 3.83 (m, 2H), 3.27 (m, 2H), 2.92 (m, 2H), 2.40 (m, 1H), 2.14 (d, J=7.2 Hz, 2H), 1.95 (m, 2H), 1.74 (m, 3H), 1.61 (m, 4H), 1.12 (m, 2H); MS (ESI(+)) m/e 421 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:36](=[O:37])[C:30]2[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=2)[C:39]1=[O:38]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3cc(-c4ccc(Cl)c(C)c4)ccc3o2)cc1N
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)c(C)c4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole (79 mg, 0.22 mmol) and 1,2,4-benzenetricarboxylic anhydride (42 mg, 0.22 mmol) the title compound was obtained (22 mg, 19%). 1H NMR (DMSO) δ 8.55(dd, 1H), 8.44(m, 3H), 8.22(d, 1H), 8.14(m, 1H), 7.90(m, 3H), 7.65(m, 3H), 4.00(s, 3H), 2.45(s, 3H). MS 527 m/z (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:18]=[CH:17][C:10]([CH:11]=[N:12][O:13][CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:18]=[CH:17][C:10]([CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCON=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc(-c4ccccc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86.3 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 483 mg of 2-(4-phenylbenzylideneaminooxy)ethanol (prepared as described in Preparation 9), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 914 mg of the title compound were obtained as a crystalline powder, melting at 157°-159° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].O[C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>O1CCCC1.C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][C@H:41]([O:44][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)[CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccnc2)C1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
Under a nitrogen atmosphere, diethyl azodicarboxylate (4.65 g, 26.70 mmol) was added to a cold (0-5° C.), stirring solution of triphenylphosphine (7.00 g, 26.70 mmol) in dry tetrahydrofuran (60 mL, distilled from sodium and benzophenone). The mixture was stirred at 0-5° C. for 15 min. The resulting yellow solution was treated drop-wise at 0-5° C. with a solution of (3R)-N-(tert-butoxycarbonyl)-3-hydroxypyrrolidine (2.50 g, 13.35 mmol) in dry THF (20 mL) producing a thick yellow mixture. At 0-5° C., 3-hydroxypyridine (2.54 g, 26.70 mmol) was added in one portion. The resulting yellow solution was allowed to stir and warm to ambient temperature over 24 h. The solution was diluted with CH2Cl2 (150 mL) and washed with saturated K2CO3 solution (2×100 mL). The combined CH2Cl2 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation and briefly dried under high vacuum to give a viscous, light-yellow gel. The crude product was purified by column chromatography on silica gel (302 g), eluting with CHCl3—CH3OH (95:5, v/v). Selected fractions containing the product (Rf 0.44) were combined and concentrated to afford 2.50 g of a light-yellow oil, that contained solids. Impure fractions were combined and concentrated to give 16 g of solids. The solids were triturated with pentane (4×75 mL) in an ultrasonic bath, and the pentane filtrate was concentrated to give 3.40 g of an oil. The oil was chromatographed on silica gel (180 g), eluting with CHCl3-acetone (4:1, v/v). Selected fractions containing the product (Rf 0.29) were combined and concentrated to afford 1.23 g of a light-yellow oil. The 2.50 g lot was triturated with pentane (2×50 mL) in an ultrasonic bath and the pentane filtrate was concentrated. The resulting oil was purified by column chromatography on silica gel (50 g), eluting with CHCl3-acetone (4:1, v/v). Selected fractions containing the product were combined and concentrated to give 0.58 g of a light-yellow oil. Impure fractions from the latter column were combined and concentrated, and the residue was chromatographed on silica gel (50 g) to give 0.28 g of a light-yellow oil. All purified materials were combined, concentrated and dried under high vacuum to yield 1.83 g (51.9%) of a light-yellow oil.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([C:19]1[CH:27]=[CH:26][C:22](C(O)=O)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:22]1[CH:21]=[CH:20][C:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:27][CH:26]=1)[CH3:4])#[N:2]
Reactant: CCCCCCc1ccc(C(=O)O)cc1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: CCCCCCc1ccc(C(=O)N[C@@H](C)C#N)cc1

