Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:29])[C:13]2[O:19][C:18]3[C:20]([Cl:25])=[CH:21][C:22]([NH2:24])=[CH:23][C:17]=3[CH2:16][S:15](=[O:27])(=[O:26])[C:14]=2[CH:28]=1)=[O:9].N1C=CC=CC=1>ClCCl>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:29])[C:13]2[O:19][C:18]3[C:20]([Cl:25])=[CH:21][C:22]([NH:24][C:3](=[O:4])[CH2:2][Cl:1])=[CH:23][C:17]=3[CH2:16][S:15](=[O:27])(=[O:26])[C:14]=2[CH:28]=1)=[O:9]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reaction time: 2 h

Procedure:
Chloroacetylchloride (3.3 mL, 40.8 mmol) was added to the solution of compound of Example 1 (5 g, 13.6 mmol) in dichloromethane (100 mL) at 20° C. Pyridine (6.6 mL, 81.6 mmol) was added and the reaction mixture was stirred for 2 h. The solvent was removed under vacuum and water (200 mL) was added. The solid obtained was filtered, washed with water and purified by stirring in ethyl acetate (200 mL) at reflux condition for 30 min. The solid was filtered and dried to obtain the title compound. Yield: 4.86 g (80.1%); mp 292-293° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.27 (s, 2H, CH2), 5.34 (s, 2H, CH2), 7.67 (s, 1H, Ar), 7.88 (s, 1H, Ar), 8.11 (s, 1H, Ar), 8.15 (s, 1H, Ar), 10.70 (s, 1H, NH); MS: m/e (ES+) 445 (M+1); analysis: C18H15Cl2NO6S requires C, 48.66; H, 3.40; N, 3.15; Cl, 15.96; S, 7.22. found: C, 48.09; H, 3.37; N, 3.38; Cl, 16.37; S, 7.72%.
Reaction SMILES: CO[C:3]1([O:17]C)[CH2:6][C:5]([C:12]([O:14]CC)=[O:13])([C:7]([O:9]CC)=[O:8])[CH2:4]1.[C:19]1(C)C=CC(S(O)(=O)=O)=C[CH:20]=1.C(=O)(O)[O-].[Na+].O.[CH3:36][C:37](C)=O>>[CH2:19]([CH:4]1[C:3](=[O:17])[CH:6]([CH2:36][CH3:37])[C:5]1([C:12]([OH:14])=[O:13])[C:7]([OH:9])=[O:8])[CH3:20]
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(OC)(OC)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCC1C(=O)C(CC)C1(C(=O)O)C(=O)O
Temperature: 65 °C

Procedure:
A stirred mixture of diethyl 3,3-dimethoxycyclobutanedicarboxylate (10.36 g, 39.8 mmol) in acetone (95 ml) and p-toluenesulphonic acid (1.38 g, 8.02 mmol) was heated to 65° C. overnight. Further p-toluenesulphonic acid (200 mg, 1.16 mmol) and acetone (15 ml) were added and the temperature raised to 75° C. for 2 hours. The reaction was cooled to room temperature. The mixture was neutralised with aqueous sodium bicarbonate. Water (15 ml) was added and then extracted with dichloromethane (3×10 ml). The extracts were dried over magnesium sulphate, filtered and evaporated in vacuo to give a brown oil. The crude oil was distilled (bulb-to-bulb) to give diethyl 3,3-dicarboxycyclobutanone as an oil, b.p. 150-155° C./0.1 mm.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[C:16]1([CH2:22][C:23]([N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=[O:11])[C:10]3=[CH:1][S:2][CH:3]=[C:4]23)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1Nc2ccccc2Nc2cscc21
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2N(C(=O)Cc2ccccc2)c2cscc21
Reaction time: 3 h

Procedure:
A reaction mixture comprising 6.48 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 25 g. of phenylacetyl chloride in 100 ml. of benzene is refluxed with stirring for 3 hours. The mixture is evaporated to an amber oil, combined with 100 ml. of ethanol and 6 ml. of 5 N sodium hydroxide and allowed to stand at room temperature for one hour. This solution is evaporated to an oily residue which is triturated with water and filtered, giving the desired product as pale pink crystals, mp. 165°-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O-:13])(=[O:12])[CH3:11].[NH4+:14].C(O)(=O)CC(O)=O>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C@@H:6]([CH2:11][C:10]([OH:13])=[O:12])[NH2:14])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccc(Br)cc1
Reactant: [NH4+]
Agent: O=C(O)CC(=O)O
Solvent: CCO
Solvent: O
Product: N[C@H](CC(=O)O)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 63 %

