Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[C:11]([C:17]([O:19][CH3:20])=[O:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].CS(O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)(=O)=O.CCOC(C)=O>CN(C=O)C.O>[C:41]([O:40][C:38]([N:35]1[CH2:36][CH2:37][CH:32]([O:16][C:12]2[C:11]([C:17]([O:19][CH3:20])=[O:18])=[N:10][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:14](=[O:15])[CH:13]=2)[CH2:33][CH2:34]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: COC(=O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 95 °C
Yield: 14.4 %

Procedure:
To a mixture of methyl 1-(3,4-dichlorophenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate (315 mg, 1.0 mmol) in DMF (3 mL) at room temperature under argon was added K2CO3 (415 mg, 3.0 mmol) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (419 mg, 1.5 mmol). The reaction mixture was heated at 95° C. overnight. EtOAc (20 mL) and water (20 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 72 mg (14.2%) of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate was obtained as a gum. 1H NMR (400 MHz, CDCl3) δ ppm 1.40-1.50 (m, 9H) 1.68-1.82 (m, 1H) 1.92 (d, J=3.08 Hz, 3H) 3.23-3.45 (m, 2H) 3.49-3.59 (m, 1H) 3.59-3.73 (m, 1H) 3.82-4.03 (m, 3H) 4.48-5.43 (m, 1H) 6.12-6.38 (m, 1H) 7.38-7.64 (m, 2H) 7.75 (dd, J=7.91, 2.20 Hz, 1H). MS (ESI) 442 (M+H-tBu).
Reaction SMILES: F[CH2:2][C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O.[ClH:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1>C(O)(=O)C>[Cl:16][CH2:2][C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[N:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[N:25]=1
Reactant: CSc1ccc(C(=O)CC(=O)CF)cc1
Reactant: Cl
Reactant: NNc1ccc(F)cc1
Solvent: CC(=O)O
Product: CSc1ccc(-c2cc(CCl)nn2-c2ccc(F)cc2)cc1
Yield: 44.2 %

Procedure:
A mixture of 4-fluoro-1-[4-(methylthio)phenyl]butan-1,3-dione (2 g) and 4-fluorophenylhydrazine hydrochloride (1.6 g) in acetic acid (10 ml) was refluxed for 5 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed with an aqueous solution of sodium bicarbonate, dried, and concentrated in vacuo. The residue (3 g) was purified by column chromatography on silica gel eluting with chloroform. An oil of 3-(chloromethyl)-1-(4-fluorophenyl) -5-[4-(methylthio)phenyl]pyrazole (1.3 g) was obtained from the first eluate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30][C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:40][S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:30])[CH:32]=2)(=[O:38])=[O:39])=[O:27])=[CH:28][CH:29]=1)[CH3:20])=[O:17]
Reactant: Cc1cccc(S(N)(=O)=O)c1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Product: Cc1cccc(S(=O)(=O)NC(=O)c2ccc([C@H](C)NC(=O)c3cc(Cl)cnc3Oc3ccc(F)cc3)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 3-methylbenzenesulfonamide: 1H-NMR (CDCl3) δ 8.90 (1H, br.s), 8.51 (1H, d, J=2.6 Hz), 8.13 (1H, d, J=2.6 Hz), 8.09 (1H, d, J=7.2 Hz), 7.97–7.89 (2H, m), 7.74 (2H, d, J=8.3 Hz), 7.48–7.38 (4H, m), 7.20–7.05 (4H, m), 5.37–5.24 (1H, m), 2.44 (3H, s), 1.56 (3H, d, J=7.0 Hz); MS (ESI) m/z 568 (M+H)+, 566 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]4[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH:4]=[N:3]1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].N1CCOCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:20]([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:32](=[O:33])[CH2:31][O:30][CH3:29])=[CH:27][CH:28]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[CH:4]=[N:3]1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN)cc3)CC2)cnn1C
Reactant: COCC(=O)Cl
Solvent: C1COCCN1
Solvent: ClCCl
Product: COCC(=O)NCc1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
Dissolve 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.2 g, 0.53 mmol) in methylene chloride (5 mL). Add methoxy-acetyl chloride (1 eq., 0.058 g, 0.53 mmol). Add polymer bounded morpholine (1.1 eq., 0.234 g, 0.58 mmol). Stir at room temperature for 3 hr. Purify by SCX followed by reverse phase chromatography to give free base N-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzyl}-2-methoxy-acetamide, (0.051 g, 21%). MS (ES): m/z=450.3 [M+H].