Procedure:
General procedure D was used to deprotect 0.210 g (1.23 mmols) of 4. The product was immediately carried on using general procedure F and coupled to 1.23 mmols of 10. The title product was purified with flash chromatography using a solvent system of ethyl acetate and hexanes (1:3) to yield 0.106 g (0.41 mmols). 1H NMR (500 MHz, CDCl3) δ 7.74-7.68 (m, 2H), 7.25 (d, J=8.2, 2H), 6.61 (s, 1H), 5.20-5.11 (m, 1H), 2.70-2.61 (m, 2H), 1.66 (t, J=6.6, 3H), 1.60 (dd, J=7.3, 14.9, 2H), 1.37-1.22 (m, 6H), 0.88 (t, J=6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 173.95, 166.58, 148.00, 148.00, 131.31, 129.95, 128.78, 128.62, 127.20, 127.03, 119.42, 77.27, 77.02, 76.76, 52.57, 48.42, 36.24, 35.85, 31.63, 31.10, 28.87, 22.56, 19.57, 18.68, 14.07.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:10]([CH:12]([CH2:19][S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH:12]([CH2:19][S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)(=[O:21])=[O:22])[C:10]([N:9]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:8][C:6]([OH:7])=[O:5])=[O:11])=[O:16]
Reactant: CCCCCN(CC(=O)OC(C)(C)C)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(CC(=O)O)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
Methyl 4-(N-tert-butoxycarbonylmethyl-N-pentylcarbamoyl)-5-(2-naphthylsulfonyl)pentanoate (0.47 g) was dissolved in trifluoroacetic acid (5 ml) at 0° C., and stirred at room temperature for 2 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was purified by flash column chromatography on silica eluting with chloroform/methanol (15:1) to give 0.34 g of N-[2-(2-methoxycarbonylethyl)-3-(2-naphthylsulfonyl)propionyl]-N-pentylglycine as an amorphous solid. ##STR18##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[Cl:23])[O:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[Cl:24])[CH3:2].C=O.[C:28]([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([C:7]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[Cl:23])[O:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[Cl:24])[CH3:28])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)CNc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)CN(C)c1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a yellow mixture of (2-chloro-5-[5-(3-chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamino)-acetic acid ethyl ester (0.360 g, 0.903 mmol), paraformaldehyde (0.271 g, 9.03 mmol) and glacial acetic acid (4.5 mL) was added sodium cyanoborohydride (0.284 g, 4.51 mmol) in small portions over 5 min. The yellow mixture became a white suspension and was stirred overnight at room temperature. The white suspension was added to a 25% NaOH(aq) solution at 0° C. The aqueous layer was extracted with dichloromethane (50 mL), washed with brine (15 mL), dried over MgSO4, filtered and concentrated in vacuo. The clear oil was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:5) to yield 0.362 g (96%) of the title compound as a white solid. 1H NMR (CDCl3): 7.94 (d, 1H, J=1.7 Hz), 7.73 (td, 1H, J=8.2, 1.9 and 1.7 Hz), 7.61 (dd, 1H, J=5.5, 5.2, 1.6 and 1.4 Hz), 7.45 (dd, 1H, J=8.5 and 1.4 Hz), 7.13 (dd, 1H, J=5.5, 5.2, 1.6 and 1.4 Hz), 4.18 (q, 2H, J=7.1 Hz), 4.04 (s, 2H), 3.07 (s, 3H), 1.26 (t, 3H, J=7.1 Hz).
Reaction SMILES: [ClH:1].[C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[C:18](/[CH:21]=[CH:22]/[CH2:23][N:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][C:15]=3[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[H][H]>O1CCCC1.[C].[Pd]>[ClH:1].[C:2]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[C:18]([CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][C:15]=3[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CN(C)C/C=C/c1ccc2c(c1)N(C(=O)c1ccc(-c3ccccc3)cc1)CCCC2
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCCc1ccc2c(c1)N(C(=O)c1ccc(-c3ccccc3)cc1)CCCC2

