Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-])=O)[O:6][N:5]=1.O.O.O.O.O.O.O.O.O.[S-][S-].[Na+].[Na+]>O1CCOCC1.O>[CH3:19][N:2]([CH2:3][C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[NH2:16])[O:6][N:5]=1)[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])c(-c2nc(CN(C)C)no2)c1
Agent: [Na+]
Agent: [S-][S-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N)c(-c2nc(CN(C)C)no2)c1
Temperature: 80 °C

Procedure:
To a solution of N,N-dimethyl-1-(5-(5-methyl-2-nitrophenyl)-1,2,4-oxadiazol-3-yl)methanamine (38 mg, 0.15 mmol) in dioxane (1 mL) at 80° C. was added a hot solution (80° C.) of sodium disulfide nonahydrate (70 mg, 0.29 mmol) in water (1 mL). The reaction was heated at 80° C. for 30 min resulting in clean conversion to the desired product. The reaction was diluted with dichloromethane then washed with 50% saturated NaHCO3 (2×20 mL) and brine. The solution was dried over Na2SO4, filtered and dried down to provide 2-(3-((dimethylamino)methyl)-1,2,4-oxadiazol-5-yl)-4-methylaniline as a light orange oil (29 mg, 86% yield). LC/MS m/z 233.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14](O)=[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]3=[C:11]([O:23][CH2:24][CH3:25])[C:10]=2[C:9]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]3=[C:11]([O:23][CH2:24][CH3:25])[C:10]=2[C:9]1=[O:26]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.4 %

Procedure:
To a solution of ethyl {3-chloro-4-[4-(ethyloxy)-9-hydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]phenyl}acetate (0.60 g, 1.32 mmol) in DMF (6 ml), was added sodium carbonate (0.280 g, 2.65 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.460 g, 1.98 mmol). This was stirred at room temperature for 5 hours. Water was added to the reaction mixture and the resulting brown solid was collected by filtration. This was purified by chromatography on silica gel eluting with 5-60% ethylacetate in hexane to give the title compound (0.258 g, 0.48 mmol). LC/MS: Rt=3.85, [MH]+ 536.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH:1]1([CH2:6][O:7][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of cyclopentan-methanol (2 g, 20 mmoles), CH2Cl2 (20 ml), triethylamine (5.85 ml, 42 mmoles) and p-toluen-sulphonyl chloride (4 g, 21 mmoles) was kept under stirring at room temperature for 1 night, then washed with water, 5% HCl and NaHCO3 and evaporated to give 5.09 g of the title compound (yield: 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl-].[CH2:23]([O:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](O)=[O:30])[CH3:24]>N1C=CC=CC=1>[C:29]([O:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:20][CH:19]=1)(=[O:30])[CH2:28][CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:32]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Reactant: CCOC(=O)CCC(=O)O
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCOC(=O)CCC(=O)Oc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 90 %

Procedure:
Compound 1 (50 mg) and succinic acid monoethyl ester chloride (51 μL) were dissolved in pyridine (1 mL), followed by stirring for a whole day and night. After completion of reaction, the resultant reaction mixture was concentrated to dryness under reduced pressure, followed by purification by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (73 mg, yield: 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=O)[O:9]C2C=CC=CC=2)[CH:2]=1.FC(F)(F)C(O)=O.[NH:24]1[CH2:29][CH2:28][C:27](=[C:30]([C:32]2[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=2)[O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=2)[CH3:31])[CH2:26][CH2:25]1.C(N(CC)CC)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:24]2[CH2:29][CH2:28][C:27](=[C:30]([C:32]3[CH:48]=[CH:47][CH:46]=[C:34]([O:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:38][N:37]=4)[CH:33]=3)[CH3:31])[CH2:26][CH2:25]2)=[O:9])[CH:2]=1
Reactant: CC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=C1CCN(C(=O)Nc2cccnc2)CC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of phenyl pyridin-3-ylcarbamate (120 mg, 0.562 mmol) in DMSO (5 mL) was added 2-(3-(1-(piperidin-4-ylidene)ethyl)phenoxy)-5-(trifluoromethyl)pyridine trifluoroacetate (260 mg, 0.516 mmol), followed by triethylamine (0.16 mL, 1.12 mmol). The reaction was stirred at 60° C. overnight. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (0-5% MeOH/CH2Cl2) to give the title compound (161 mg, 61% yield) as a clear oil which formed a foam under high vacuum. MS (APCI 10V) AP+ 469.18; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.99 (s, 3H) 2.31 (t, 2H) 2.50 (t, 2H) 3.40 (t, 2H) 3.61 (t, 2H) 6.63 (br. s., 1H) 6.89 (t, 1H) 6.97-7.04 (m, 3H) 7.17-7.22 (m, 1H) 7.37 (t, 1H) 7.89 (dd, 1H) 7.96 (dd, 1H) 8.23 (dd, 1H) 8.41 (dd, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[CH:14]=3)=[CH:11][C:10]([C:22]([O:24]CC)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([F:21])[CH:14]=3)=[CH:11][C:10]([C:22]([OH:24])=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(OC)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: COc1cc(F)cc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 41A in analogy to the synthesis of the compound of Example 71A. 1.31 g of the title compound are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH3:47])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:47][N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[C:34](=[O:35])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:39]1
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Product: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC2Cc3cccc(N4CCCC4=O)c3N(Cc3ccsc3)C2=O)c2ccccc21
Yield: 110.8 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (268 mg) and (R)-2-(tert-butoxycarbonylamino)-3-(1-methyl-1H-indol-3-yl)propanoic acid (284 mg) synthesized in Referential Example 1(a) were used, whereby the title compound (558 mg) was yielded.
Reaction SMILES: [N:1]1([C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[P:12]([O-:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[N:1]1([C:6]2([P:12]([O:16][CH2:17][CH3:18])(=[O:19])[O:13][CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1=C(N2CCCC2)CCCC1
Reactant: CCOP([O-])OCC
Product: CCOP(=O)(OCC)C1(N2CCCC2)CCCCC1

