Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:27]1[C:35]3[C:30](=[N:31][CH:32]=[C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:34]=3)[C:29]3([CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH2:28]1)=[C:5]([CH3:26])[C:6]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[N:7]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:27]1[C:35]3[C:30](=[N:31][CH:32]=[C:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)[CH:34]=3)[C:29]3([CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)[CH2:28]1)=[C:5]([CH3:26])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Tert-Butyl 4-(5,7-difluoro-3-methyl-4-(6′-(4-morpholinyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-2-quinolinyl)-1-piperazinecarboxylate (450 mg, 0.70 mmol) was dissolved in DCM (5.0 mL) and cooled to 0° C. TFA (5.0 mL, 65.0 mmol) was then added and the reaction mixture was allowed to warm to rt and stirred for 2.5 h. The reaction was diluted with DCM and concentrated to dryness. The residue was then converted to the free amine by eluting through an SCX column with 0 to 2M ammonia in MeOH to give 1′-(5,7-difluoro-3-methyl-2-(1-piperazinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 7.56 (1H, d, J=2.3 Hz), 7.36 (1H, ddd, J=9.9, 2.5, 1.3 Hz), 6.73 (1H, ddd, J=11.8, 9.1, 2.5 Hz), 5.66 (1H, d, J=2.3 Hz), 4.04-4.21 (2H, m), 3.80-3.97 (2H, m), 3.70-3.79 (4H, m), 3.56 (2H, qd, J=11.6, 2.4 Hz), 3.27-3.46 (4H, m), 3.02-3.18 (4H, m), 2.90-3.02 (4H, m), 2.26-2.38 (2H, m), 2.24 (3H, s), 1.97 (1H, br. s.), 1.79 (1H, d, J=13.3 Hz), 1.70 (1H, dd, J=13.6, 1.9 Hz). Mass Spectrum (ESI) m/e=537.3 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:32]([C:33]#[N:34])=[C:18]3[N:19]=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N+:29]([O-])=O)[N:17]3[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH:22]1[N:17]2[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:32]([C:33]#[N:34])=[C:18]2[NH:19][CH2:20][CH2:21]1
Reactant: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)nn2c(-c3ccccc3[N+](=O)[O-])ccnc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of 2-(4-(benzyloxy)phenyl)-7-(2-nitrophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (2 g, 4.47 mmol) in CH3OH (20 mL) and DCM (20 mL) was added 10% w/w Pd/C (300 mg). The mixture was stirred at RT under H2 for 16 hr. Filtered and purified by chromatography column on silica gel (elution with DCM/CH3OH) to afford 0.92 g (62%) of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI, m/e) [M+1]+ 331.9.
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:6])[CH2:4][OH:5].Cl[C:8]1[N:9]=[C:10]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:11]2[N:16]=[C:15](Cl)[N:14]=[C:13]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:12]=2[N:24]=1.[OH2:31]>C1COCC1>[CH3:2][CH:3]([CH3:6])[CH2:4][O:5][C:8]1[N:9]=[C:10]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:11]2[N:16]=[C:15]([O:31][CH2:2][CH:3]([CH3:6])[CH3:4])[N:14]=[C:13]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:12]=2[N:24]=1
Reactant: Clc1nc(N2CCCCC2)c2nc(Cl)nc(N3CCCCC3)c2n1
Reactant: O
Reactant: CC(C)CO
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)COc1nc(N2CCCCC2)c2nc(OCC(C)C)nc(N3CCCCC3)c2n1
Temperature: 25 °C
Yield: 54 %

Procedure:
Sodium metal (0.115 g, 5 mmol) was added to 2-methylpropan-1-ol (0.37 g, 5 mmol) in dry THF (5 ml) and stirred until all had dissolved. 2,6-dichloro-4,8-dipiperidinopyrimidopyrimidine (0.184 g, 0.5 mmol) dissolved in dry THF (10 ml) was added to the alkoxide and the mixture heated under reflux for 42 hours. After cooling to room temperature, water (20 ml) was added and the product extracted into ethyl acetate (4×20 ml). The organic layers were combined, dried (MgSO4), filtered and the solvent removed in vacuo. Recrystallisation from methanol/water yielded the title compound as a yellow crystalline solid (0.122 g, 54%), m.p. 114-116° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[CH2:14](SSCCC)[CH2:15]C.BrC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C.C(OCC)C>[CH2:1]([S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1)[CH2:14][CH3:15]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCSSCCC
Agent: Brc1c[nH]nc1-c1cccnc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCSc1c[nH]nc1-c1cccnc1
Yield: 76 %

