Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[N:31]1([CH2:36][C:37]([N:39]2[CH2:43][C:42](=O)[CH2:41][C@H:40]2[C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)=[CH:50][CH:49]=2)=[O:46])=[O:38])[CH:35]=[N:34][CH:33]=[N:32]1>CS(C)=O>[N:31]1([CH2:36][C:37]([N:39]2[CH2:43][C:42](=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=3)[CH2:41][C@H:40]2[C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55]3[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=3)=[CH:50][CH:49]=2)=[O:46])=[O:38])[CH:35]=[N:34][CH:33]=[N:32]1
Reactant: O=C1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Reactant: Fc1ccc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CC(=Cc2ccc(F)cc2)CN1C(=O)Cn1cncn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 10.8 %

Procedure:
Step (b) 4-Fluorobenzyl triphenylphosphine chloride (1 g, 2.46 mmol) in DMSO (2 mL) was added to a flask charged with sodium hydride (60% dispersion in oil, 124 mg, 3.10 mmol) and DMSO (2 mL). The reaction mixture was stirred at 70° C. for 3 hours and then (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-oxopyrrolidine-2-carboxamide (0.11 g, 0.25 mmol) in DMSO (2 mL) was added. The mixture was stirred for 16 hours at 70° C. and then quenched with saturated ammonium chloride (aq., 10 mL). This mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL). Product was purified from the mixture directly by column chromatography (EtOAc to EtOAc/MeOH (9:1)+1% NEt3) to give with (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzylidene)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (15 mg, 0.027 mmol, 11% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:16])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12
Reactant: O=S(=O)(O)O
Reactant: CCn1ncc2c(Cl)c(C#N)cnc21
Product: CCn1ncc2c(Cl)c(C(N)=O)cnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
4.25 g. of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]-pyridine-5-carbonitrile (0.02 mol.) are added to 21 ml. of concentrated sulfuric acid. The mixture is stirred at room temperature for 3 days. Then 200 ml. of ice-water are introduced, while cooling with ice-water, and the mixture is allowed to stand overnight in a refrigerator. 2.04 g. (46%) of pure 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxamide are obtained, m.p. 192°-193°.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:16][CH2:17]OS(C)(=O)=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:29]([O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:30].C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([N:11]1[CH2:15][CH2:14][C:13]([CH2:16][CH2:17][N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:35]3[N:34]([CH2:33][CH2:32][O:31][CH2:29][CH3:30])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:49][CH2:48]2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)OCc4ccccc4)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (10.2 g, 25.3 mmol), (1.34 g, 2.5 mmol), (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (30.4 mmol), and N,N-diisopropylethylamine (18 mL, 101 mmol) in acetonitrile (300 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give 1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2cnn(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2cnn(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c2c1
Reaction time: 15 h
Yield: 48.1 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-methyl-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 209 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane, 15 min gradient) gave 2-(6-methyl-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (35 mg, 48%). MS (M+H)+=349; 1H NMR (DMSO-d6) δ: 8.95 (s, 1H), 8.45 (d, J=0.8 Hz, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.71 (s, 1H), 7.21 (dd, J=8.3, 0.8 Hz, 1H), 2.53 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][N:16](COCCOC)[C:13]3=[N:14][CH:15]=2)[CH:5]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:5]=1
Reactant: COCCOCn1nc(-c2ccccc2OC)c2cc(-c3cccc(C(=O)OC)c3)cnc21
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of 3-[1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (573 mg, 1.28 mmol) in dichloromethane (25 mL) was cooled down to 0-5° C. and boron trifluoride etherate (0.8 ml, 6.4 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 16 h. A yellow precipitate was formed was filtered off to afford 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (110 mg (0.29 mmol; 23% yield). 1H-NMR (500 MHz, d6-DMSO) δ 8.88 (d, 1H), 8.39 (d, 1H), 8.27 (t, 1H), 8.06 (td, 1H), 7.99 (td, 1H), 7.65-7.68 (m, 2H), 7.48 (ddd, 1H), 7.23 (d, 1H), 7.11 (dt, 1H), 3.90 (s, 3H), 3.87 (s, 3H). MS: m/z 360 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C.CN(C1C=CN=CC=1)C>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
29.0 g (0.111 mol) of 7-amino-1-(2-ethylbutyl)-2,3(1H,4H)-quinoxalinedione were dissolved in 200 ml of acetic acid. A spatula tip of 4-(N,N-dimethylamino)pyridine was added and then 11.4 g (0.111 mol) of acetic anhydride were added dropwise. The mixture was stirred at room temperature for 30 minutes and then poured into ice-water, and the precipitate was filtered off with suction and dried to yield 22.5 g (67%) of the product.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[C:22](F)[CH:23]=2)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]1)[CH3:14]>CCOCC>[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([CH2:6][N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)[CH2:12]3)[CH:23]=2)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]1)[CH3:14]
Reactant: c1ccn(CC2CNCCN2)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(Cn4cccc4)C3)cc21