Procedure:
Palladium-carbon (200 mg) was added to a solution of (E)-3-[1-([1,1′-biphenyl]-4-ylcarbonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl]-N,N-dimethyl-2-propen-1-amine (238 mg, 0.580 mmol) obtained in Example 2 in tetrahydrofuran, and the mixture was stirred in a hydrogen atmosphere for 1.5 days. The catalyst was filtered off, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=3:1). 4 N hydrogen chloride in ethyl acetate was added to the resultant oily matter, and the formed crystals were washed with diethyl ether, whereby the title compound (97.9 mg) was obtained as colorless powder with a mp. of 84 to 86° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12](O)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=2)[CH:19]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(-c3ccc(OC)c(F)c3)cc2c1
Product: COc1ccc2c(Cl)nc(-c3ccc(OC)c(F)c3)cc2c1
Yield: 73.2 %

Procedure:
A solution of 3-(3-fluoro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (1.2 g, 4.01 mmol) in POCl3 (5.61 ml, 60.1 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum to give 1-chloro-3-(3-fluoro-4-methoxyphenyl)-6-methoxyisoquinoline (933 mg, 95% yield). δ ppm 1H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J=9.3 Hz, 1H), 7.90-7.87 (m, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.27-7.23 (m, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.10-7.04 (m, 1H), 3.98 (d, J=6.0 Hz, 6H); MS: MS m/z 318.1 (M++1).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[C:24]([C@@H:28]2[CH2:30][O:29]2)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>CC(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:30][C@@H:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=1)[OH:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCOCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1cccc([C@@H]2CO2)c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc([C@@H](O)CN(CCOCc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 133.8 %

Procedure:
N-Benzyl-2-(benzyloxy)ethane amine (13.6532 g) which can be prepared according to the method described in Reference example 56, etc. was added with (R)-2-(3-nitrophenyl)oxirane (20.21 g) and 2-propanol (205 mL), followed by stirring for 36 hours at reflux. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Toluene (100 mL) was added to the residue and the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-D”; n-hexane:ethyl acetate=85:15→80:20) to obtain the title compound (30.761 g).
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:11])[NH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:13]#[N:14].O.[C-]#N.[Na+]>CN(C=O)C>[C:13]([C:2]1[C:7]2[C:8](=[O:11])[NH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:14]
Reactant: O=c1[nH]oc2cccc(Br)c12
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2o[nH]c(=O)c12
Temperature: 165 °C
Reaction time: 6.5 h
Yield: 51.6 %

Procedure:
To a solution of 4-bromo-1,2-benzoxazolinone (5.0 g, 23 mmol) in DMF (11 mL) was added copper (I) cyanide (3.6 g, 39 mmol) and the reaction heated at 165° C. After 6.5 h, the reaction mixture was cooled to rt and water (20 mL) and sodium cyanide (3.6 g) were added and the reaction heated at 100° C. After 12 h, the reaction mixture was extracted with ethyl acetate and the combined organic layers were filtered through a scrub pad of silica gel eluting with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1.9 g (51%) of 4-cyano-1,2-benzoxazolinone as a brown solid which required no further purification. 1H NMR (400 MHz, DMSO) δ 7.8 (s, 1H), 7.6 (d, 1H), 7.2 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[N:10]=1.C(N(CC)CC)C.[F-].[K+].Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[N:10]=1)=[O:4]
Reactant: Nc1cccc(Br)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(Br)n1
Reaction time: 42 h
Yield: 383.9 %