Procedure:
Compound 21E was prepared following the procedure as described for the synthesis of compound 21A using (see scheme 3) 1-propyldisulfanyl-propane as the disulfide and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A). (flash chromatography conditions ethyl acetate/diethyl ether 5/1).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]([CH3:11])[C:7](=[O:10])[NH:8][N:9]=1.[C:12]([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH3:11])[C:7](=[O:10])[N:8]([CH3:12])[N:9]=1
Reactant: Cc1cc(Cl)n[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Cl)nn(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (1.3 mL) was added to a mixture of 6-chloro-4-methyl-2H-pyridazin-3-one (2.70 g) and K2CO3 (3.40 g) in dimethylformamide (27 mL). The resulting mixture was stirred at ambient temperature overnight. Then, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). After removal of the solvent, the title compound was obtained as a solid. Yield: 2.97 g (100% of theory). Mass spectrum (ESI+): m/z=159/161 (CI) [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[I:8].[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10]1.O1CCCC1.CN(C)C=O.[H-].[Na+]>O>[I:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][S:9][CH:10]=1
Reactant: Clc1ccncc1I
Reactant: OCCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cnccc1OCCc1ccsc1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 4-chloro-3-iodo-pyridine (4.79 g, 20.0 mmol) and 2-(3-thienyl)ethanol (2.43 mL, 22.0 mmol) in a mixture of tetrahydrofuran (60 mL, 700 mmol) and N,N-dimethylformamide (20 mL, 200 mmol) was added sodium hydride, 60% dispersion in mineral oil (0.960 g, 24.0 mmol) portionwise over 30 min. The mixture was stirred for 2 hours, poured carefully into 200 ml of cold water and extracted with diethylether twice. The organic extract was washed with water and brine, and dried over MgSO4. After concentration under vacuum, the crude residue was purified on silica gel column, eluting with 50% ethyl acetate in hexane to give 3-iodo-4-(2-(thiophen-3-yl)ethoxy)pyridine (yield 5.34 g, 81%). 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.35 (d, J=5.6, 1H), 7.29 (dd, J=3.0, 4.8, 1H), 7.19 (s, 1H), 7.12 (d, J=4.9, 1H), 6.70 (d, J=5.6, 1H), 4.26 (t, J=6.5, 2H), 3.21 (t, J=6.5, 2H). MS (ESI+) 332.0, 221.9.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[NH2:27].CCCCCC>CCOC(C)=O>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[NH:27][C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:11]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)c(Cl)cc1NC(=O)C(C)c1ccccc1
Yield: 95 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-phenyl-propionic acid (2.00 g, 13.3 mmol), SOCl2 (2.28 mL, 40.0 mmol), and 2-amino-4,5-dichloro-benzoic acid methyl ester (1.95 g, 8.88 mmol). After normal workup, the pure objective compound (2.97 g, 95%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=20:1): 1H NMR (200 MHz, CDCl3) δ 1.59 (d, J=7.1 Hz, 3H, CH3), 3.70-3.89 (m, 4H, CO2CH3& CH), 7.28-7.42 (m, 5H, ArH), 8.03 (s, 1H, ArH), 8.99 (s, 1H, ArH), 11.00 (br s, 1H, NH).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=1)=[O:8].B(O)(O)[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCCC1>O>[C:31]1([CH3:34])[CH:32]=[CH:33][C:28]([C:2]2[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=2)[C:7]([NH:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OCC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide (example BP; 100 mg, 223 μmol), p-tolylboronic acid (CAN 5720-05-8; 33 mg, 243 μmol), 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (4 mg, 5.27 μmol) and Na2CO3 (35 mg, 330 μmol) were combined with tetrahydrofuran (5 mL) and water (1.5 mL). The reaction mixture was heated to 90° C., stirred for 15 h, cooled down and poured into 25 mL H2O. The mixture was extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine (1×25 mL), dried with MgSO4 and concentrated in vacuo. The crude material was purified twice by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in hexanes) to give 48 mg (46%) of the title compound as a light yellow solid; MS (ESI): 459.090 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)[CH:15]=1.[OH-].[Na+]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)[CH:15]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(Nc3nc(C)cs3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3Cl)ccn2)n1
Product: Cl
Yield: 184.2 %

