Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[N:4]([CH:7]([CH2:12][CH2:13]I)[C:8]([O:10][CH3:11])=[O:9])=[N+:5]=[N-:6].O>CS(C)=O>[N:4]([CH:7]([CH2:12][CH2:13][C:1]#[N:2])[C:8]([O:10][CH3:11])=[O:9])=[N+:5]=[N-:6]
Reactant: [C-]#N
Reactant: COC(=O)C(CCI)N=[N+]=[N-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(CCC#N)N=[N+]=[N-]
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a cold (10°) suspension of potassium cyanide (1.5 g, 23 mmol) in dry DMSO (25 ml) was added methyl 2-azido-4-iodobutyrate (4.0 g, 15 mmol) and the mixture stirred at 10° C. for 10 min and at room temperature for 45 min. The reaction mixture was poured into cold water (200 ml) and the solution was extracted with chloroform (4×80 ml). The chloroform extract was washed with water (4×50 ml), dried and evaporated to give a syrup (2.0 g) which on tlc (silica, 10% ether-benzene) showed a major spot of Rf 0.4 and some impurities (Rf 0, 0.67, and 1.0). The product was purified by chromatography on a silica column (20 cm×2.9 cm 1-D) using 10% ether in benzene as eluent to give 1.1 g (44%) of title compound as a syrup; ir (neat) νmax : 2100, 1745 cm-1 ; 1Hmr (CDCl3) δ:2.17 (m, 2H, --CH2 --), 2.5 (m, 2H, CH2CN), 3.83 (s, 3H, OCH3) and 4.13 ppm (q, J=9, 6 Hz, 1H, CHN3). Anal. calcl for C6H8N4O2 : C 42.84, H 4.89, N 33.31; found: C 42.76, H 4.72, N 33.16.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl.[CH:8]([O:10][CH2:11][CH3:12])=[CH2:9]>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][CH2:8][O:10][CH2:11][CH3:12])[CH:6]=1
Reactant: C=COCC
Reactant: Brc1cn[nH]c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.4 %

Procedure:
To a solution of 4-bromopyrazole (70.0 g, 0.476 mol) in CH2Cl2 (600 mL) was added a solution of 3.1 M HCl in dioxane (4 mL) and ethyl vinyl ether (41 g, 0.569 mol, 1.2 equiv) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction was quenched with aqueous NaHCO3 and the two layers were separated. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to dryness to afford 4-bromo-1-(ethoxyethyl)-1H-pyrazole (113 g, 104.3 g theoretical, 97% yield) as an oil (GC purity: 89%), which was directly used in the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:11]1(=O)NCCCCC1>O>[CH3:11][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:9]
Reactant: COC(=O)CCCCCN
Reactant: O=C1CCCCCN1
Solvent: O
Product: CN1CCCCCC1=O
Yield: 4.5 %

Procedure:
A solution of 15.7% of methyl 6-aminocaproate and 8.2% of caprolactam in water was pumped through a 40 ml tube reactor at 270° C. and 100 bar with a residence time of 4.2 minutes. The exit stream contained according to quantitative gas chromatography 14.98% by weight of caprolactam, corresponding to a yield of 55.4%, based on methyl 6-aminocaproate. N-methylcaprolactam was formed as a by-product in a 4.5% yield.
Reaction SMILES: [Li+].CCC[CH2-].C1C[O:9][CH2:8]C1.C(NC(C)C)(C)C.[Cl:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]>CN(C=O)C>[Cl:18][C:19]1[C:20]2[C:21](=[O:23])[O:22][CH:8]([OH:9])[C:24]=2[CH:25]=[C:26]([Cl:28])[N:27]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: C1CCOC1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C1OC(O)c2cc(Cl)nc(Cl)c21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-Butyllithium (46.7 ml) was added to 100 ml of THF at −78° C., followed by the addition of diisopropylamine (16.65 ml) over 15 min. The mixture was stirred for 1 h at −78° C., then 2,6-dichloronicotinic acid (7.12 g) was added over 10 min. Stirring at −78° C. was continued for 2 h, then DMF (23.26 ml) was added dropwise maintaining the T<−70° C. The mixture was stirred for 1 h at −78° C., warmed to −50° C. for 30 min, and allowed to warm to RT. The mixture was quenched carefully by the addition of 2 N HCl (167 ml) until acidic pH was reached. The mixture was extracted with EtOAc, the organic layers were washed with brine and dried over MgSO4. After evaporation of the solvents the crude material was used without further purification: brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:10])[C:7]=1[CH2:8][CH3:9].O.[NH2:13][NH2:14]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[C:6]([CH3:10])[C:7]=1[CH2:8][CH3:9]
Reactant: NN
Reactant: CCc1c(Cl)nnc(Cl)c1C
Solvent: C1COCCO1
Solvent: O
Product: CCc1c(Cl)nnc(NN)c1C
Reaction time: 1 h

