Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13](=O)[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13](=[S:27])[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2ccccc2N(C(=O)CN2CCCCC2)c2ncccc21
Solvent: c1ccncc1
Product: O=C(CN1CCCCC1)N1c2ccccc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 6,11-dihydro-11-(piperidinoacetyl)-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 6,11-dihydro-11-(piperidinoacetyl)-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][NH2:19]>>[CH:2]1[C:11]2[C:6](=[C:7]([S:12]([NH:19][CH2:18][CH2:17][CH2:16][NH2:20])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Product: NCCCNS(=O)(=O)c1cccc2cnccc12
Yield: 81.1 %

Procedure:
According to the method of Reference Example 2, a reaction was performed by using isoquinoline-5-sulfonyl chloride hydrochloride (20 g) and 1,3-propylenediamine (22.2 g) to obtain the title compound (16.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23](=[O:25])[CH3:24].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][C:23](=[O:25])[CH3:24])[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: CC(=O)CCl
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (950 mg, 4.94 mmol) and potassium carbonate (4.10 g, 29.64 mmol) in 12 mL DMF was treated with chloroacetone (787 μL, 9.89 mmol) and stirred at room temperature overnight. After this time, the mixture was cooled to 0° C. and treated with 50 mL H2O under rapid stirring. A precipitate formed and it was filtered then washed with 50 mL H2O. The solid was collected and dried under reduced pressure overnight (1.01 g, 82.1%). 1H-NMR (DMSO-d6) δ: 8.17 (d, J=2.4 Hz, 1H), 8.05 (dd, J=2.4, 8.7 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.33 (s, 2H), 3.05 (t, J=7.8 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 2.24 (s, 3H). MS (EI): 248 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][CH:5]=[N:6][C:7]=1[SH:8].[CH3:10][N:11]1[C:15]([C:16](O)=O)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=[CH:12]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:10][N:11]1[C:15]([C:16]2[S:9][C:3]3[N:4]=[CH:5][N:6]=[C:7]([SH:8])[C:2]=3[N:1]=2)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=[CH:12]1
Reactant: Cn1cnc(-c2ccccc2)c1C(=O)O
Reactant: Nc1c(S)ncnc1S
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cnc(-c2ccccc2)c1-c1nc2c(S)ncnc2s1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
5-Aminopyrimidin-4,6-dithiol (Intermediate 41) (1.26 g) and 1-methyl-4-phenyl-1H-imidazole-5-carboxylic acid (Intermediate 3) (1.6 g) were dissolved/ suspended in pyridine (30 mL) and heated at 55° C. under an inert atmosphere. POCl3 (1.55 mL) was added dropwise over 5 minutes, after 2 hours the reaction mixture was concentrated in vacuo and 2M NaOH (15 mL) added cautiously. After stirring for 15 minutes, concentrated HCl was added to acidify to pH 5, the precipitated solid was filtered, washed with water (40 mL), diethyl ether (50 mL) then dried under high vacuum to give the title compound as a yellow solid (1.83 g, 71%);
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:23][C:24]=3[C:25]([F:28])([F:27])[F:26])=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:29]1([C:22]2[O:23][C:24]([C:25]([F:26])([F:27])[F:28])=[C:20]([C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([N:8]4[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)=[O:19])[N:21]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
The above 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid methyl ester (470 mg, 1 mmol) was dissolved in a mixture of methanol (7 mL) and THF (2 mL). To this solution was added 1N sodium hydroxide solution (3 mL). The mixture was stirred at room temperature for 4 hrs until all starting material was consumed. Solvents were evaporated and the residue was diluted with water (8 mL). The solution was filtered and the filtrate was acidified with 1N hydrochloric acid (3.5 mL). The yellow precipitate was filtered and dried in the air to give 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid (395 mg). 1H-NMR is consistent with the desired structure. LC-MS indicated a single peak (Rf=3.23 min). LRMS for C23H20F3N3O4 (m/e) calcd 459.14, obsd 460.2 (M+1).
Reaction SMILES: C([C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[C:13]=1[O:26][CH3:27])([CH2:9][CH2:10][CH3:11])[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:27][O:26][C:13]1[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[CH:15][CH:16]=[CH:17][C:12]=1[CH:3]([CH2:9][CH2:10][CH3:11])[C:4]([OH:6])=[O:5]
Reactant: CCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1OC
Yield: 94 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]valerate (4.6 g) and potassium hydroxide (3.5 g) in ethanol (50 ml) and water (25 ml) was treated in a similar manner to that of Example 14-(7) to give oily 2-[2-methoxy-3-(o-tolyloxy)phenyl]valeric acid (3.7 g).
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH:9][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1]
Reactant: CC(N)c1ccccc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(CNC(C)c1ccccc1)OC
Yield: 69.9 %