Procedure:
Following the method of Example 31, ethyl 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoate (0.600 g, 1.54 mmol), ethanol (30 ml), 1M NaOH (10 mL) were combined to give the desired product (0.565 g, 89.4% yield) as a light green solid. 1H NMR (d6-DMSO) δ 8.25 (d, 1H), 7.91 (dd, 1H), 7.83 (d, 1H), 7.81 (d, 1H), 6.66 (dd, 1H), 6.64 (m, 1H), 6.61 (d, 1H), 2.23 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][CH2:13][S:14](Cl)(=[O:16])=[O:15].CN(C1C=CC=CN=1)C>ClCCl.N1C=CC=CC=1>[Cl:12][CH2:13][S:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)CCl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(NS(=O)(=O)CCl)ccc1F
Reaction time: 3 h
Yield: 93.1 %

Procedure:
20 g of 4-fluoro-3-nitroaniline (128 mmol) was dissolved in a mixture of 200 mL of dichloromethane and 40 mL of pyridine. To this solution was added 21 g (140 mmol) of chloromethylsulfonyl chloride dropwise at 20-30° C., followed by the addition of 3.21 g of dimethylaminopyridine. The solution was stirred for an additional 3 hours. The reaction mixture was transferred into a separatory funnel and washed sequentially with water (twice with 25 mL), 5% HCl (twice with 25 mL), and water (25 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to yield 32 g (93%) of the title compound as a solid melting at 112-113° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[CH:19](=[N+:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Reactant: C(c1ccccc1)=[N+]1CCCC1
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccccc2)N2CCCC2)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and 1-benzylidene-pyrrolidinium chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.N1C=CC=CC=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CCOCC>[CH3:9][O:8][C:7]1[C:2]([NH:1][C:19](=[O:20])[CH2:18][Cl:17])=[N:3][CH:4]=[C:5]([Br:10])[CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc(Br)cnc1N
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1cc(Br)cnc1NC(=O)CCl
Reaction time: 0.5 h

Procedure:
A solution of 2-amino-3-methoxy-5-bromopyridine (20.3 grams) in absolute ether (200 ml) is charged into a glass reaction vessel equipped with mechanical stirrer and addition funnel. The solution is cooled to a temperature of about 5° C and pyridine (20 ml) is added thereto. A solution of chloroacetyl chloride (11.3 grams) in ether (50 ml) is then slowly added, with stirring, to the flask over a period of about 30 minutes resulting in the formation of a precipitate. The temperature of the reaction mixture is kept below about 10° C during the addition of the chloroacetyl chloride and stirring is continued thereafter for a period of about 1 hour to ensure the completion of the reaction. The precipitate which has formed is then recovered by filtration and is washed first with aqueous potassium carbonate and then with water. The washed product is then dried in a vacuum desiccator to yield the desired product N-(3-methoxy-5-bromo-2-pyridyl)-α-chloroacetamide.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CCCCN[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:28][C@H:29]([C:45]([N:47]1[CH2:55][CH2:54][CH2:53][C@H:48]1[C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH2:30][CH2:31]CCNC(OCC1C=CC=CC=1)=O.[F:56][C:57]([C:60]([OH:62])=[O:61])([F:59])[F:58]>N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CCC(=O)OCC1C=CC=CC=1>[NH2:28][C@H:29]([C:45]([N:47]1[CH2:55][CH2:54][CH2:53][C@H:48]1[C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH2:30][CH2:31][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1.[F:56][C:57]([C:60]([OH:62])=[O:61])([F:59])[F:58]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCC(=O)OCc1ccccc1

Procedure:
Instead of Boc-Lys(Z)-OH in (b), Boc-Glu(Bzl)-OH was used as a starting compound to obtain H-Glu(Bzl)-Pro-OMe trifluoroacetate (oil).
Reaction SMILES: C=O.N[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:5]1([CH2:18][CH3:19])[CH3:17].[C:20]([BH3-])#[N:21].[Na+].[C:24](O)(=O)C>CO>[CH2:10]([N:7]1[CH2:8][CH2:9][CH:4]([N:21]([CH3:20])[CH3:24])[C:5]([CH2:18][CH3:19])([CH3:17])[CH2:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCC1(C)CN(Cc2ccccc2)CCC1N(C)C
Reaction time: 24 h