Procedure:
Trimethylacetyl chloride (180.9 g, 1.500 mols) was added over 1 h to a mixture of 2-amino-6-bromo-pyridine (264.7 g, 1.530 mols), triethylamine (166.7 g, 1.650 mols) and toluene (1 L, KF=2 mg moisture/L) maintaining the temperature below 50° C. The mixture was aged at 25° C. for 42 h. A solution of 1M aqueous HCl (500 mL) was added and the biphasic mixture was filtered (after agitation for 5 min) through a pad of solka floc (10 g) which was washed with toluene (50 mL). The organic phase was separated from the filtrates and was washed with 1M aqueous HCl (2×500 mL), 2% aqueous NaCl (500 mL) and a mixture of saturated aqueous NaCl (250 mL) and saturated aqueous NaHCO3 (25 mL). The organic phase was dried over MgSO4 (10 g), filtered and evaporated to dryness to provide 380.7 g of crude title compound, which was diluted with toluene to give 1480.8 g of crude solution.
Reaction SMILES: [NH3:1].C([O:5][CH2:6][C@@H:7]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([NH:24][C@@H:25]([C@H:30]([OH:32])[CH3:31])[C:26]([O:28]C)=[O:27])=[O:23])=[O:16])=[O:9])(=O)C>>[CH2:37]([O:36][C:34](=[O:35])[NH:33][C@H:7]([CH2:6][OH:5])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:23])[NH:24][C@@H:25]([C@H:30]([OH:32])[CH3:31])[C:26]([O:28][NH2:1])=[O:27])=[O:16])=[O:9])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](COC(C)=O)NC(=O)OCc1ccccc1)[C@@H](C)O
Product: C[C@@H](O)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](CO)NC(=O)OCc1ccccc1)C(=O)ON
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
A solution of methanolic ammonia (3 mL) was added to compound 5 (0.28 g, 0.47 mmol) and stirred at RT for 18 h. The volatiles were evaporated under reduced pressure to afford compound 6 (0.21 g, 82.3%).
Reaction SMILES: C([N:8]([C@H:20]([CH2:41][OH:42])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:40])[C:30]2[CH:39]=[CH:38][C:33]([C:34]([NH:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:42][CH2:41][C@@H:20]([NH:8][CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:40])[C:30]2[CH:39]=[CH:38][C:33]([C:34]([NH:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[CH:26][CH:27]=1
Reactant: CNC(=O)c1ccc(C(=O)Nc2ccc(C[C@@H](CO)N(Cc3ccccc3)C[C@H](O)COc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ccc(C(=O)Nc2ccc(C[C@@H](CO)NC[C@H](O)COc3ccccc3)cc2)cc1
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of N1-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-N4-methylterephthalamide (14.0 mg) in methanol (0.5 ml) was added 10% palladium on activated carbon (50% wet, 14.0 mg) and the mixture was hydrogenated at 1 atm for 3 hours. The catalyst was filtered off and washed with methanol. The filtrate was concentrated in vacuo to give N1-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]-phenyl]-N4-methylterephthalamide (9.7 mg) as a white solid.
Reaction SMILES: O.O.O.O.[C:5]([O-:8])(=[O:7])[CH3:6].[Co+2:9].[C:10]([O-:13])(=[O:12])[CH3:11]>C(O)CO>[C:5]([O-:8])(=[O:7])[CH2:6][OH:12].[Co+2:9].[C:10]([O-:13])(=[O:12])[CH2:11][OH:7]
Reactant: CC(=O)[O-]
Agent: [Co+2]
Solvent: O
Solvent: OCCO
Product: O=C([O-])CO

Procedure:
A cobalt solution was obtained by dissolving cobalt acetate tetrahydrate (CoAc.4H2O, 4 g) in ethylene glycol (36 g) to produce a cobalt glycolate solution containing 10% cobalt acetate tetrahydrate. After stirring for 60 minutes, large particles dissolved, it became uniform red purple solution. A portion (9 g) of the cobalt acetate tetrahydrate solution and 1 g of a phosphoric acid solution (10% H3PO4 in ethylene glycol) were mixed in an open glass beaker. After shaking, flocculates in dark bluish purple formed in the bottom of the glass beaker. After 10 days, top 3 ml was red liquid mainly ethylene glycol, bottom 7 ml was dark purple flocculates.