Procedure:
A solution of α-methylbenzylamine (8.37 g, 0.069 mol) and bromoacetaldehyde dimethylacetal (11.67 g, 0.069 mol) in acetonitrile (150 ml) containing potassium carbonate (12.39 g, 0.09 mol) was heated at reflux for 2 days then cooled. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo to give the crude product as an oil. Chromatography on silica gel eluting with ethyl acetate afforded the title compound as an oil (10.1 g). 1H NMR (400 MHz, CDCl3) δ(ppm): 7.31 (m, 3H), 7.23 (m, 2H), 4.43 (t, 1H), 3.75 (q, 1H), 3.35 (s, 3H), 3.31 (s, 3H), 2.63 (dd, 1H), 2.55 (dd, 1H), 1.36 (d, 3H).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]=[C:12]([C:17](=[O:21])[CH2:18][O:19][CH3:20])[C:13]([O:15][CH3:16])=[O:14].[CH3:23]OC(OC)N(C)C>>[F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:23]=[C:18]([O:19][CH3:20])[C:17](=[O:21])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[N:11]1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1ccccc1OC(F)F)C(=O)OC
Product: COC(=O)c1nn(-c2ccccc2OC(F)F)cc(OC)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
A solution of methyl 2-{[2-(difluoromethoxy)phenyl]hydrazono}-4-methoxy-3-oxobutanoate (8.70 g, 27.5 mmol) in N,N-dimethylformamide dimethyl acetal (60 mL) was refluxed for 3 h and stirred at room temperature for 3 days. The precipitate was collected by filtration and washed with hexane/AcOEt (3/1) to give the title compound (7.92 g, 88% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.89 (3H, s), 3.96 (3H, s), 6.55 (1H, d, J=72.7 Hz), 7.35-7.45 (2H, m), 7.49-7.56 (1H, m), 7.61 (1H, dd, J=7.9, 1.5 Hz), 7.73 (1H, s).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2ccccc2n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.59 min.; [M+H]+: 377.18 g/mol.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][C:8]=2[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][NH:5][CH2:4]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>CN(C=O)C>[CH2:20]([O:19][C:17]([C:7]1[C:8]2[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]=2[CH2:3][CH2:4][N:5]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)=[O:18])[CH3:21]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CN(Cc2ccccc2)CCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
Sodium hydride (60% in mineral oil, 320 mg, 8 mmol) was added to a stirred solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (520 mg, 2 mmol) in anhydrous DMF (8 mL) at 0° C. under nitrogen, and the resulting mixture was stirred at ambient temperature for 30 minutes. Benzyl bromide (345 mg, 2 mmol) was then added dropwise to the above mixture at 0° C. The resulting mixture was stirred at ambient temperature for 6 hours. Ammonium chloride solution was added carefully to quench the reaction at 0° C. The mixture was extracted with DCM. The combined extracts were washed with saturated ammonium chloride solution, water and brine, dried over sodium sulfate, and evaporated in vacuo to give a brown oil, which was purified by chromatography on silica gel eluting with EtOAc-Hexane (5:95) to give the title compound (421 mg); 1H-NMR (CDCl3): δ 10.53 (1H, s), 7.96 (1H, s), 7.41-7.25 (7H, m), 7.08-6.99 (2H, m), 4.57 (2H, s), 4.33-4.27 (2H, q), 3.48 (2H, m), 3.01 (2H, m), 1.36 (3H, t); MS (ES): 347 (MH+).
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26])(OC(C)(C)C)=O.[CH2:34]([C:36]1[N:37]=[N:38]N[N:40]=1)[CH3:35]>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]3[N:38]=[N:37][C:36]([CH2:34][CH3:35])=[N:40]3)[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CCc1nn[nH]n1
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared analogously to (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (Step AA4) by replacing di-t-butyliminodicarboxylate (Step AA3) with 5-ethyl-2H-tetrazole.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: FC(F)(F)Oc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)Oc1ccc(NC2CCNCC2)cc1
Yield: 93.5 %

