Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]2[C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=2[CH3:29])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[N:30]1([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]3[C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=3[CH3:29])=[CH:4][CH:3]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CCc1ccn(-c2ccc(Br)cc2)c1-c1ccc(C(N)=O)cc1C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccn(-c2ccc(-n3ccnc3)cc2)c1-c1ccc(C(N)=O)cc1C
Temperature: 130 °C
Yield: 51 %

Procedure:
A mixture of ethyl 3-(1-(4-bromophenyl)-2-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-3-yl)propanoate (50 mg, 0.11 mmol), imidazole (68 mg, 10 mmol), L-proline (13 mg, 0.11 mmol), CuI (42 mg, 0.22 mmol), K2CO3 (76 mg, 0.55 mmol) and 4 Å molecular sieve (100 mg) in DMSO (3 mL) was heated at 130° C. for 24 h. After being cooled down to room temperature, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL×3). The combined filtrate was washed with saturated NaHCO3 aqueous solution (30 mL), and the aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by preparative TLC (eluting with 7% methanol in dichloromethane) to give ethyl 3-(1-(4-(1H-imidazol-1-yl)phenyl)-2-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-3-yl)propanoate, (5-3, R1=1H-imidazol-1-yl) (25 mg, yield: 51%), which was used in the next step without further purification.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[SH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[S:21]=[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccccn1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCn2ccccc2=S)cc1)c1ccccc1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-mercaptopyridine. HPLC-MS: m/z=365.2 (M+1); Rt=4.08 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([O:21]C)=O)=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:21])=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1
Reactant: C=COCCON
Reactant: COC(=O)c1nn(C)c(=O)cc1Nc1ccc(SC)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1nn(C)c(=O)cc1Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of methyl 4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (25 mg, 0.077 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (24 mg, 0.23 mmol) in THF (2 mL) at 0° C. was added LiHMDS (0.54 mL, 0.54 mmol, 1 M in THF). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% CH2Cl2 to 1.5% MeOH in CH2Cl2) to afford 30 mg (99%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([C@H:6]([CH3:19])[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([CH2:17][CH3:18])[CH:8]=1)[NH2:5].[C:21]([O:25][C:26]([NH:28][C@@H:29]([C:37](O)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([C@H:6]([CH3:19])[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([CH2:17][CH3:18])[CH:8]=1)[NH:5][C:37](=[O:38])[C@@H:29]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:27]
Reactant: CCn1cc([C@@H](C)[C@@H](N)C(=O)OC)c2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCn1cc([C@@H](C)[C@@H](NC(=O)[C@@H](Cc2ccccn2)NC(=O)OC(C)(C)C)C(=O)OC)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of (αR,βR)-5-chloro-1-ethyl-β-methyltryptophan methyl ester (1.24 g) and N-t-butoxycarbonyl-3-(2-pyridyl)-D-alanine (1.12 g) in dry methylene chloride (30 ml) which was cooled on an ice bath, was added a solution of N,N'-dicyclohexylcarbodiimide (0.9 g) in dry methylene chloride (5 ml). The mixture was stirred overnight at room temperature. After removal of the solvent, the crude residue was taken up with a mixture of ethyl acetate and water, filtered, and the organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and solvent was evaporated off to give Nα -[N-t-butoxycarbonyl-3-(2-pyridyl)-D-alanyl](αR,βR)-5-chloro-1-ethyl-β-methyltryptophan methyl ester (2.29 g). To this compound was added trifluoroacetic acid (10 ml) and the mixture was stirred for 30 minutes on an ice bath. After evaporation of the solvent, the crude residue was dissolved in chloroform (50 ml), washed with saturated sodium bicarbonate solution, treated with active charcoal, dried over magnesium sulfate, and the solvent was evaporated off to give an oil (1.43 g). The crude material was dissolved in ethanol (10 ml) and saturated alcoholic ammonia (10 ml) was added. The resulting mixture was allowed to stand for 3 days at room temperature and concentrated in vacuo. The crude residue was chromatographed on silica gel (70 g) (chloroform and 50:1 mixture of chloroform and methanol as eluent) to give an oil (0.56 g) which was crystallized from ethanol to afford (3R,6R)-3-[(R)-1-(5-chloro-1-ethylindol-3-yl)ethyl]-6-(2-pyridylmethyl)piperazine-2,5-dione (0.34 g).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:3][OH:4].[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.CCCCCCC>C1(C)C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[N:1]/[C@H:2]([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:3][OH:4])=[CH:26][CH:27]=1
Reactant: N[C@@H](CO)COc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: COc1ccc(C=O)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N/[C@@H](CO)COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of Example 1G (3.236 kg) and para-anisaldehyde (1.484 kg) in toluene (6.631 kg) was heated at 80° C. for 2 hours, treated with heptane (33.147 kg) over 50 minutes, cooled to room temperature over 20 hours, and filtered. The filter cake was rinsed with heptane (6.994 kg), air dried, then vacuum dried (100 mmHg) at 50° C. to provide 4.297 kg (97.6%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ8.35 (s, 1H), 7.73 (dt, 2H, J=8.9, 2.9 Hz), 7.61 (dt, 2H, J=8.8, 2.9 Hz), 7.41 (dd, 2H, J=8.9, 1.1 Hz), 7.05 (dt, 2H, J=8.8, 2.9 Hz), 7.01 (dt, 2H, J=8.8, 2.9 Hz), 4.87 (br s, 1H), 4.31 (dd, 1H, J=9.9, 4.1 Hz), 4.13 (dd, 1H, J=9.9, 7.4 Hz), 3.81 (s, 3H), 3.64-3.80 (m, 2H), 3.56 (dd, 1H, J=10.0, 6.3 Hz).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2](C)=[CH2:3].[C:8]1(C)[CH:13]=CC=C[CH:9]=1>>[CH2:7]([O:6][C:1](=[O:5])[CH:2]=[CH2:3])[CH2:9][CH2:8][CH3:13]
Reactant: C=C(C)C(=O)OC
Reactant: Cc1ccccc1
Product: C=CC(=O)OCCCC
Reaction time: 4 h