Procedure:
3,6-Dichloro-4-ethyl-5-methylpyridazine (W4.007; 1 g) was initially charged in dioxane (8 ml) with addition of hydrazine monohydrate (2 ml) in a microwave vessel at RT. Thereafter, the reaction mixture was kept at 140° C. in the microwave for 1 h. In the course of standing overnight, a solid precipitated out, which was filtered off with suction, washed and dried. 345 mg of (6-chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine were obtained as the free base. The mother liquor was concentrated to dryness and the residue was purified by means of preparative HPLC (met. F). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure and freeze-dried. 340 mg of 6-chloro-4-ethyl-5-methylpyridazin-3-yl)hydrazine trifluoroacetic acid salt and 239 mg of (6-chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine as the trifluoroacetate were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[F:12][C:10]1[CH:11]=[C:2]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([F:14])[CH:16]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Oc1ccc2cc(Br)cc(F)c2c1
Product: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-bromo-8-fluoro-2-naphthol (0.66 g, 2.74 mmol) with 3-fluoro-4-methoxyphenyl boronic acid (0.56 g, 3.3 mmol) according to method A to yield 0.67 g (85%) of a white solid: mp 138–140° C.; 1H NMR (DMSO-d6): δ 3.90 (3H, s), 7.17–7.30 (3H, m), 7.60- 7.65 (2H, m), 7.71 (1H, dd, J=2.19 Hz), J=13.14 Hz), 7.90 (1H, d, J=8.37 Hz), 7.99 (1H, bs), 10.15 (1H, bs); MS (ESI) m/z 285 (M−H)−.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1>[C:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)NCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
10 g (55.05 mmol) tert.-butyl β-alaninate hydrochloride are dissolved in 50 ml tetrahydrofuran, and 11.14 g (110.1 mmol) triethylamine and 5.53 g (36.7 mmol) ethyl 3-chloro-3-oxopropanoate are added at 0° C. The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the product is isolated by column chromatography (silica, eluent dichloromethane/methanol 100:1→50:1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14]([CH2:17][N:18]1[C:22](=[O:23])[C:21](=[CH:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[S:20][C:19]1=[S:34])([OH:16])=[O:15].S1CC(=O)NC1=S.CO>O>[CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14]([CH2:17][N:18]1[C:22](=[O:23])/[C:21](=[CH:24]\[CH:25]=[CH:26]\[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])/[S:20][C:19]1=[S:34])([OH:16])=[O:15]
Reactant: Cc1ccccc1C=CC=C1SC(=S)N(CC(=O)O)C1=O
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C1CSC(=S)N1
Solvent: O
Solvent: CO
Product: Cc1ccccc1/C=C/C=C1/SC(=S)N(CC(=O)O)C1=O
Temperature: 25 °C
Yield: 72.5 %