Procedure:
A mixture of (1-benzylpiperidin-4-yl)-(4-trifluoromethoxyphenyl)amine (3.0 g, 8.3 mmol) prepared in Reference Example 129 and a catalytic amount of 10% palladium/carbon in ethanol (30 ml) was refluxed under an atmospheric pressure of hydrogen for 20 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) to afford piperidin-4-yl-(4-trifluoromethoxyphenyl)amine (2.02 g, yield 94%) as a colorless crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24](F)[N:23]=4)=[CH:20][N:21]=3)[N:18]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=[O:31])C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[N:23]=[C:24]([OH:31])[CH:25]=[CH:26][CH:27]=4)=[CH:20][N:21]=3)[N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(F)n4)n3n2)c1
Solvent: ClCCl
Product: Oc1cccc(-c2cnc3ccc(N4CCC[C@@H]4c4cccc(F)c4)nn23)n1
Temperature: 120 °C

Procedure:
In step 16-1, a suspension of (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine (16 g, 42 mmol) in acetic acid (150 mL) was heated overnight at 120° C. (approx. 20 hours). The suspension turned clear after heating. The mixture was concentrated under vacuum to give a brown oil. The oil was dissolved in CH2Cl2 (750 mL) and washed with saturated NaHCO3 (300 mL×3), brine (300 mL×2). The organic layer was separated, dried over (Na2SO4) and concentrated to give 15.5 g of the crude (R)-6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-ol (16-1) which was used in the next step without further purification. LC/MS: 376.2 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=2[CH2:33][CH2:34][CH3:35])[C:10]=1[CH2:36][CH2:37][CH3:38])C>CO.[OH-].[Na+]>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:39])=[O:3])=[C:10]([CH2:36][CH2:37][CH3:38])[C:11]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=1[CH2:33][CH2:34][CH3:35])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O

Procedure:
A solution of 6.22 g of 4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoic acid ethyl ester in 100 ml of methanol and 57 ml of 1N sodium hydroxide was stirred at reflux for 2 hours. The solvent was removed in vacuo and the pH of the residue was adjusted to 2.0 with 6N hydrochloric acid. The solid was filtered and dried to give 5.16 g (87%), mp 96°-99°, 4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([CH2:9][CH3:10])[CH3:8])[N:6]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[C:21]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([CH2:9][CH3:10])[CH3:8])[N:6]=1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCC(C)c1csc(N)n1
Product: CCOC(=O)C(=CNc1nc(C(C)CC)cs1)C(=O)OCC
Yield: 99.9 %

Procedure:
2-Amino-4-(2-butyl)thiazole (8.44 g., 54 mmoles) and diethyl ethoxymethylenemalonate (11.7 g., 54 mmoles) were combined and heated on a steam bath for 1 hour and cooled to yield 2-(2,2-dicarbethoxyethenylamino)-4-(2-butyl)thiazole (17.6 g., Rf 0.75 on silica gel thin layer chromatography with chloroform/1% ethanol as eluant).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=O)=[O:9])=[CH:4][CH:3]=1.[C:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCCC1.O>C1C=CC=CC=1>[C:12]([C:20](=[CH:10][C:8](=[O:9])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=CC(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=CC(=O)c1ccc(Cl)cc1)C(=O)c1ccccc1

Procedure:
A solution containing 13.5 g of 4-chloro-phenylglyoxal and 15.4 g of ethyl benzoylacetate in 100 ml of anhydrous benzene was heated at the boiling temperature in the presence of a catalytic amount of piperidine (0.3 ml), till complete azeotropic distillation of the water formed during the reaction (about 6 hours).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:36][NH2:37]>>[CH3:36][NH:37][C:32]([CH2:31][NH:30][C:28]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:35])=[O:29])=[O:33]
Reactant: CN
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Product: CNC(=O)CNC(=O)N1CC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 77.1 %