Reaction SMILES: C(OO)(C)(C)C.[CH3:7][O:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10].[CH:17](=[O:20])[CH2:18][CH3:19]>O.OS(O)(=O)=O>[CH3:7][O:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][N:12]=1)=[O:10]
Reactant: CCC=O
Reactant: COC(=O)c1cnccn1
Agent: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)c1cnc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Tert-butyl hydroperoxide (70%, 1.0 ml, 7.25 mmol) and a solution of FeSO4.7H2O (3.02 g, 10.9 mmol) in water (8 ml) were added concurrently to a solution of methyl-2-pyrazine carboxylate (250 mg, 1.81 mmol) and propionaldehyde (0.78 ml, 0.9 mmol) in H2SO4 (0.75 ml) at 0 C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. Solid Na2S2O5 was added (until starch/iodide test negative) and the mixture extracted with dichloromethane. Concentration in vacuo and flash column chromatography over silica gel in ethyl acetate:hexane (15:85) yielded methyl-5-propionyl-2-pyrazinecarboxylate as a pale yellow solid (106 mg). The methyl ester was treated with LiOH (25 mg, 0.6 mmol) in tetrahydrofuran (15 ml) and water (0.5 ml). After 2 hours at room temperature the mixture was acidified with HCl (2N). Work-up followed by concentration of the organic phase in vacuo gave the title compound (92 mg).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25]C(OC(C)C)=O)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC)CC)C.C(Cl)Cl>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:25])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The same reaction was done in parallel, using of ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (for a preparation see Intermediate 15) (0.89 g 2.030 mmol), aluminium chloride (1.03 g, 7.72 mmol), triethylamine (3.4 mL, 24.53 mmol), DCM (16 mL) and MeOH (1.3 mL). The products of both reactions were combined at this stage and the resulting mixture was stirred at room temperature for approximately 10 min (total volume: approximately 1 L). The mixture was filtered through Celite™, the insoluble residue was washed with EtOAc and a saturated NaHCO3 aqueous solution and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried (hydrophobic frit) and concentrated in vacuo to give ethyl 4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (6.6 g, 84%—allowing for the addition of the parallel experiment) as a cream solid. LCMS (formate, 2 min), Retention time 0.73 min, [M-NH2]+=336
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][N:51]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc([N+](=O)[O-])cn1)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (10.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10 min, the reaction mixture was treated with 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 87, 304 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 20 min and at 25° C. for 30 min. At this time, the reaction mixture was treated with 2-amino-5-nitropyridine (290 mg, 1.5 mmol) and pyridine (0.14 mL, 1.8 mmol). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 200-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide (425 mg, 60%) as a white solid: mp 121-122° C.; EI-HRMS m/e calcd for C20H19F4N3O3 (M+) 425.1363, found 425.1363.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[H-].[Na+].[CH:26]12[O:32][CH:31]1[CH2:30][CH2:29][CH2:28][CH2:27]2>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:10][N:11]([CH:30]3[CH2:29][CH2:28][CH2:27][CH2:26][CH:31]3[OH:32])[C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: C1CCC2OC2C1
Reactant: COc1nccc2[nH]nc(-c3ccc(N4CCOCC4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2C1CCCCC1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of 4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (500 mg) obtained in Step G of Example 305 in anhydrous DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 72.0 mg), and the mixture was stirred for 30 min. To the reaction mixture was added 7-oxabicyclo[4.1.0]heptane (1.60 g) at room temperature, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was added to ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (400 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)[NH:3]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>CN(C=O)C>[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH:40][C:19]([C@H:16]1[CH2:15][CH2:14][C@@H:13]([CH2:12][C:4]2[NH:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:18][CH2:17]1)=[O:20]
Reactant: O=C(O)C1CCC(Cc2nc3ccccc3c(=O)[nH]2)CC1
Reactant: NCc1ccccc1F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=c1[nH]c(C[C@H]2CC[C@@H](C(=O)NCc3ccccc3F)CC2)nc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic acid (275 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol), and the resulting reaction mixture was stirred for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc, and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. Preparative chromatography eluting with chloroform:methanol gave the cis 4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide as a white solid: mass spectrum m/z 394 [(M+H)+; calcd for C23H24FN3O2: 393].