Procedure:
To a solution of 2.001 g of N-methyl-D-glucamine in 20 ml of water was added 3.194 g of 3-carboxymethyl-5-(2-methylcinnamylidene)-rhodanine [prepared as described in Example 1 (35)], and the mixture was heated to dissolve the rhodanine derivative, and then 40 ml of methanol was added to the solution at the same temperature. The mixture was cooled to room temperature and the precipitated crystals were filtered. The resulting crystals were washed with 5 ml of mixture of water and methanol (1:2), and 5 ml of methanol, and dried under reduced pressure to obtain 3.73 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].O[CH:13]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C1(C)C=CC=CC=1>[CH3:11][C:6]1[C:7](=[O:10])[C:8]([CH3:9])=[C:2]([CH3:1])[C:3](=[O:4])[C:5]=1[CH:13]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: COc1ccc(C(O)CCCCC(=O)O)cc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1ccc(C(CCCCC(=O)O)C2=C(C)C(=O)C(C)=C(C)C2=O)cc1
Temperature: 70 °C
Yield: 68.8 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (60 ml) of 2,3,5-trimethylhydroquinone (3.1 g, 0.02 mole) and 6-hydroxy-6-(4-methoxyphenyl)hexanoic acid (5.0 g, 0.021 mole), and the mixture was heated at 70° C. for 20 hours, with stirring. The reaction solution was evaporated under reduced pressure, and tetrahydrofuran (50 ml) was added to dissolve the residue, followed by adding furthermore a 10% aqueous solution of ferric chloride and stirring at room temperature for 10 minutes. The reaction product was extracted with ethyl acetate, and the organic layer was washed with water, dried and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether to give 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(4-methoxyphenyl)hexanoic acid (5.1 g, 76%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 23 to 34 and 68 were prepared.
Reaction SMILES: [NH2:1][C@H:2]([CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([F:13])=[C:8]([Cl:14])[CH:7]=1)=[O:4].[CH:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.CCCCCC>[C:17]([C@@H:20]1[N:5]([C:6]2[CH:7]=[C:8]([Cl:14])[C:9]([F:13])=[C:10]([Cl:12])[CH:11]=2)[C:3](=[O:4])[C@@H:2]([CH3:15])[NH:1]1)([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)C=O
Reactant: C[C@@H](N)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C[C@H]1N[C@H](C(C)(C)C)N(c2cc(Cl)c(F)c(Cl)c2)C1=O
Temperature: 50 °C
Reaction time: 22 h
Yield: 59.2 %

Procedure:
To a solution of (R)-2-amino-N-(3,5-dichloro-4-fluoro-phenyl)-propionamide (149 g crude, max 594 mmol) in toluene (743 mL) at 40° C., was added pivalaldehyde (67.1 mL, 618 mmol) in one portion. The reaction was stirred at 50° C. for 22 h and then all volatiles were removed in vacuo to give a viscous brown oil. Hexane (500 mL) was added and the resulting suspension was stirred at room temperature for 30 min. The mixture was filtered and the solids rinsed with cold hexane. The filtrate was concentrated in vacuo and reprocessed in a similar manner to obtain additional precipitate. The remaining filtrate was diluted with hexane until a black oil separated from the solution. The hexane layer was decanted from this black oil and concentrated in vacuo. The residue was re-dissolved in warm diethyl ether (300 mL) and stored in the freezer for 1.5 h over which time crystal growth was observed. The solids were filtered, and the filtrate reprocessed in a similar manner to obtain additional crystals. All of the collected solids were combined to give 112.2 g of (2S,5R)-2-tert-butyl-3-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-imidazolidin-4-one as a tan solid. To a solution of this solid in toluene (639 mL) at 0° C. was added triethylamine (73.5 mL, 527 mmol) in one portion. Trifluoroacetic anhydride (58.6 mL, 422 mmol) was added to the reaction mixture over 1 h at a rate to keep the internal temperature below 5° C. The reaction mixture was stirred at 0° C. for 1 h and then warmed to 20° C. over 1 h. The mixture was then cooled to 10° C. and water (1.2 L) was added. The layers were separated and the organic layer was washed with water (1.2 L and then 0.6 L). The combined aqueous layers were extracted with toluene (0.6 L). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give 149.4 g of the title compound as a tan solid, m/z 456.4 [M+MeCN+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][C:8]1([CH2:21][NH2:22])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)CC)C>O1CCCC1>[CH3:7][C:8]1([CH2:21][NH:22][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CCCC(=O)Cl
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Yield: 94.4 %