Procedure:
A 1 g portion of 2-(1H-pyrrol-1-ylmethyl)piperazine and 0.76 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid were heated at 70°-75° C. in a sealed pressure bottle, filled with argon, for 18 hours, then ether was added and the solid collected, washed with ether and purified by chromatography, giving 595 mg of the desired product, mp 185°-188° C.
Reaction SMILES: [CH2:1](O)C.[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][C:8]([C:21]([O:23][CH3:24])=[O:22])([C:9]4[C:14]3=[CH:13][CH:12]=[C:11]([OH:20])[CH:10]=4)[C:7]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)C>[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][C:8]([C:21]([O:23][CH3:24])=[O:22])([C:9]4[C:14]3=[CH:13][CH:12]=[C:11]([O:20][CH3:1])[CH:10]=4)[C:7]=2[CH:6]=1
Reactant: COC(=O)C12CC(c3ccc(O)cc31)c1ccc(Cl)cc12
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: COC(=O)C12CC(c3ccc(Cl)cc31)c1ccc(OC)cc12
Yield: 90 %

Procedure:
To an ethanol solution of methyl 2-chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in example 90a) was added potassium carbonate and methyl iodide. The suspension was heated to reflux, cooled and diluted with diethyl ether, filtered to remove salts, and concentrated to a solid. The title compound was formed in 90% yield. TLC analysis (Rf 0.40, 20% ethyl acetate in hexane). MS (CI, CH4) m/z 315 (M+1,100), 343 (M+29,13), 301 (38), 287 (9), 279 (14), 265 (6), 255 (42).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[NH:15][C:14](=S)[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:20]>>[Br:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:20])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC1
Reactant: N
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Temperature: 90 °C
Yield: 65.1 %

Procedure:
6′-Bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 54 Step 3, 1.62 g, 4.83 mmol) and ammonia (7M in MeOH, 15.2 mL, 106 mmol) were mixed together in a microwave vial. The vial was sealed and the reaction was heated at 90° C. for 30 min in a microwave reactor. The mixture was concentrated and the residue was dissolved in ammonia (7M in MeOH, 15.2 mL, 106 mmol), and heated once more at 90° C. for 30 min in a microwave reactor. This cycle was repeated four more times. After evaporation of the solvent, the crude was acidified with 2 M aq. hydrochloric acid, and washed with EtOAc. The aqueous phase was treated with 2M NaOH until basic pH was reached and then it was extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated. The organic phase was then acidified with 2M citric acid. The aqueous phase was treated with 2M NaOH until basic pH was reached and then it was extracted with EtOAc. The organic phases containing the title compound were combined, dried over MgSO4 and concentrated. The residue was dissolved in EtOAc and was washed with 50% aq. NaOH The organic layer was dried over MgSO4 and concentrated to afford the title compound (1.0 g, 65% yield): NMR: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.48-1.67 (m, 4 H), 1.73-1.86 (m, 1 H), 2.08-2.17 (m, 1 H), 2.19 (s, 3 H), 3.06-3.20 (m, 2 H), 6.65 (br. s., 2 H), 6.71 (d, 1 H), 7.26 (d, 1 H), 7.35 (dd, 1 H); MS (ES+) m/z 318 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([S:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C)C(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([S:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)(=[O:25])=[O:26])=[CH:23][C:17]=1[O:16][CH3:15])=[O:5]
Reactant: COc1cc(S(=O)(=O)c2ccncc2)ccc1N
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(S(=O)(=O)c2ccncc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.35 g) in N,N-dimethylacetamide (20 mL) was rapidly added thionyl chloride (1.01 g) and the mixture (a precipitate formed after a few minutes) was stirred at -15° to -5° C. for 1 hour. 2-Methoxy-4-(4-pyridylsulfonyl)aniline (1.50 g) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into ice water (200 mL) and the resulting tan solid was collected and recrystallized from absolute ethanol to yield the title compound as a white solid (1.58 g); mp 220°-222° C.; MS: 405(M+1); NMR (250 MHz): 1.53 (s,3,), 4.02 (s,3), 7.62 (d,1, J=1.9), 7.68 (dd,1, J=1.9, J=8.5), 7.92-7.95 (m,2,), 8.02 (s, 1,), 8.46 (d,1, J=10) 8.80-8.89 (m,2,), 9.90 (s,1,). Analysis for C16H15F3N2O5S: Calculated: C, 47.53; H, 3.74; N, 6.93; Found: C, 47.56; H, 3.77; N, 6.76.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[CH:8]2)C=C.[CH2:16]1[C:25]2C(=CC=CC=2)CC[CH2:17]1>>[CH2:25]([C:6]1[C:5]([OH:4])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:15])[NH:11]2)[CH:16]=[CH2:17]
Reactant: c1ccc2c(c1)CCCC2
Reactant: C=CCOc1ccc2[nH]c(=O)ccc2c1
Product: C=CCc1c(O)ccc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
10 Grams of 6-allyloxy-2(1H)-quinolinone was suspended in 50 ml of tetralin, and this suspension was stirred at 200° to 230° C. for 4 hours in nitrogen gas atmosphere. After the reaction, the reaction mixture was cooled to room temperature. The crystals thus precipitated were collected by filtration, washed with n-hexane and a small amount of diethyl ether in this order and dried. There was obtained 10 g (100%) of 5-allyl-6-hydroxy-2(1H)-quinolinone as crystalline powder. Melting point: Decomposed from 290° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:12]=[CH:11]2
Reactant: C=C[Mg]Cl
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cccc2cc[nH]c12
Temperature: -50 °C
Reaction time: 1 h