Procedure:
A mixture of 1-pyrrolidinocyclohexene (15.1 g; 0.1 mole) and diethyl phosphite (13.8 g; 0.1 mole) was heated for 2 hours on a steam bath. The resulting liquid showed no absorption in the infrared for C=C or P-H. Distillation yielded pure diethyl 1-pyrrolidinocyclohexane-1-phosphonate, bp 80°-85°/0.1 mm. ##STR8##
Reaction SMILES: [CH2:1]([C:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][C:20](=[O:26])[NH:21]2>>[CH2:1]([C:8]1([OH:15])[CH2:13][CH2:12][N:11]([C:14]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[NH:19][C:20](=[O:26])[NH:21]3)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(O)(Cc2ccccc2)CC1
Reactant: O=c1[nH]c2ncnc(Cl)c2[nH]1
Product: O=c1[nH]c2ncnc(N3CCC(O)(Cc4ccccc4)CC3)c2[nH]1

Procedure:
4-Benzyl-1-methyl-piperidin-4-ol was reacted with 6-chloro-7,9-dihydro-purin-8-one under conditions analogous to those set out in Example 3A to give the title compound LC/MS: (LCT) Rt 5.68 [M+H]+326.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]2([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)[CH2:41][CH2:40]2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[F:48][C:45]1[CH:44]=[CH:43][C:42]([C:39]2([C:28]3[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=3)[CH2:41][CH2:40]2)=[CH:47][CH:46]=1
Reactant: Fc1ccc(C2(c3cc(OCc4ccccc4)c(OCc4ccccc4)nn3)CC2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(C2(c3ccc(F)cc3)CC2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[1-(4-fluorophenyl)cyclopropyl]pyridazine (Intermediate 42) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and MTBE.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][N:35]=1)[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH2:26]([NH:25][C:23](=[O:24])[C:22]1[CH:33]=[CH:34][N:35]=[C:20]([NH:19][C:16]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:17])[CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)C2CCCC2)c1
Yield: 88 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with cyclopentanecarbonyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(cyclopentanecarboxamido)-isonicotinamide was obtained as a colorless solid in 88% yield: mp 55-57° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.49 (s, 1H), 8.27 (d, J=5.1 Hz, 1H), 7.49 (d, J=5.1 Hz, 1H), 7.23-7.18 (m, 6H), 4.54 (d, J=5.7 Hz, 2H), 2.82-2.80 (m, 1H), 1.22-0.82 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 175.7, 165.3, 152.2, 148.2, 144.1, 137.5, 128.7, 128.4, 127.9, 127.6, 118.2, 110.9, 46.4, 44.1, 30.3, 25.9; MS (ES+) m/z 324.6 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][CH:13]1[O:18][CH:17]([CH3:19])[CH2:16][NH:15][CH2:14]1>C(#N)C>[CH3:19][C@H:17]1[CH2:16][N:15]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:14][C@@H:13]([CH3:12])[O:18]1
Reactant: OCCCCl
Reactant: CC1CNCC(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(CCCO)C[C@H](C)O1
Yield: 28.9 %