Procedure:
Butanoyl chloride (5.3 g) is added to a stirring mixture at 0° C. of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine (10.0 g, described in Example 3), triethylamine (5 g) and dry tetrahydrofuran (400 ml). The temperature is allowed to rise to room temperature, the reaction mixture is filtered, and the filtrate is evaporated to give the title compound (12.5 g): ir(CHCl3) 3420, 3250, 2855 and 1660 cm-1 ; nmr(CDCl3) δ0.75(t), 1.57(s), 1.62(m), 2.08(t), 2.87(m), 3.91(t), 4.10(t), 6.12(s), 7.0-7.7(m) and 9.86(s)
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>C(OCC)(=O)C>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Clc1ccnc2ccsc12
Temperature: 105 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of thieno[3,2-b]pyridin-7-ol (3.8 g, 25 mmol) and phosphorus oxychloride (18 g, 120 mmol) was stirred at 105° C. for 2 hr. The reaction mixture was added to ice water, and basified with 8N aqueous sodium hydroxide solution. Ethyl acetate was added, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70), and the obtained solution was concentrated under reduced pressure to give the title compound (2.8 g, 66%) as a pale-yellow solid.
Reaction SMILES: II.[C:3]([C:6]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[OH-:24].[Na+].[CH3:26][CH2:27][OH:28]>N1C=CC=CC=1.O>[CH:12]1[C:11]2[C:10]3[C:23](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][C:26]=1[C:27]([OH:24])=[O:28].[C:3]([C:6]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: [OH-]
Reactant: CCO
Agent: CC(=O)c1cccc2c3ccccc3c3ccccc3c12
Agent: II
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc2c3ccccc3c3ccccc3c2c1

Procedure:
The reaction product obtained in step a) is admixed with 2.2 equivalents of I2 (based on the crude yield of acetyltriphenylene) in pyridine solvent at room temperature. Thereafter, the mixture is kept at reflux for 45 min, and then a further portion of I2 (1.0 equivalent) is added. After reflux for a further hour, NaOH, EtOH and water are added and the reaction mixture is heated to reflux for 2 h. 2-triphenylenecarboxylic acid is obtained in 76% yield (based on crude yield of acetyltriphenylene, or 74% based on triphenylene).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[C:3]=1[Cl:18].S(Cl)(Cl)=O.O.[OH-].[Na+].[CH2:26](O)[CH3:27]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([O:17][CH2:26][CH3:27])=[O:16])[C:3]=1[Cl:18]
Reactant: Nc1nc(-c2ccc(Cl)cc2)nc(C(=O)O)c1Cl
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)nc(N)c1Cl

Procedure:
To a solution of 6-amino-5-chloro-2-(4-chlorophenyl)-4-pyrimidinecarboxylic acid (i.e. the product of Example 4, Step C) (20.0 g, 70.4 mmol) in ethanol (70 mL) was added thionyl chloride (5.14 mL, 70.4 mmol) while maintaining the temperature below 15° C. using an ice bath. The reaction mixture was then heated at reflux overnight. Water was added. Then with external cooling aqueous sodium hydroxide (50%) was added to adjust the pH to 7. The resulting solid was isolated by filtration and dried to afford the title product, a compound of the present invention, as a light beige solid (20.1 g).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[N:15]=[CH:16][C:17]2[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=2[N:19]=1.Cl.C1(N2CCNCC2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:14]3[N:15]=[CH:16][C:17]4[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=4[N:19]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(c4ccccc4)CC3)ncc2c1=O
Yield: 83 %