Reaction SMILES: CS([Cl:5])(=O)=O.[CH2:6](O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:22][C:23]1([CH3:46])[CH:27]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:26]2[C:33]([CH3:45])=[C:34]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:35]([CH3:38])=[C:36]([CH3:37])[C:25]=2[O:24]1.[ClH:47]>C(#N)C.C(OCC)(=O)C>[ClH:5].[ClH:47].[CH3:22][C:23]1([CH3:46])[CH:27]([N:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[C:26]2[C:33]([CH3:45])=[C:34]([N:39]3[CH2:40][CH2:41][N:42]([CH2:6][CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:43][CH2:44]3)[C:35]([CH3:38])=[C:36]([CH3:37])[C:25]=2[O:24]1
Reactant: OCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(C)c(N2CCN(CCc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Reaction time: 1 h
Yield: 18 %

Procedure:
Methanesulfonyl chloride (0.09 mL, 1.2 mmol) was added to a solution of phenethyl alcohol (0.14 mL, 1.2 mmol) and triethylamine (0.21 mL, 1.5 mmol) in acetonitrile (5 ml) at room temperature. The mixture was stirred for 1 hour, and then (2,2,4,6,7-pentamethyl-3-pyrrolidinyl-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 134 (343 mg, 1 mmol) was added. After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate/hexan=4/1) to obtain 166 mg as a free base. The free base was treated with 4N hydrogenchloride in ethyl acetate to obtain 96 mg (yield 18%) of the title compound. mp. 176–180° C. (decomposition) (ethanol-ethyl acetate).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](F)=[O:7])#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].[Si](Cl)(Cl)(Cl)[Cl:20]>>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([Cl:20])=[O:7])#[N:2]
Reactant: N#Cc1c(F)c(F)cc(C(=O)F)c1F
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
76.6 g of 3-cyano-2,4,5-trifluoro-benzoyl fluoride were initially introduced together with 1 g of anhydrous aluminium chloride at 60-65° C., and 25 g of silicon tetrachloride were then added dropwise at the rate of gas evolution. After the evolution of gas at 65° C. had ceased, the mixture was distilled under reduced pressure. In the boiling range from 120-122° C./14 mbar, 73.2 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride passed over.
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH2:9]([O:16][C:17]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Br)C=C>C1COCC1>[CH2:9]([O:16][C:17]([C:19]1([CH2:8][CH:6]=[CH2:7])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(OCc1ccccc1)C1CCCC1
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCc2ccccc2)CCCC1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Next, to a stirred solution of LDA (4 mmol, 2M in Hexane) in THF (8 mL) at −78° C. is added a solution of cyclopentanecarboxylic acid benzyl ester (817 mg, 4 mmol) in THF (3 mL) dropwise. After the addition, the mixture is stirred at −78° C. for 5 hours then allyl bromide (726 mg, 6 mmol) is added dropwise. The mixture is warmed to room temperature during 4 hours then the reaction mixture is quenched with saturated NaHCO3. Magnesium sulfate (2 g) is added and stirred until all the MgSO4 is dissolved. The mixture is extracted with ethyl acetate and the organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (hep:EtOAc, 10:1) to give 1-allyl-cyclopentanecarboxylic acid benzyl ester. Next, Ozone is bubbled through a solution of 1-allyl-cyclopentanecarboxylic acid benzyl ester in methylene chloride (15 mL) for 30 min then PS-triphenolphosphine (300 mg) is added and the mixture is stirred at room temperature for 5 hours. The resin is filtered and solvent is removed under reduced pressure. The residue is purified by flash chromatography (heptane:EtOAc, 10:1) to give 1-(2-oxo-ethyl)-cyclopentanecarboxylic acid benzyl ester MS 247.3 (M+1).