Procedure:
3-Chloro-1-propanol (1.04 g, 11 mmol) followed by potassium carbonate (2.07 g, 15 mmol) was added to a solution of 2,6-dimethylmorpholine (1.15 g, 10 mmol), (supplied by Aldrich Chemical Company Limited as a mixture of isomers), in acetonitrile (15 ml). The mixture was heated at reflux overnight and allowed to cool, the insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/acetonitrile/methanol (60/35/5 followed by 60/30/10) to give cis-3-(2,6-dimethylmorpholino)-1-propanol (500 mg).
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[F:15][C:16]([F:23])([F:22])[CH:17]([OH:21])[C:18](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[F:15][C:16]([F:23])([F:22])[CH:17]([C:18]1[NH:1][C:2]2[CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[C:5]([C:6]#[N:7])=[CH:8][C:9]=2[N:10]=1)[OH:21]
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: N#Cc1cc(N)c(N)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc2nc(C(O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Diamino-2-trifluoromethyl-benzonitrile (4.14 g; 20.6 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (4.50 g; 31.2 mmoles) were suspended in 6N HCl (7 mL; 42 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (5.19 g; 62.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude dark solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a dark brown solid.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[CH:18]=[CH:17][C:16]2[C:15](=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:20])[C:7]=2[C:6]=1[N+:21]([O-:23])=[O:22].Cl.[OH2:26]>>[N+:21]([C:6]1[C:7]2[C:8](=[O:20])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:19])[C:16]=2[CH:17]=[CH:18][C:5]=1[CH2:4][CH:3]=[O:26])([O-:23])=[O:22]
Reactant: CN(C)C=Cc1ccc2c(c1[N+](=O)[O-])C(=O)c1ccccc1C2=O
Reactant: O
Agent: Cl
Product: O=CCc1ccc2c(c1[N+](=O)[O-])C(=O)c1ccccc1C2=O

Procedure:
100 g (0.31 mol) of 2-(2'-dimethylaminoethenyl)-1-nitroanthraquinone are refluxed with 200 g of concentrated hydrochloric acid (38% strength) and 600 g of water for 2 hours. After cooling, the precipitated crystals are filtered off, washed with water until neutral and dried at 70° C. This leaves 90.5 g (98.7%) of 1-nitro-2-(2'-oxoethyl)anthraquinone; melting point: 192° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:23]([CH2:24][NH:25][CH2:26][CH3:27])=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=1)[CH3:2].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:23]([CH2:24][N:25]([CH2:26][CH3:27])[C:46](=[O:47])[CH2:45][O:44][CH3:43])=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=1)[CH3:2]
Reactant: COCC(=O)Cl
Reactant: CCNCc1cc2ccccc2nc1-c1cc(CC(=O)OCC)ccc1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(=O)COC)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: [3-(3-ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester; dihydrochloride and methoxyacetyl chloride.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([CH:10]2[CH2:12][CH:11]2[C:13]#[N:14])=[O:9])=[CH:6][CH:5]=1.O>C(O)C.C(OCC)(=O)C>[OH:9][CH:8]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:16][CH:15]=1)[CH:10]1[CH2:12][CH:11]1[C:13]#[N:14]
Reactant: Cc1ccc(C(=O)C2CC2C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(O)C2CC2C#N)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
607 mg (16.0 mmol) of sodium borohydride were added to 2.70 g (14.6 mmol) of the compound from Example 126A in 60 ml of ethanol and 16 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 2 h. The reaction mixture was added to water and extracted with dichloromethane, and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.56 g (94% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:12][CH2:13][C:14]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Cl:1])[NH:8][C:7](=[O:11])[CH2:6]2)=[O:15]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)CCl)c(Cl)cc2N1
Temperature: 75 °C
Yield: 68 %

