Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[OH:18].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC(=O)C)C.CCCCCC>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:18][C:6]1[CH:7]=[C:8]([S:12][CH2:13][C:14]([F:15])([F:17])[F:16])[C:9]([Cl:11])=[CH:10][C:5]=1[Cl:4]
Reactant: BrCCCCCCBr
Reactant: Oc1cc(SCC(F)(F)F)c(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: FC(F)(F)CSc1cc(OCCCCCCBr)c(Cl)cc1Cl
Yield: 95 %

Procedure:
To 30 ml of acetonitrile were added 1.0 g (3.61 mmol) of 2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenol, 3.5 g (14.4 mmol) of 1,6-dibromohexane, 0.65 g (15.0 mmol) of potassium carbonate and 0.12 g (0.37 mmol) of tetra-n-butylammonium bromide. The mixture was refluxed for 3 hours under heating. The mixture was allowed to stand at room temperature, and insoluble matters were removed by filtration. Then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane ethyl acetate=20:1), to obtain 1.51 g (yield: 95%) of an intended product.
Reaction SMILES: C[Mg]Br.C([O:6][CH2:7][CH3:8])C.C(N(CC)CC)C.C(OC(=O)[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][C:26]=1[CH3:27])[OH:22])C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[OH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:20]=1[C:7](=[O:6])[CH3:8]
Reactant: CCOC(=O)c1c(C)cccc1O
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1c(C)cccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
A solution of methyl magnesium bromide 3M in diethyl ether (18.5 mL, 55.5 mmol) and triethylamine (6.0 mL, 44.4 mmol) in anhydrous toluene (14 mL) was cooled to 0° C. 6-methylsalicylic acid ethyl ester (2.0 g, 11.1 mmol) in anhydrous toluene (14 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. A saturated solution of ammonium chloride (10 mL) was added and the mixture was filtered over Celite®. The filtrate was diluted with ethyl acetate (20 mL) and water (10 mL) and layers were separated. The organic layer was washed with brine (10 mL), dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 9/1) to provide the desired ketone (26a) (1.21 g, 8.0 mmol, 72%).
Reaction SMILES: [K].CC(C)([O-])C.O1CCOCCOCCOCCOCCOCC1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1.C[O:39][C:40](=O)[CH:41]([O:43][CH3:44])[CH3:42].Cl>O1CCCC1>[OH:35][C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:26]([F:36])([F:37])[F:25])=[CH:32][CH:31]=1)=[CH:34][C:40](=[O:39])[CH:41]([O:43][CH3:44])[CH3:42]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(C)OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: COC(C)C(=O)C=C(O)c1ccc(C(F)(F)F)cc1

Procedure:
10.14 g Potassium-tert.-butoxide and 225 mg 1,4,7,10,13,16-hexaoxacyclooctadecan are dissolved in 80 ml tetrahydrofurane. Then a solution of 10.0 g 1-(4-Trifluoromethyl-phenyl)-ethanone in 40 ml of tetrahydrofurane and a solution of 12.6 g racemic 2-Methoxy-propionic acid methyl ester in 40 ml of tetrahydrofurane are simultaneously added dropwise. After completion of addition the mixture is heated for four hours to reflux, cooled to 0° C. and hydrolyzed by dropwise addition of 50 ml of a 4 M solution of hydrochloric acid. The residue is partitioned between water and ethylacetate and the phases are separated. The aqueous phase is twice extracted with ethylacetate and the combined organic phases are washed with brine. After drying with magnesium sulphate the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethylacetate 95:5 to 85:15).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][C:4]=2[NH:3]1.C1CCCCC=1>>[O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([CH:21]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][C:4]=2[NH:3]1
Reactant: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Solvent: C1=CCCCC1
Product: N#Cc1cccc(C2=Nc3ccc(C=Cc4ccccc4)cc3NC(=O)C2)c1