Procedure:
p-Bromo-benzaldehyde (10.0 g, 54 mmol) was mixed with 100 ml of ethanol/water (95/5), 8.3 g of ammonium acetate (108 mmol), and 11.2 g of malonic acid (108 mmol), heated under reflux at 80° C. with stirring for 17 hours, filtered under heating and dried under reduced pressure to give 8.3 g of p-bromo-β-phenylalanine crystals at a yield of 62.8%.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([C@@H:9]([CH:13]2[CH2:15][CH2:14]2)[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[C:22]([NH2:26])=[CH:21][C:20]=1[CH3:27].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:26][C:22]2[C:23]([CH3:25])=[N:24][C:19]([O:18][CH3:17])=[C:20]([CH3:27])[CH:21]=2)[C:3](=[O:16])[N:4]([C@@H:9]([CH:13]2[CH2:15][CH2:14]2)[CH2:10][O:11][CH3:12])[CH:5]=1
Reactant: COc1nc(C)c(N)cc1C
Reactant: COC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H](C1CC1)n1cc(Cl)nc(Nc2cc(C)c(OC)nc2C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of (S)-3,5-dichloro-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-one (4.00 g, 15.2 mmol) from Part G and 6-methoxy-2,5-dimethylpyridin-3-amine (2.31 g, 15.2 mmol) from Part K in THF (76 mL) at 0° C. was added NaHMDS (31.9 mL, 31.9 mmol, 1 M in THF). The reaction mixture was stirred at room temperature for 1 h. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% 40% ethyl acetate in hexanes) to afford (S)-5-chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one (4.94 g, 86% yield) as a light-brown amorphous solid. Recrystallization from hexanes/ethyl acetate (1:1, 10 mL) to afforded a light-brown crystalline solid: mp 99-100.5° C.; [α]25D −52.3 (c 0.636, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.88 (s, 1H), 6.90 (s, 1H), 4.19-4.14 (m, 1H), 3.92 (s, 3H), 3.74 (dd, JAB10.3, JAX=6.2 Hz, 1H), 3.67 (dd, JBA=10.3, JBX=3.5 Hz, 1H), 3.34 (s, 3H), 2.41 (s, 3H), 2.17 (s, 3H), 1.31-1.24 (m, 1H), 0.80-0.73 (m, 1H), 0.62-0.56 (m, 1H), 0.53-0.47 (m, 1H), 0.36-0.30 (m, 1H); HRMS (ESI) m/e 379.1537 [(M+H)+, calcd for C18H24N4O3Cl 379.1537].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:34][CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-phenylethylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:30])[C@H:17]([N:27]=[C:28]=[O:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:33])[CH3:32]>ClCCl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:30])[C@H:17]([NH:27][C:28]([NH:33][CH2:31][CH3:32])=[O:29])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: COc1ccc(C[C@@H](N=C=O)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Product: CCNC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 42 %