Procedure:
In a 50 ml internal volume flask, 1 g of the olefin copolymer obtained in the above described step (1) was introduced, and 3 ml of toluene and 5 ml of methyl methacrylate were added under nitrogen gas atmosphere. Thermal graft polymerization of methyl methacrylate was conducted at 80° C. for 4 hours.
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[NH:13][C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([C:2]2[C:14](=[O:15])[NH:13][C:5]3[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=2)=[CH:20][CH:19]=1
Reactant: CSc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(C)nc(SC)nc3[nH]c2=O)cn1
Temperature: 100 °C

Procedure:
To a solution of 6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (50 mg, 0.17 mmol), 6-methoxypyridin-3-ylboronic acid (40.1 mg, 1.1 equiv), dichlorobis(triphenylphosphine) palladium(II) (6.13 mg, 0.008 mmol), DMF (2 mL) in a 5 mL microwave vial was added potassium carbonate (3 M, 1.1 equiv). The solution was degassed with N2 for 10 min before being capped and heated in the microwave reactor for 1 h. at 100° C. The reaction was poured into 20 ml brine and the precipitate was collected by filtration. It was further purified by chromatography (80% thylacetate/hexane). The title compound was obtained as a solid (30 mg, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:17])=[CH:10][CH:9]=2)=[O:7])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Yield: 62.6 %