Procedure:
Prepared from 3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile (Example 2) by catalytic hydrogenation with Lindlar-catalyst in the presence of 10 eq. cyclohexene according to the general procedure G (method a). Obtained as a light yellow solid (159 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33].[NH:36]1[CH:40]=[CH:39][N:38]=[N:37]1>CN(C=O)C>[N:36]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21](=[O:24])[CH:20]=[C:19]3[NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=2[Cl:33])[CH:40]=[CH:39][N:38]=[N:37]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCn1ccnn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Potassium carbonate (350 mg, 2.54 mmol) was added to a solution of 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (1.0 g, 2.0 mmol, Example 28), 1H-1,2,3-triazole (210 mg, 3.04 mmol), and DMF (15 mL) at rt. After 3.5 h at 80° C., the mixture was allowed to cool to rt, quenched with water (10 mL), and then extracted with ethyl acetate (20 mL×3). The combined extracts were washed with brine, dried, filtered, concentrated, and then purified by silica gel chromatography (dichloromethane:methanol) to give 8-(5-(1H-1,2,3-triazol-1-yl)pentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.81 (s, 2H), 8.13 (s, 1H), 7.94 (d, 1H), 7.69 (s, 1H), 7.19 (d, 1H), 4.63 (s, 1H), 4.40 (t, 2H), 3.97 (t, 2H), 3.90 (s, 3H), 1.88 (m, 2H), 1.75 (m, 2H), 1.45 (m, 2H); MS (ESI): 490.0.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].C(O)(=O)C.[CH3:15][C:16]([CH3:18])=O.C([O-])(=O)C.[Na+]>CCCCCC.CCOCC.O.C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([NH:7][CH:16]([CH3:18])[CH3:15])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (16.5 g, 435 mmol) was added slowly over 2 hours to a mixture of 3-bromoaniline (10 g, 58.13 mmol), ethanol (58 mL), acetic acid (50 mL, 866.1 mmol), water (140 mL), acetone (35 mL, 482.5 mmol), and sodium acetate (15.8 g, 116.2 mmol). The solution was stirred at 0° C. for 3 hours. The reaction mixture was poured into 1:1 mixture of ether and hexane containing 2N KOH. The layers were separated and the aqueous layer was extracted with ether/hexane (1:1). The combined organic layers were washed once with water and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.31) to give the title compound (23.10 g, 93% as an oil:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]#[N:17])=[CH:3][CH:2]=1.CCCCC.[H-].[Na+].Cl.Cl[CH2:27][C:28]1[N:29]=[C:30]([CH3:33])[S:31][CH:32]=1>CN(C=O)C>[CH3:33][C:30]1[S:31][CH:32]=[C:28]([CH2:27][N:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]#[N:17])[C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:29]=1
Reactant: Cc1nc(CCl)cs1
Reactant: N#CCOc1cccc2[nH]c3ccccc3c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c3ccccc3c3c(OCC#N)cccc32)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.9 %

Procedure:
2-(9H-Carbazol-4-yloxy)acetonitrile (0.143 g, 0.64 mmol)) is added to a slurry of pentane-washed NaH (0.0825 g, 0.0021 mol) in DMF (1 mL) and allowed to stir for 20 min at room temperature. 4-Chloromethyl-2-methylthiazole hydrochloride (0163 g, 0.89 mmol) is added and after stirring for 2 h the mixture is partitioned between ethyl acetate and water. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (75 mL) using ethyl acetate/hexane (20/80 and 40/60) and solids are crystallized from dichloromethane/ether to give 0.162 g (76%) of the title compound; MS (ESI+) for C19H15N3OS m/z 334.2 (M+H)+; IR (drift) 1581, 1459, 1440, 1341, 1333, 1275, 1228, 1215, 1182, 1157, 1151, 1113, 782, 754, 718 cm−1; 1H NMR (CDCl3) δ2.74, 5.09, 5.62, 6.38, 6.78, 7.19, 7.31, 7.44, 8.32. Anal. Calcd for C19H15N3OS: C, 68.45; H, 4.53; N, 12.60. Found: C, 68.27; H, 4.53; N, 12.33.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([OH:13])=O)[CH2:6]1)=[O:4].C1C=CC2N(O)N=[N:20][C:18]=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][NH:20][C:11]([CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[O:13]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)[C@@H]1CCC[C@H](C(=O)O)C1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CNC(=O)C1CCCC(C(=O)OC)C1
Reaction time: 8 h
Yield: 85.8 %

Procedure:
(±)-cis-3-(Methoxycarbonyl)cyclohexanecarboxylic acid (500 mg, 2.69 mmol), methylamine, HCl (218 mg, 3.22 mmol), HOBT (493 mg, 3.22 mmol), EDC (618 mg, 3.22 mmol) and triethylamine (0.75 mL, 5.37 mmol) were mixed and stirred in methylene chloride (10 mL) at 25° C. The reaction was stirred overnight then washed with 1N HCl, sat'd sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give (±)-cis-3-(methyl 3-(methylcarbamoyl)cyclohexanecarboxylate (460 mg, 2.309 mmol, 86% yield) as a white glass. MS found: (M+H)+=200.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)C(=[C:9]([O:11][CH3:12])[CH:10]=1)C=O.[C:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1CCCCC1.C(#N)C>[C:14]([C:22]1[C:23](=[O:24])[O:25][C:26]2[C:4]([CH:5]=1)=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:27]=2)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1cc(O)c(C=O)c(OC)c1
Solvent: CC#N
Solvent: C1CCNCC1
Product: COc1cc(OC)c2cc(C(=O)c3ccccc3)c(=O)oc2c1