Procedure:
1-[2-(R)-Isocyanato-3-(4-methoxyphenyl)-propionyl]-pyrrolidin-2-(S)-carboxylic acid benzyl ester (0.60 g) was dissolved under nitrogene in 20 mL of dichloromethane and ethyl amine was allowed to pass through at −20° C. for 5 minutes. The mixture was kept stirring for 16 h. The volatiles were pumped off and the remaining residue was purified by silica chromatography (dichloromethane/methanol 80/20) to give 0.29 g (42%) of the title compound as a colorless oil. (+)-APCI-MS: 454(MH+).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@:50]([C:59]2[CH:64]=[C:63]([O:65][C:66]([F:71])([F:70])[CH:67]([F:69])[F:68])[CH:62]=[C:61]([F:72])[CH:60]=2)([NH2:58])[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:46][C:45]=1[O:73][CH:74]([CH3:76])[CH3:75].CN1CCOCC1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH:58][C@:50]([C:47]1[CH:48]=[CH:49][C:44]([F:43])=[C:45]([O:73][CH:74]([CH3:76])[CH3:75])[CH:46]=1)([C:59]1[CH:64]=[C:63]([O:65][C:66]([F:71])([F:70])[CH:67]([F:69])[F:68])[CH:62]=[C:61]([F:72])[CH:60]=1)[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:6]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CC(C)Oc1cc([C@](N)(Cc2ccccc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)CCC(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 4,4,4-trifluorobutyric acid (13 mg, 0.09 mmol) in DCM (0:8 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (52 mg, 0.1 mmol), (R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (40 mg, 0.08 mmol), followed by NMM (28 μl, 0.25 mmol). The reaction mixture was stirred at room temperature for 16 h, then another 16 h at 60° C. The reaction mixture was diluted with EtOAc (10 mL) and the organic layer was washed with H2O, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC Phenomenex Luna C18 column, 30×50 mm eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm; 40-100% ACN (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2,-tetrafluoroethoxy)phenyl)-2-phenylethyl)butanamide (Example 312) was isolated as a lyophillate (27 mg, 55% yield). LCMS: RT=2.15 min [M+H] 608.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.79 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% ACN/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (d, J=6.05 Hz, 3H), 1.24 (d, J=6.05 Hz, 3H), 2.34-2.48 (m, 2H), 2.51-2.61 (m, 2H), 3.79 (d, J=13.19 Hz, 1H), 3.98 (d, J=13.19 Hz, 1H), 4.29-4.39 (m, 1H), 6.12-6.44 (m, 1H), 6.67-6.82 (m, 4H), 6.91-7.07 (m, 4H), 7.10-7.19 (m, 3H), 8.29 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:25]=[O:26].O>C(OCC)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:25]=[O:26])=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COCOCc1coc(-c2ccc(Cl)cc2)n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: COCOCc1nc(-c2ccc(Cl)cc2)oc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
200 mg (0.91 mmol) of the crude product from Example 40A are initially charged in 3.5 ml of dry diethyl ether and cooled to −78° C. 0.63 ml (1.00 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added dropwise. The reaction mixture is stirred at −78° C. for 1 h. 0.21 ml (2.74 mmol) of N,N-dimethylformamide is then slowly added dropwise. The mixture is allowed to warm to RT and stirred at RT for another 1 h. The mixture is then poured into about 3 ml of water. The mixture is extracted three times with in each case 10 ml of diethyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is purified by column chromatography on silica gel 60 (mobile phase gradient: cyclohexane/ethyl acetate 20:1→2:1).
Reaction SMILES: [O:1]([CH:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[O:1]([CH:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Solvent: C1CCOC1
Product: O=C1CCC(Oc2ccccc2)CC1

Procedure:
A solution of 8-phenoxy-1,4-dioxaspiro[4.5]decane (1.05 g, 4.48 mmol) in 20 mL of THF/3N HCl (1:1) was stirred overnight at room temperature. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), and concentrated to give 4-phenoxycyclohexanone as an oil. MS (EI) calcd: M+H=191.1; found: 191.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[C:14](=[O:16])[N:13]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:25]([O:35]C([O-])=O)([O:27][CH:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:29])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:29][CH:28]([O:27][C:25]([N:13]1[C:12]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:11]2[C:15](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:25]([O:27][CH:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:29])=[O:35])[C:10]2=[O:24])[C:14]1=[O:16])=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCC(C)OC(=O)OC(=O)[O-]
Reactant: O=c1nc(-c2ccc(Cl)cc2)c2c(=O)nc(-c3ccc(Cl)cc3)c1=2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(C)OC(=O)N1C(=O)C2=C(c3ccc(Cl)cc3)N(C(=O)OC(C)CCCCC)C(=O)C2=C1c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
4.28 g of 3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione, 7.26 g of 2-heptyl dicarbonate from Example B3, 0.20 g of 4-dimethylaminopyridine and 300 ml of dry tetrahydrofuran are mixed and the mixture is stirred at 55° C. for 4 hours. The suspension is filtered off with suction on a glass microfilter supporting a cotton filter, the solvent is evaporated off under reduced pressure, and the residue is admixed with 100 ml of isopropanol. After 30 minutes the precipitate is filtered off with suction, washed with isopropanol and dried under reduced pressure to leave 3.46 g (45% of theory) of 2,5-di-2-heptyloxycarbonyl-3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione as orange crystals. NMR (CDCl3) [ppm]: δ=7.67 (d,4H), 7.45 (d,2H), 4.67 (q,2H), 1.53 (m,2H), 1.48 (m,2H), 1.28 (m,16H), 0.88 (t,6H).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH3:11].[C:28]([Cl:33])(=[O:32])[CH:29]([CH3:31])[CH3:30]>C(OCC)C>[ClH:33].[OH:7][CH:8]([C:16]1[CH:25]=[CH:24][C:23]([O:26][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:27])[NH:21]2)[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH3:11]
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CC(C)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(NC(C)C)C(O)c1ccc(OC(=O)C(C)C)c2[nH]c(=O)ccc12
Product: Cl
Temperature: 0 °C