Procedure:
2 Fluoronitrobenzene (20.0 g, 0.142 mol) was dissolved in dry tetrahydrofuran (400 ml) and cooled to -50° C. Vinylmagnesium chloride (288 ml, 15% wt/vol) was added at -45° C. and stirred at this temperature for one hour. Poured onto saturated ammonium chloride (600 ml). Separated and aqueous extracted with diethyl ether (2×200 ml). Dried (MgSO4), filtered and concentrated in vacuo to yield a dark oil which was purified by column chromatography on silica using toluene as mobile phase. Fractions concentrated to yield a crystalline solid.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13]1([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
By following the manipulative procedure described above in Example 4(a), 32.0 g of 1-acetylisonipecotoyl chloride, [Example 1(b)] are added to a stirring solution of 30.6 g of diphenylether and 45.3 g of aluminum chloride in 100 ml of ethylene dichloride to produce a yellow oil of 1-acetyl- 4-(4-phenoxybenzoyl)piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:27]>CN(C=O)C>[Cl:27][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nccc(-c2cc(C#N)c(O)nc2-c2ccc(F)cc2)n1
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 60.1 %

Procedure:
A mixture of 6-(4-fluorophenyl)-2-(hydroxy)-5-(2-methylsulfanylpyrimidin-4-yl)pyridin-3-carbonitrile (48.84 g, 144.6 mmol, obtained in reference example 21), POCl3 (166 mL, 1.8 mol) and DMF (2.2 mL) was heated to 100° C. for 2 h. It was allowed to cool to room temperature and concentrated. It was cooled with an acetone-CO2 bath and EtOAc and ice were subsequently added. The organic phase was decanted, washed with saturated NaHCO3, dried over Na2SO4 and concentrated to dryness. The crude obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity, to afford 31.00 g of the title compound (yield: 60%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17](O)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][C:9]=2[O:20][CH3:21].C(Cl)(=O)C([Cl:25])=O.CN(C=O)C>ClCCl>[F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([Cl:25])=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][C:9]=2[O:20][CH3:21]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (17) (347 mg, 1.2 mmol) in dry dichloromethane (2 mL) was stirred under nitrogen. Oxalyl chloride (453 mg, 3.6 mmol, 300 μL) was added followed by a drop of DMF. The reaction mixture was stirred at RT under nitrogen for 2 h then evaporated in vacuo to give 371 mg (quantitative) of 9-(2-fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride as a gum which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 20.2, 21.7, 26.4, 43.3 (d, JCF=23 Hz), 54.9, 80.5, 83.1, 100.2, 102.2, 105.8, 116.7, 122.4, 135.5, 137.4, 153.5, and 176.6.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)C.[CH3:17][NH2:18]>>[CH3:17][NH:18][C:4](=[O:3])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Reactant: CN
Product: CNC(=O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of naphthalen-2-yl-acetic acid ethyl ester (42.8 g, 200 mmol) and 64 mL of methylamine (40 wt % in H2O) were stirred at room temperature overnight. Then the white precipitate was filtered off and washed with water. After drying in vacuum the title compound was obtained as a white solid. MS (ES+): 226 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(F)c1
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(F)cc(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture solution of 3-amino-5-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-5-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+] 336.0 & 338.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][CH3:40])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][CH2:39][CH3:40])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCCc1ccccc1O/C(=C/C(=O)OCC)CBr
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (623 mg, 0.003 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (1.98 g, 0.015 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0440 mg, 34%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:38]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:47])[CH3:46])[CH:40]=[CH:41][CH:42]=2)[CH2:33][CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([NH:27][CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:46])[CH3:47])[CH:38]=3)[CH2:33][CH2:32]2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C1OC[C@H](c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)N3C(=O)OC[C@@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure AF and Scheme H using 4-nitrophenyl (4S)-4-(3,4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 529.1 (M+H)+.