Procedure:
A mixture of 18.2 g 4,6-dimethoxysalicylaldehyde, 20.0 g ethyl benzoylacetate, 20 ml acetonitrile and 30 drops piperidine was heated gently on a hot plate for 45 minutes. After cooling the product was collected and recrystallized twice from acetonitrile and once from benzene containing a small amount of acetonitrile. m.p. 178° C.-179° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:25][O:26][CH2:27][CH3:28])[C@@H:10]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1>C(#N)C>[Cl:1][C:2]1[C:3](/[C:9](=[N:25]\[O:26][CH2:27][CH3:28])/[C@@H:10]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:22])([F:21])[F:23])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCON=C(c1ncc(Cl)cc1Cl)[C@H](C)NC(=O)c1ccccc1C(F)(F)F
Solvent: CC#N
Product: CCO/N=C(\c1ncc(Cl)cc1Cl)[C@H](C)NC(=O)c1ccccc1C(F)(F)F
Yield: 96 %

Procedure:
580 mg of (S)—N-[2-(3,5-dichloropyridin-2-yl)-2-ethoxyimino-1-methylethyl]-2-(trifluoromethyl)benzamide was dissolved in 3 ml of acetonitrile, and the solution was irradiated with light for 8 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 5:5) as the eluent to obtain 557 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CSC.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid (25.00 g, 116 mmol) in THF (250 mL) at 0° C. was added borane dimethyl sulfide complex (2.0 M in THF, 87 mL, 174 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. The mixture was cooled to 0° C. and quenched by dropwise addition of MeOH (100 mL) within 15 minutes. The mixture was stirred at 0° C. for 15 minutes and concentrated. The residue was taken up in EtOAc and washed with 1 M HCl, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated to give INT 29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Clc1ccc2nccn2c1
Solvent: CC(=O)O
Product: Clc1ccc2ncc(Br)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.3 %

Procedure:
To 6-chloro-imidazo[1,2-a]pyridine (1 eq, 253 mmol, 39 g) in acetic acid (500 ml) under inert atmosphere, is added dropwise bromine (1 eq, 253 mmol, 13 ml). After 1 hour stirring at room temperature, the reaction mixture is filtered and to give a beige solid (64 g) 3-Bromo-6-chloro-imidazo[1,2-a]pyridine hydrobromide; [M+H]+232 (234)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13])#[N:2].[NH2:14][OH:15]>CCO>[NH2:2][C:1](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13]
Reactant: COC(=O)c1ccc(C#N)c(F)c1
Reactant: NO
Solvent: CCO
Product: COC(=O)c1ccc(C(N)=NO)c(F)c1
Temperature: 74 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-cyano-3-fluorobenzoate obtained in Step 1 (834.5 mg; 4.66 mmol) in EtOH (9 mL) was added hydroxylamine (50% in water, 1.37 mL; 23.29 mmol). The solution was stirred at 74° C. for 4 h. The solvents were evaporated and the residue was taken in EtOAc (20 mL), washed with brine (3×15 mL), dried over MgSO4 and evaporated, affording the title compound as a yellow solid. 1H NMR: (DMSO-d6, 300 MHz) δ 9.89 (s, 1H), 7.92 (t, J=7.91 Hz, 1H), 7.69 (dd, J=1.70 Hz, J=8.10 Hz, 1H), 7.64 (dd, J=1.51 Hz, J=12.81 Hz, 1H), 5.97 (s, 2H), 3.92 (s, 3H). HPLC (Method A) Rt 2.90 min (Purity: 90.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C(Cl)Cl>[CH3:16][S:17]([N:6]1[CH:5]=[C:4]([NH2:1])[CH:8]=[N:7]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)n1cc(N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (250 mg, 2.2 mmol) in DCM (5 mL) were added triethylamine (0.46 mL, 1.5 eq) and methanesulfonyl chloride (0.20 mL, 1.2 eq). After stirring for 1 h at rt, water was added and the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 5 mL methanol and palladium on carbon added under an inert atmosphere. The reaction mixture was stirred overnight at rt under an hydrogen atmosphere. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give 1-(methylsulfonyl)-1H-pyrazol-4-amine as a brown oil (0.34 g, 2.1 mmol, 96%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17].C(N(CC)CC)C>[Pd].C(O)C>[O:17]=[C:7]1[C:6]2[C:11](=[CH:2][CH:3]=[CH:4][C:5]=2[C:18]([F:19])([F:20])[F:21])[NH:10][CH:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 5 °C
Reaction time: 20 h