Procedure:
In a manner similar to the method described in Example 60, a mixture of rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-acetic acid (22.6 mg, 0.0432 mmole, example 64) was reacted with a solution of methylamine (0.04 mL, 2M in THF, 0.080 mmol, Aldrich) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid methylcarbamoylmethyl-amide (17.9 mg, 77%) as a white solid. HRMS (ES+) m/z Calcd for C26H28Cl2F2N4O2+H [(M+H)+]: 537.1630; Found: 537.1630.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16](=[O:34])[N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)[C:12](O)=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:35][O:36][C:37](=[O:51])[CH2:38][N:39]1[CH2:44][CH2:43][CH:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16](=[O:34])[N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:21][CH2:22]3)[C:12]([N:48]3[CH2:49][CH2:50][CH:45]([CH:42]4[CH2:41][CH2:40][N:39]([CH2:38][C:37]([O:36][CH3:35])=[O:51])[CH2:44][CH2:43]4)[CH2:46][CH2:47]3)=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCC2
Reactant: COC(=O)CN1CCC(C2CCNCC2)CC1
Product: COC(=O)CN1CCC(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from and 2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and methyl[4,4′]bipiperidinyl-1-yl-acetate.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[NH2:26][C@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>>[C:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:26])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)(C)OC(=O)N1CCC(N)C1

Procedure:
After 2.5 hours in reaction, 0.625 g of N-Boc-3-pyrrolidinone, 0.91 g of D-glucose, 1.8 g of L-alanine, and 3.3 mg of pyridoxal phosphate were added. Further, after five hours in reaction, 0.625 g of N-Boc-3-pyrrolidinone, 0.91 g of D-glucose, and 3.3 mg of pyridoxal phosphate were added. Furthermore, after nine hours in reaction, 0.25 g of N-Boc-3-pyrrolidinone, 0.36 g of D-glucose, 19 mg of NAD+, and 3.3 mg of pyridoxal phosphate were added. During the reaction, the reaction liquid was sampled. From the sample, N-Boc-3-aminopyrrolidine was extracted by the addition of ethyl acetate after basifying the sample with 6 N aqueous solution of sodium hydroxide. The amount of N-Boc-3-aminopyrrolidine produced was measured by analyzing N-Boc-3-aminopyrrolidine under the following GC conditions. Further, by the law of the art, N-Boc-3-aminopyrrolidine thus obtained was acted on by 3,5-dinitrobenzyl chloride to form a dinitrobenzyl derivative. After that, the dinitrobenzyl derivative was analyzed under the following HPLC conditions, whereby the optical purity thereof was measured. In the result, the amount of N-Boc-3-aminopyrrolidine produced after 23 hours in reaction was 2.14 g. The absolute configuration of N-Boc-3-aminopyrrolidine was (S), and the optical purity was 99.4% e.e.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[CH:19][C:20](=[O:21])[CH3:22])=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C=Cc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In a 250 ml single neck flask was charged 12.1 g (100 mmoles,1.0 eq) of p-tolualdehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.5 g of 4-(p-tolyl)-3-buten-2-one as a faintly yellow oil in 84.3% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[CH:22]1([C:25](C(Cl)=O)=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1>[NH2:15][C:11]1[N:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[CH:13][C:12]=1[NH:14][C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26]
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: O=C(Cl)C(=O)C1CC1
Solvent: c1ccncc1
Product: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1NC(=O)C1CC1
Temperature: 80 °C
Yield: 81.4 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.2 g, 0.71 mmol) in pyridine (2 mL), 0.071 mL (0.78 mmol) of cyclopropanoylcarbonyl chloride were added. The mixture was heated at 80° C. for 4 h and the solvent was evaporated. The crude mixture was extracted between ethyl acetate and water, the organic layer was dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (90:10 dichloromethane/methanol) to give the title compound (0.202 g, 82% of yield).