Procedure:
Paraformaldehyde (10 g) was added to the stirred solution of 4-amino-1-benzyl-3-ethyl-3-methylpiperidine (8.0 g, 34 mmol) in methanol (100 ml) at 0° C. and sodium cyanoborohydride (2.14 g, 34 mmol) was added to it. Then, acetic acid (2 ml) was added to the resulting mixture and stirring was continued for 24 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to give 1-benzyl-4-dimethylamino-3-ethyl-3-methylpiperidine. Yield 6 g (67%), C17H28N2, m/z 261 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH:10]2[N:25]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:26][CH2:27][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:25]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:26][CH2:27][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)C2C1CCN2C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87.8 %

Procedure:
The crude ester (42, 11.7 g crude, ˜11.0 mmol) was dissolved in 1:1 THF/MeOH (75 mL) and cooled to 0° C. and 1M NaOH (45 mL) was added in one portion. After 45 min, the reaction mixture was quenched with glacial HOAc (10 mL) and concentrated in vacuo. The residue was dissolved in EtOAc and the organic solution was washed successively with aqueous NaHCO3 (5×) and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was absorbed onto silica gel and purified by flash silica gel chromatography (2:1 to 1:2 hexanes/EtOAc) to provide 43 as a white foam (3.5 g, 88%, 2 steps): 1H NMR (300 MHz, CDCl3): δ7.39 (m, 5H), 5.15 (m, 2H), 4.40 (m, 2H), 4.13 (m, 1H), 3.54 (m, 3H), 3.35 (m, 1H), 2.83 (m, 1H), 2.11 (m, 2H), 1.49 (s, 9H) ppm. Mass spectrum, m/z [306.6] (M−t-Bu)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][CH:31]=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(C1C=CC(C2SC=C(CCl)N=2)=CC=1)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:24][CH:25]=3)[S:30][CH:31]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc(CCO)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CC(C)(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(C)(C)C)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-tert-butyl-phenyl)-thiazol-4-yl]-ethanol (prepared from 2-(4-tert-butyl-phenyl)-4-chloromethyl-thiazole (example 4 a]) in analogy to the sequence described in examples 13 a] to 13 d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-thiazol-4-yl]-ethoxy}-3-fluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-thiazol-4-yl]-ethoxy}-3-fluoro-phenyl)-2-ethoxy-propionic acid as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][CH2:14][C:4]=2[N:5]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.CC(O)=O.C(OCC)(=O)C>Cl.O>[Cl:13][C:10]1[S:9][C:8]([C:6]2[N:7]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=3)[C:3]3[CH2:16][CH2:15][CH2:14][C:4]=3[N:5]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(Nc2nc(-c3ccc(Cl)s3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
An 18-mL vial was charged with 4-chloro-2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30 mg, 0.11 mmol, 1.1 eq.), 2-(4-aminophenyl)acetic acid (15 mg, 0.1 mmol, 1 eq.), and AcOH (1 ml). To the mixture was added HCl (4 N in dioxane, 5 drops) The resulting mixture was stirred at 100° C. for 2 hr. After cooling to rt, the reaction mixture was diluted with addition of water. The precipitate was collected by filtration and washed with water followed by dichloromethane, The product thus obtained (30 mg, 78% yield) was further treated with ethyl acetate to afford 2-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetic acid (7.2 mg). MW=385.87. 1H NMR (DMSO-D6, 360 MHz) δ 9.22 (brs, 1H), 7.76 (d, J=3.9 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.21 (d, J=3.9 Hz, 1H), 3.55 (s, 2H), 2.87 (m, 4H), 2.09 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:36](Cl)(=O)CCC>>[CH3:12][C:8]1[N:7]=[C:6]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[O:24])=[CH:18][CH:19]=3)[C:3]([CH2:1][CH2:2][CH3:36])=[N:4][C:5]2=[C:10]([CH3:11])[CH:9]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCCC(=O)Cl
Product: CCCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and butyryl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:32][CH3:33])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:30]=O)=[C:24]([C:27](=[O:29])[CH3:28])[C:25]=1[CH3:26])=[O:20])[CH3:13].C(OC(C1NC(C=O)=C(C(=O)C)C=1C)=O)C>>[CH2:32]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:30]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[C:24]([C:27](=[O:29])[CH3:28])[C:25]=1[CH3:26])=[O:20])[CH3:33]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)c(C(C)=O)c1C
Agent: CCOC(=O)c1[nH]c(C=O)c(C(C)=O)c1C
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C(C)=O)c1C

Procedure:
5-Bromo-1,3-dihydro-indol-2-one was condensed with 4-acetyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide (prepared from 4-acetyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester by method B then C) to give the title compound.