Procedure:
A 3-neck, 5-L flask was charged with of ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate 15 (100 g, 0.3 mol), ethanol (1250 mL, 12.5 mL/g) and triethylamine (220 mL, 1.6 mol). The vessel was then charged with 10 g of 10% Pd/C (50% wet) at 5° C. The reaction was stirred vigorously under hydrogen atmosphere for 20 h at 5° C., after which time the reaction mixture was concentrated to a volume of approximately 150 mL. The product, ethyl 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylate 16, as a slurry with Pd/C, was taken directly into the next step.
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[B:11]([OH:13])[OH:12])=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].Cl>O.CCOC(C)=O>[N+:14]([CH:17]([CH:3]1[O:13][B:11]([OH:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]1=2)[CH3:18])([O-:16])=[O:15]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CC[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C1OB(O)c2ccccc21)[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
A solution of NaOH (1.6 g, 41 mmol) in H2O (20 mL) was added to 2-formyl phenylboronic acid (5.1 g, 34 mmol) at rt. The mixture was stirred for 15 min then nitroethane (2.9 mL, 41 mmol) was added dropwise. The mixture was stirred for 30 min and then the clear reaction solution was acidified with 2 N HCl and EtOAc was added. The organic layer was separated, washed with H2O then brine, dried (Na2SO4), and concentrated in vacuo. Purification by flash chromatography (2:1 hexane/EtOAc) gave the title compound as a colorless oil: yield 6.72 g (quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([CH3:30])[CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([CH3:30])[CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Br)cc4)nc23)cc(C)n1
Yield: 41.6 %

Procedure:
Reaction of 1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3-dione (148 mg, 0.5 mmol), prepared from commercially available 4-bromo-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (93 mg, 42%). MS (ISP) 447.2 [(M+H)+]; mp 258° C.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C>[O:16]([CH2:15][CH:12]1[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)N1CCC(COc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(OCC2CCNCC2)cc1
Yield: 83.7 %

Procedure:
A mixture of 22.0 g (0.075 mole) of N-benzoyl-4-phenoxymethylpiperidine, 25 ml of 10 N aqueous sodium hydroxide solution and 175 ml of ethanol is heated under reflux for 18 hours. The reaction mixture is then evaporated in a vacuum and the residue is taken up in diethyl ether, washed with water, dried over anhydrous sodium sulfate and the solvent then evaporated off. There are obtained 12.0 g of 4-phenoxymethylpiperidine (84% of theory); m.p. 42°-43° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]>CCO.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: N#Cc1cccc(CN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c1
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Temperature: 55 °C
Yield: 85.9 %

Procedure:
To a stirred solution of 1-(3-cyano-benzyl)-4-(4-nitro-phenyl)-piperazine (52 g) in EtOH (1.2 L) and THF (300 mL) was added portionwise SnC2.2H2O (145.6 g) at room temperature and the mixture was heated at 55° C. for 16 hours. After evaporation of the solvents, the residue was taken in water, basified with NaOH at pH 14 and extracted with CH2Cl2. The organic layer was then washed with water, dried over Na2SO4, and evaporated. The residue was cristallized from disopropyl ether to give the title compound (40.5 g) as pale yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]3C3CCCCO3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>CO>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22][CH3:23])[NH:13]3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1
Reactant: COc1nc2c(N)nc(NCCC3CC3)nc2n1C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2c(N)nc(NCCC3CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a solution of N2-(2-cyclopropylethyl)-8-(methoxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (3.30 g) in methanol (33.0 ml) at room temperature was added trifluoroacetic acid (3.30 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 70 hours. The reaction mixture was concentrated in vacuo to give a yellow solid which was then triturated in diethyl ether (100 ml) and filtered under vacuum to give an off-white solid (2.4 g).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[N:5][C:4](B(O)O)=[CH:3]1.[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1Br)(=[O:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1[C:4]1[N:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(B(O)O)nc(Nc2ccc(N3CCOCC3)cc2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(N4CCOCC4)cc3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 130 °C
Yield: 31.2 %

Procedure:
A mixture of 4-methyl-6-(4-morpholinophenylamino)-5-oxo-4,5-dihydropyrazin-2-yl boronic acid 122b (330 mg, 1 mmol), 2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 197d (434 mg, 1 mmol), PdCl2(dppf) (82 mg, 0.1 mmol), 2.0M Na2CO3 (1 mL, 2.0 equiv) in DME (10 mL) was heated at 130° C. under microwave irradiation for 0.5 h. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 127a (200 mg, 45%). LCMS: [M+H]+ 641.