Procedure:
A mixture of 4-(4-chlorobenzoyl)toluene (5.48 g, 23.8 mmol), dibenzoylperoxide (100 mg, 0.413 mmol), and N-bromosuccinimide (4.56 g, 25.6 mmol) in carbon tetrachloride (70 ml) was refluxed for 2 hours, cooled, filtered, and evaporated under vacuum. The residue was chromatographed on silica gel (1 kg) eluted with 97:3 (v/v) hexane-ethyl acetate using a preparative high-performance liquid chromatograph. Appropriate fractions were pooled and evaporated under vacuum to provide 4.61 g (63%) of 4-(4-chlorobenzoyl)benzyl bromide, m.p. 103°-104° C.
Reaction SMILES: BrC1SC(Cl)=C(Cl)C=1C(=O)CCl.[C:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])[CH3:14].[Cl:21][CH2:22][C:23](Cl)=[O:24]>>[C:13]([C:16]1[S:17][C:18]([C:23](=[O:24])[CH2:22][Cl:21])=[CH:19][CH:20]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cccs1
Reactant: O=C(Cl)CCl
Agent: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Product: CC(=O)c1ccc(C(=O)CCl)s1
Yield: 25 %

Procedure:
General procedure described for compounds 1 and 2 starting from 2-acetylthiophene and chloroacetyl chloride. Purified by column chromatography column (hexane:ethyl acetate 3:1), yield 25%, m.p.: 94-95° C., 1H-NMR (CDCl3): δ8.3 (d, J=4.2 Hz, 1H, Ar), 8.1 (d, J=4.2 Hz, 1H, Ar), 4.55 (s, 2H, CH2), 2.6 (s, 3H, CH3); 13C-NMR (CDCl3). δ193.0 (CO), 187.8 (CO), 148.3 (C—CO), 142.0 (CH), 141.7 (C—CO), 133.7 (CH), 48.3 (CH2), 29.2 (CH3); M/z (EI): 204, 202 (M +, 4, 10%), 153 (M-CH2Cl, 100%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 98%, r.t.=3.50 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: C([Li])CCC.[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:12][Si:13]([CH3:23])([CH:21]=[CH2:22])[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.O>C1COCC1>[CH3:12][Si:13]([CH3:23])([CH2:21][CH2:22][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1
Reactant: C=C[Si](C)(C)c1ccc(N)cc1
Reactant: C1CCNCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(CCN1CCCCC1)c1ccc(N)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
At 50° C., n-butyl lithium (8 ml/L, 21 ml) was slowly added dropwise into the THF solution of piperidine (3.5 g, 41 mmol). After the solution was stirred at 50° C. for 30 minutes, compound 6c (0.6 g, 3.4 mmol) in THF was slowly added into the reaction mixture. After the reaction mixture was stirred at 50° C. for 2 hours, three times of water was added into the reaction solution, followed by extracted with ethyl acetate. The organic layer was dried and evaporated to give a crude product, which was purified using column chromatography to give the product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:16]([O:19][CH2:20][CH2:21][OH:22])([CH3:18])[CH3:17].[H-].[Na+]>CN(C=O)C>[Cl:11][C:9]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:22][CH2:21][CH2:20][O:19][CH:16]([CH3:18])[CH3:17])[N:10]=1
Reactant: NC(=O)c1cc(C(F)(F)F)c(Cl)nc1Cl
Reactant: CC(C)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCOc1nc(Cl)c(C(F)(F)F)cc1C(N)=O
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A mixture of 2,6-dichloro-5-(trifluoromethyl)nicotinamide (0.35 g, 1.35 mmol) and 2-isopropoxyethanol (0.14 g, 1.35 mol) in DMF (20 mL) was added sodium hydride (59 mg, 1.48 mmol) in portions at 0° C. The mixture was stirred at r.t for 2 hrs, quenched by water, extracted by EtOAc and the organic layer was concentrated in vacuo to afford 6-chloro-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinamide (0.2 g, 45.4%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.45 (s, 1H), 8.05 (bs, 1H), 7.63 (bs, 1H), 4.54-4.52 (m, 2H), 3.75-3.72 (m, 2H), 3.64-3.58 (m, 1H), 1.07-1.06 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:16].O.O.[C:19](O)(=[O:23])[C:20](O)=[O:21]>Cl>[OH:21][C:20]1[C:19]([OH:23])=[N:16][C:3]2[CH:4]=[CH:5][C:6]3[C:7]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[N:1]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1N
Agent: Cl
Solvent: O
Product: O=S(=O)(O)c1cccc2c1ccc1nc(O)c(O)nc12
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 0,5 g (2,1 mmol) 1,2-diaminonaphthalene-5-sulphonic acid and 0,75 g (5,8 mmol) oxalic acid dihydrate in 25 ml 4N hydrochloric acid was refluxed for 4 h. After cooling to 25° C., the precipitate was filtered off and washed with 5 ml 4N hydrochloric acid and 5 ml ice-cooled water. The crude product was dissolved in 15 ml 4N sodium hydroxide, and then reprecipitated with 4N hydrochlorid acid to give 0,35 g (57%) of 2,3-dihydroxy-benzo(f)quinoxaline-7-sulphonic acid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13]O.S(=O)(=O)(O)O.O>C(OCC)C>[CH3:13][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: COC(=O)C=Cc1ccc(F)cc1
Reaction time: 18 h