Procedure:
12 ml of pyridine was added to 0.4 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril, and 0.6 ml of isobutyryl chloride was added dropwise to the mixture while cooling with ice-water and stirring followed by stirring for 3 hours. After addition of about 200 ml of diethyl ether, the precipitate formed was washed thoroughly with diethyl ether and dissolved in 50 ml of water. The solution was washed with dichloroethane and the aqueous layer was concentrated to dryness. Acetone was added to the residue to crystallize the product which was then recrystallized from acetone to obtain 0.33 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-isobutyryloxycarbostyril hydrochloride having a melting point of 228°-229° C. (with coloration and decomposition).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].S(Cl)([Cl:11])=O.CC1OC(C)O[CH:16]([CH3:21])O1>[Cl-].[Zn+2].[Cl-]>[Cl:11][CH:16]([O:7][C:1](=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6])[CH3:21]
Reactant: C/C=C/C=C/C(=O)O
Reactant: CC1OC(C)OC(C)O1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC=CC=CC(=O)OC(C)Cl
Yield: 64.2 %

Procedure:
A mixture of 5.6 g. (50 mmoles) of sorbic acid and 7.8 g. (65 mmoles) of thionyl chloride was stirred at a room temperature for one hour, and then reacted at 50° C. for 30 minutes with stirring to complete the reaction. The end point of the reaction was judged by cessation of SO2 gas production and disappearance (dissolution) of sorbic acid. The resulting reaction mixture was cooled with ice, and then 0.27 g. (2 mmoles) of 96% zinc chloride was added thereto. After adding dropwise 2.2 g. of paraldehyde at 0° C., the reaction was carried out at a room temperature for one hour. The resulting reaction mixture was treated and purified in the same manner as in Reference Example 1 to give 5.43 g. (yield: 64.2%) of the desired compound being a clear solution.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.CN1CCOCC1>[CH2:22]([NH:29][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: NCc1ccccc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled (−20° C.) solution of N-Boc-O-benzyl-D-serine (26 g) in tetrahydrofuran (208 mL), N-methylmorpholine (15 mL) was added and reaction mixture was stirred for 5 minutes. isobutylchloformate (18 mL) was added to the reaction mixture in 5 minutes at −20° C. The solution was further stirred for 5 minutes at −20° C. and benzyl amine (15.01 mL) was added to in it in 5 minutes at −20° C. The solution was stirred for 1 hr at −20° C. The solution was allowed to warm at room temperature and stirred for 1 hour. The precipitated hydrochloride salt of N-methylmorpholine was filtered. The filtrate was concentrated under vacuum to obtain solid 17 g N-benzyl-O-benzyl-N2-Boc-D-serinamide after crystallization from diisopropylether.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2.[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCCC3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2-methylpiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (107.9 mg, 0.30 mmol, 1.00 equiv) in methanol (20 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (60 mg, 1.50 mmol, 5.00 equiv) in water (3 mL) with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath and concentrated under vacuum and diluted by 10 ml of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration and washed with methanol. This resulted in 54 mg (50%) of 3-(2-methylpiperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.C(P(CCCC)CCCC)CCC.[C:48]1([S:54]C2C=CC=CC=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>N1C=CC=CC=1>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][S:54][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12]1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCSc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 200 mg (0.43 mmol) of tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate, 263 mg (1.29 mmol) of tributylphosphine and 284 mg (1.29 mmol) of diphenyl sulphide in 1 ml of pyridine was stirred at room temperature for 18 hours. Subsequently, the reaction mixture was evaporated under reduced pressure and the residue, without further working-up, was chromatographed directly on silica gel using methylene chloride as the eluent. The tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-phenylsulphanyl-ethyl)-phenyl]-piperidine-1-carboxylate was obtained as a colourless oil in quantitative yield; MS: 554 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]>C(O)(C)C.C(N(CC)CC)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Clc1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Yield: 92.6 %

Procedure:
3.00 g (0.015 mol) of 4,6-dichloroquinazoline and 3.80 g (0.0170 mol) of 4-chloro-3-nitrobenzylamine hydrochloride were dissolved in a mixture comprising 100 ml of isopropyl alcohol and 15 ml of triethylamine. The obtained solution was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate) and recrystallized from chloroform/n-hexane to give 4.85 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36]>>[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH:36][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:30]
Reactant: COC(=O)CN
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2ccc(C(=O)O)c(C)c2)cc1C
Agent: Cl
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2ccc(C(=O)NCC(=O)OC)c(C)c2)cc1C
Yield: 96.1 %

Procedure:
Using a procedure analogous to Example 1J, 4-{1-ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.64 g, 1.55 mmol) and glycine methyl ester hydrochloride (195 mg, 1.55 mmol) gives the title compound (0.72 g, 1.49 mmol, 96%). %).