Procedure:
A mixture of 750 ml of dichloromethane, 150 g of 6-chlorooxindole, 161.6 g of chloroacetyl chloride and 477.2 g of aluminium chloride was refluxed for 9.5 hours. The reaction mass was quenched into a mixture of crushed ice and 135 ml of hydrochloric acid. The formed solid was filtered, and the wet compound was washed with water. The wet compound was dissolved in 3525 ml acetic acid by heating to 70 to 80° C., then carbon was added and the mixture was stirred briefly at the same temperature, and the carbon was removed by filtration and washed with 15 ml of acetic acid. The filtrate was allowed to cool to about 20° C. for solid formation. The solid was filtered, washed three times with 600 ml of water, and then dried to yield 148.5 g of the title compound.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([N:8]1[C:12](=O)[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]1=O)[CH3:7])(=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH3:14][C:10]1([CH3:15])[CH2:11][CH2:12][N:8]([C@@H:6]([CH3:7])[CH2:5][OH:4])[CH2:9]1
Reactant: CC(=O)OC[C@H](C)N1C(=O)CC(C)(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@@H](CO)N1CCC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of (S)-2-(3,3-dimethyl-2,5-dioxopyrrolidin-1-yl)propyl acetate (6.15 g, 27.1 mmol) in anhydrous diethyl ether (20 mL) was added to a suspension of LiAlH4 (3.0 g, 79 mmol) in anhydrous diethyl ether (250 mL) at room temperature under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was quenched with H2O (3 mL). The resulting suspension was filtered, and the filter cake was washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column (eluting with DCM/MeOH=20/1) to give (S)-2-(3,3-dimethylpyrrolidin-1-yl)propan-1-ol (2.37 g, 59%). 1H NMR (CDCl3): δ 3.53 (dd, 1H), 3.27 (dd, 1H), 2.70 (m, 3H), 2.37 (s, 2H), 1.55 (m, 2H), 1.07 (s, 3H), 1.06 (s, 3H), 0.94 (d, 3H); LCMS: 158 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][N:28]5[CH:32]=[CH:31][N:30]=[N:29]5)[O:24][C:23]4=[O:33])=[CH:17][C:16]=3[F:34])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:26][C@H:25]([CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[O:24][C:23]3=[O:33])=[CH:17][C:16]=2[F:34])=[CH:11][CH2:10]1)=[O:8]
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)CC2)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C([C@@H](O)CO)N1CC=C(c2c(F)cc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
To a stirred solution of (5R)-3-(4-(1-((4S)-2,2-dimethyl-1,3-dioxolane-4-carbonyl)-1,2,5,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (700 mg, 1.43 mM) in tetrahydrofuran (25 ml) was added aqueous hydrochloric acid (1M, 15 ml) and the mixture stirred at ambient temperature for 2 days. Solvent was evaporated and the residue treated with water (10 ml). Aqueous sodium acetate (10%, 10 ml) was added, and the precipitate filtered and washed with ethanol and diethyl ether to give the title compound (514 mg).
Reaction SMILES: [CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].C(OC([NH:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16])=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].[NH2:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCS(N)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
A mixture of N-t-butoxycarbonyl-L-alanyl-L-proline ethanesulphonamide (22.5 g.) and trifluoroacetic acid (60 ml.) was stirred at laboratory temperature for 1 hour, the excess of trifluoroacetic acid was removed by evaporation and toluene was twice added and removed by evaporation, finally at 0.5 mm.Hg. A solution of the L-alanyl-L-proline ethanesulphonamide trifluoroacetate thus obtained in ethanol (350 ml.) was cooled to 10° C. and triethylamine (17 ml.), a solution of ethyl 2-oxo-4-phenylbutyrate (18.6 g.) in ethanol (50 ml.), powdered activated 3 Å molecular sieve (75 g.) and Raney nickel (15 g.) were successively added. The mixture was stirred under an atmosphere of hydrogen at laboratory temperature and pressure for 20 hours and then filtered through a filter-aid, and the filtrate was evaporated to dryness. The residue was shaken with diethyl ether and 10% aqueous potassium carbonate solution and the aqueous layer was separated, washed with diethyl ether, acidified to pH 3 with citric acid and extracted four times with ethyl acetate. The combined extracts were dried and evaporated to dryness and there were thus obtained the mixed isomers of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline ethanesulphonamide in a ratio (as shown by high pressure liquid chromatography) of approximately 22:3 by weight, the more active (as an inhibitor of ACE) isomer predominating.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].O>O1CCCC1.O.CO>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:3]([OH:19])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(CC2CCCC2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
A solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid methyl ester (1.39 g, 5.29 mmol) in tetrahydrofuran/water/methanol (13.2 mL, 3:1:1) at 25° C. was treated with a 2N aqueous sodium hydroxide solution (3.97 mL, 7.94 mmol). The reaction was stirred at 25° C. for 48 h. At this time, the reaction mixture was poured into water (50 mL) and extracted with chloroform (3×25 mL). The aqueous layer was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The aqueous layer was extracted with a solution of chloroform/methanol (9:1). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate with glacial acetic acid) afforded 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid (1.05 g, 79.8%) as a clear wax: EI-HRMS m/e calcd for C15H20O3 (M+) 248.1412, found 248.1409.