Procedure:
A one liter round bottom flask was charged with 50 grams (0.30 moles) of 4-fluorocinnamic acid, 500 milliliters of methanol, and 5.0 grams of concentrated sulfuric acid. This mixture was brought to reflux and kept there for 18 hours. After cooling, one half of the methanol was stripped under vacuum, and the remaining solution was poured into 600 milliliters of water. The precipitated solid was taken into 500 milliliters of diethyl ether and the aqueous phase was discarded. The ether solution was washed three times with 10% aqueous sodium hydroxide and once with water. After drying over magnesium sulfate, the mixture was filtered and stripped under vacuum to give methyl-4-fluorocinnamate as a white crystalline powder. Yield was 40 grams.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].Br[C:6]1[CH:7]=[CH:8][C:9]([O:26][CH2:27][CH3:28])=[C:10]([C:12]2[NH:13][C:14](=O)[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)[CH:11]=1>>[CH2:27]([O:26][C:9]1[CH:8]=[CH:7][C:6](/[CH:3]=[CH:2]/[C:1]#[N:4])=[CH:11][C:10]=1[C:12]1[NH:13][CH2:14][C:15]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=2[N:17]=1)[CH3:28]
Reactant: C=CC#N
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Product: CCCc1nn(C)c2c1N=C(c1cc(/C=C/C#N)ccc1OCC)NC2

Procedure:
The title compound was prepared from acrylonitrile and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one following the procedure of Example 19 and was obtained as off-white crystals (33%). Found C,65.99; H,5.52; N,19.07. C20H21N5O2 requires C,66.10; H,5.82; N,19.27%.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:10]=2[CH:9]=1)=[O:7].[OH-].[K+].Cl>O1CCOCC1.O>[O:18]=[C:17]1[C:10]2[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:23])=[O:2])[S:12][C:11]=2[CH2:13][CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]1=2
Reactant: COC(=O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2=O