Procedure:
A solution of 3.2 g of (0.02 mol) of N-phenyl-piperazine in 30 cm3 of toluene is added to 2.8 g (0.01 mol) of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine dissolved in 30 cm3 of toluene. Reaction takes place practically instantaneously with evolution of heat and the mixture sets solid due to formation of phenylpiperazine hydrochloride. The mixture is diluted with 100 cm3 of ethyl acetate, the solution is filtered, washed with water and dried (MgSO4) and the solvent is evaporated. The residue is recrystallised from 110 cm3 of isopropanol and yields 3.38 g (84%) of 2-(4'-phenyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine; melting point 186° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Br:11][C:12]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2>>[Br:11][C:12]1[CH:20]=[C:19]([CH:21]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2
Reactant: O=Cc1cc(Br)c2cn[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Nc2ccccc2C1=Cc1cc(Br)c2cn[nH]c2c1

Procedure:
According to the method described for Example A1, oxindole (15 mg, 0.11 mmol) was reacted with 4-bromo-1H-indazole-6-carbaldehyde (25 mg, 0.11 mmol) to give the title compound as an orange solid. The E and Z stereoisomers were separated by HPLC.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[CH2:27][CH2:28][C:29]([OH:31])=O)[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:74]([O:78][C:79](=[O:83])[CH2:80][CH2:81][NH2:82])([CH3:77])([CH3:76])[CH3:75]>CN(C=O)C>[C:74]([O:78][C:79](=[O:83])[CH2:80][CH2:81][NH:82][C:29](=[O:31])[CH2:28][CH2:27][C:4]1[C:5]([CH3:26])=[CH:6][C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:24])[CH3:25])[CH3:22])[CH:15]=3)[O:11][N:10]=2)=[CH:8][C:3]=1[CH2:1][CH3:2])([CH3:77])([CH3:76])[CH3:75]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)NCCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid (43 mg, 0.101 mmol) and DIPEA (40 mg, 0.304 mmol) in DMF (3 mL) is added PyBOP (58 mg, 0.111 mmol) at 0° C. The mixture is stirred for 15 min at 0° C. before β-alanine tert.-butyl ester (20 mg, 0.111 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched with 2 mL water, and the mixture is diluted in sat. aq. NaHCO3-solution, and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and dried to give crude 3-[3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionylamino]-propionic acid tert-butyl ester (46 mg). This material is dissolved in 4 N HCl in dioxane (5 mL) and the mixture is stirred at rt for 18 h. The solvent is evaporated and the crude product is purified on prep. TLC plates with DCM containing 18% of 7 N NH3 in methanol to give 3-[3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionylamino]-propionic acid (37 mg) as a yellow solid; LC-MS: tR=0.86 min; [M+1]+=494.24.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.Cl[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl>[CH3:26][O:25][C:23]([N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13]1)=[O:24]
Reactant: CSc1cccc(C2=CCNCC2)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC=C(c2cccc(SC)c2)CC1
Temperature: 0 °C

Procedure:
4-(3-Methylsulfanyl-phenyl)-1,2,3,6-tetrahydro-pyridine (2 g) and NEt3 (1 g) were dissolved in CH2Cl2 (75 ml) and cooled to 0° C. Methyl chloroformate (0.96 g) dissolved in CH2Cl2 (20 ml) was added dropwise and the reaction mixture was then allowed to reach room temperature. After an additional two hours at room temperature the reaction mixture was washed with 10% Na2CO3 solution, dried (MgSO4), filtered and concentrated by evaporation. The oily residue was chromatographed on a silica column using CH2Cl2:MeOH (19:1 (v/v)) as eluent, 4-(3-methylsulfanyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester (1.4 g). MS m/z (relative intensity, 70 eV) 263 (M+45), 248 (89), 129 (83), 128 (bp), 59 (96).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Yield: 33.9 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-isopropyl-1-phenyl-1H-pyrazol-5-amine (423 mg, 2.1 mmol) and potassium carbonate (378 mg, 2.7 mmol) in anhydrous DCM (8 ml) was added dropwise phenyl chloroformate (0.39 ml, 3.1 mmol) as a solution in DCM (2 ml) to afford phenyl 3-isopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (229 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 1.27 (d, J=6 Hz, 6H), 3.01 (m, 1H), 6.46 (s, 1H), 7.14-7.36 (m, 2H), 7.38-7.57 (m, 8H); LC-MS (ESI) m/z 322 (M+H)+.