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.[C:7]([O:11][C:12]([N:14]1[CH2:21][C:20]2[C:16](=[N:17][NH:18][C:19]=2[NH2:22])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CC(O)=O>[C:7]([O:11][C:12]([N:14]1[CH2:21][C:20]2=[C:19]3[N:18]([N:17]=[C:16]2[CH2:15]1)[CH:3]=[C:2]([Br:1])[CH:5]=[N:22]3)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1Cc2nn3cc(Br)cnc3c2C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.5 %

Procedure:
A mixture of bromomalonaldehyde (2.02 g; 13.38 mmol; 1 eq.) and 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (3 g; 13.38 mmol; 1 eq.) in AcOH (21 mL) was stirred at room temperature for 40 minutes. The insoluble material was removed by filtration and the solution diluted with water (60 mL). The precipitate was filtered off, washed with water (3×) and dried. Recrystallization from iPrOH afforded the title compound (2.02 g, 45%) as beige solid. 1H NMR (DMSO-d6) δ 9.60 (d, J=2.2 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 4.62-4.55 (m, 4H), 1.47 (s, 9H). HPLC (max plot) 99.8%; Rt 3.54 min. UPLC/MS: (MS+) 339.3 and 341.3 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[NH:16]=[C:17]1[NH:21][C:20](=[O:22])[CH2:19][S:18]1>>[NH:16]=[C:17]1[NH:21][C:20](=[O:22])[C:19](=[CH:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][N:4]=[C:3]3[N:2]([CH3:15])[CH3:1])[S:18]1
Reactant: CN(C)c1ncnc2ccc(C=O)cc12
Reactant: N=C1NC(=O)CS1
Product: CN(C)c1ncnc2ccc(C=C3SC(=N)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 4-piperidine-quinazoline-6-carbaldehyde (intermediate 14) and 2-imino-1,3-thiazolidin-4-one, the title compound was obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([NH2:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1Cl>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1[NH:12][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: COc1ccc(C(N)=O)cc1OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1

Procedure:
Alternatively, a suspension of 3-cyclopentyloxy-4-methoxybenzamide (2.58 g; that is prepared as described in Reference Example 73) in dry toluene (40 mL) is heated at reflux and treated with potassium t-butoxide (1.4 g), followed by 3,4,5-trichloro-pyridine (1.82 g). The mixture is then heated at reflux for 3 hours and 45 minutes, and is then treated with a further quantity of potassium t-butoxide (1.4 g) and heated at reflux for a further period of 7 hours. The mixture is allowed to cool and is then filtered. The filtrate is evaporated and the resulting residue is extracted with aqueous sodium hydroxide solution (2M). The alkaline solution is then acidified by treatment with acetic acid, and the solid which separates is collected by filtration, washed with water and dried, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (2.09 g) in the form of a buff solid, m.p. 153°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]([O:7][Si](C)(C)C)=[C:4]([CH3:6])[CH3:5].F[B-](F)(F)F.[C:17]1([N+:23]#[N:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)C>[CH3:5][C:4]([N:24]=[N:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:6])[C:3]([O:2][CH3:1])=[O:7]
Reactant: N#[N+]c1ccccc1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C(C)(C)N=Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1.0 mmol of (1-methoxy-2,2-dimethylethenyl)oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The obtained mixture was stirred at 0° C. in a nitrogen atmoshere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5N hydrochloric acid, water and a saturated aqueous solution of common salt successively. The obtained organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.90 mmol of methyl 2-methyl-2-phenylazopropionate.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Li+].[CH3:14]CC[CH2-].IC>O1CCCC1>[CH3:14][C:3]1[C:4]2[O:5][CH2:6][O:7][C:8]=2[CH:9]=[CH:10][C:2]=1[C:1]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: [CH2-]CCC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc2c1OCO2
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a round bottom flask equipped with an overhead stirrer and a nitrogen inlet was added piperonylic acid (50.0 g, 301 mmol) and tetrahydrofuran (753 mL). This was cooled to −75° C. in a dry ice-acetone bath. N-Butyllithium (1.6 M in hexanes) (414 mL, 662 mmol) was added dropwise maintaining the temperature of the reaction at or below −65° C. When the addition was complete the cooling bath was removed and the reaction was allowed to warm to −20° C. The reaction was returned to the bath and cooled to at least −60° C. at which time iodomethane (37.5 mL, 602 mmol) was added dropwise. Cooling was removed and the reaction allowed to warm to 10° C. at which time the reaction was placed in an ice bath and stirred at 0° C. for 30 minutes. The reaction was quenched by addition of 1N HCl and the tetrahydrofuran removed by evaporation. The residue was slurried in 1N HCl and filtered. The filtrate was washed with water, and dried at 50–60° C. in vacuo to give a pale yellow solid, 4-methyl-benzo[1,3]dioxole-5-carboxylic acid (52.8 g, 293 mmol) in 97% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.44 (s, 3H), 6.10 (s, 2H), 6.77 (d, 1H), 7.64 (d, 1H). TLC Rf=0.54 (1:1 ethyl acetate/hexane, piperonylic acid=0.41).