Procedure:
A solution of 3.0 g of 4-(9,10-dihydro-4- oxo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-4- oxobutyric acid methyl ester and 1.5 g of potassium hydroxide in 60 cc of dioxane and 30 cc of water is stirred at room temperature for 3 hours, dilution is effected with 200 cc of water and the pH of the solution is adjusted to 1 with concentrated hydrochloric acid at 10°-15°. The resulting title compound is extracted with methylene chloride, the organic solution is washed with water, dried over magnesium sulphate, concentrated by evaporation, and the title compound is recrystallized from dimethyl formamide/acetone. M.P. 167°-168°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH2:14][CH2:15]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:17]12[NH:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]([NH:25][C:26]1[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[CH:29]3)[CH2:18]2>CN(C)C=O>[O:7]([CH2:14][CH2:15][N:24]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][CH:19]([NH:25][C:26]1[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[CH:29]3)[CH2:20]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC(C1)N2
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(OCCN2C3CCC2CC(Nc2ccc4[nH]ncc4c2)C3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
Potassium carbonate (52 mg, 0.376 mmol) and then 2-phenoxyethyl bromide (38 mg, 0.189 mmol) were added to a suspension of the N-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (30 mg, 0.124 mmol) obtained in Example 525 in dimethylformamide (1 ml), and the resulting mixture was stirred at room temperature for 20 hours. After the solid was removed by filtration, the dimethylformamide was distilled off under reduced pressure as an azeotrope with toluene to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol/triethylamine=20/1/1) to obtain N-(8-(2-phenoxyethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (40 mg, 89%).
Reaction SMILES: N1CCCCC1.[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21]>C(OCC)C>[N+:7]([C:10]1[CH:17]=[CH:16][C:13](/[CH:14]=[C:19](/[C:20](=[O:21])[CH3:22])\[C:18]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CCOCC
Product: CCOC(=O)/C(=C\c1ccc([N+](=O)[O-])cc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Piperidine (0.5ml) was added to a solution of paranitrobenzaldehyde (7.5g, 0.05 moles) and ethyl acetoacetate (6.5g, 0.05 moles) and stirred at room temperature for 48 hrs. Ethyl ether (50ml) was added and stirring continued for 7 days. After removal of the ethyl ether by rotary evaporator the titled products were separated and purified by silica gel chromatography. The structure assignments were supported by NMR, infrared and uv spectra and elemental analysis (263.2).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]12[CH2:15][NH:14][CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:10]2[CH2:11][CH:12]3[CH:8]([CH2:15][NH:14][CH2:13]3)[CH2:9]2)[CH:3]=1
Reactant: Fc1cccnc1
Reactant: C1NCC2CNCC12
Product: c1cncc(N2CC3CNCC3C2)c1

Procedure:
Prepared by heating 3-fluoropyridine and 3.7-Diazabicyclo[3.3.0]octane in an autoclave in the absence of solvent at 180° C. for 24 hours. Workup-procedure A/B.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[S:10][C:11]([S:14]([N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:18]3)(=[O:16])=[O:15])=[CH:12][CH:13]=2)C=CC=CC=1.Cl[C:37]1[N:42]=[CH:41][C:40]([C:43]([OH:52])([C:48]([F:51])([F:50])[F:49])[C:44]([F:47])([F:46])[F:45])=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:8][C:9]1[S:10][C:11]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([C:37]3[N:38]=[CH:39][C:40]([C:43]([OH:52])([C:44]([F:45])([F:46])[F:47])[C:48]([F:50])([F:51])[F:49])=[CH:41][N:42]=3)[C@@H:19]([CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:18]2)(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(c1ccc(N=C(c2ccccc2)c2ccccc2)s1)N1CCN[C@@H](CC2CCOCC2)C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ncc(C(O)(C(F)(F)F)C(F)(F)F)cn3)[C@@H](CC3CCOCC3)C2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
In a 20-mL vial was charged with N-(diphenylmethylidene)-5-(((3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)sulfonyl)-2-thiophenamine (170 mg, 0.334 mmol)), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (187 mg, 0.667 mmol, Intermediate D), and Hünig's base (175 μL, 1.001 mmol), and dioxane (5 mL). The vial was sealed and heated to 90° C. for 16 h. Afterwards, the mixture was concentrated in vacuo. The crude material was dissolved in THF (20 mL) and 4 N HCl in dioxane (5 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated, absorbed onto silica gel, and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (88 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35]C[C@@H]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1C[CH2:49][CH2:48][C@H:47]1[CH2:51]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH:47]([CH3:51])[CH2:48][CH3:49])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Reactant: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)NCc1cc(F)cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 50.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-butanamine (37 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.7 mg of the title compound (50.6%).