Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](Cl)(Cl)=[S:10].C(N(CC)CC)C.[CH3:20][O:21][C:22]([O:31][CH3:32])([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH2:23][NH2:24]>C(Cl)Cl>[CH3:20][O:21][C:22]([O:31][CH3:32])([C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1)[CH2:23][NH:24][C:9]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)=[S:10]
Reactant: Cc1cccnc1N
Reactant: COC(CN)(OC)c1ccncc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CNC(=S)Nc1ncccc1C)(OC)c1ccncc1

Procedure:
2-Amino-3-methylpyridine (19-1, 0.281 g, 2.60 mmol) was stirred in 6 mL anhydrous DCM under N2. Thiophosgene (0.198 mL, 2.60 mmol) was added followed by the addition of triethylamine (1.09 mL, 7.79 mmol) and an additional 4 mL anhydrous DCM. After 30 min 2,2-dimethoxy-2-pyridin-4-yl-ethylamine (0.430 g, 2.36 mmol, Ganellin, C. R.; Hosseini, S. K.; Khalaf, Y. S.; Tertiuk, W.; Arrang, J.-M.; et al. J.Med.Chem. 1995, 38, 3342-3350) was added as a solution in 2 mL anhydrous DCM. After 16 h the reaction was quenched with sat NaHCO3 (aq) and extracted 3× with DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide the pure titled compound as a tan solid. 1H NMR (CDCl3) δ11.88 (s, 1H), 8.65 (d, 2H, J=6.0 Hz), 7.76 (m, 2H), 7.50 (d, 2H, J=6.2 Hz), 7.44 (m, 1H), 6.87 (dd, 1H, J=5.1, 7.3 Hz), 4.22 (d, 2H, J=5.0 Hz), 3.29 (s, 6H), 2.22 (s, 3H).
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[C:8]2[C:36]([CH3:43])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:35](=[O:44])[NH:34][C:9]=2[N:10]=[C:11]([NH:13]/[N:14]=[C:15](\[C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2Br)/[CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=2[F:25])[N:12]=1.CNCCNC>CCOC(C)=O.[Cu]I>[NH2:6][C:7]1[C:8]2[C:36]([CH3:43])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:35](=[O:44])[NH:34][C:9]=2[N:10]=[C:11]([N:13]2[C:27]3[C:26](=[CH:31][C:30]([Cl:32])=[CH:29][CH:28]=3)[C:15]([CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=3[F:25])=[N:14]2)[N:12]=1
Reactant: CC1(c2ccccc2)C(=O)Nc2nc(N/N=C(/Cc3c(F)ccc(F)c3F)c3cc(Cl)ccc3Br)nc(N)c21
Agent: [Cu]I
Agent: CNCCNC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)C(=O)Nc2nc(-n3nc(Cc4c(F)ccc(F)c4F)c4cc(Cl)ccc43)nc(N)c21

Procedure:
A DMF (5 mL) solution of the crude intermediate from Step C (ca 0.24 mmol), copper (I) iodide (45.3 mg, 0.24 mmol) and N,N′-dimethylethylenediamine (25.2 mg, 0.29 mmol) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with 10% aqueous NH4OH solution (2×), water (2×), 0.5 N HCl (1×), and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography using 5% MeOH/CHCl3 as eluent. The isolated material was purified again by silica gel column chromatography using a hexanes/EtOAc gradient to give the indicated compound. 1H NMR (500 MHz, DMSO-d6): δ (ppm) 11.19 (1H, s), 8.86 (1H, d, J=9.0 Hz), 7.93 (1H, d, J=2.0 Hz), 7.55-7.43 (2H, m), 7.34-7.24 (5H, m), 7.20 (1H, t, J=9.7 Hz), 6.74 (2H, s), 4.46 (2H, s), 1.77 (3H, s). m/z=535.4 (M+H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][C:5](O)=O.[NH2:8][C:9]1[CH:29]=[C:28]([Cl:30])[C:12]2[O:13][C:14]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:15]=3[S:16](=[O:19])(=[O:18])[CH2:17][C:11]=2[CH:10]=1.[C:31](=O)(O)[O-].[Na+]>C1C=CC=CC=1.O1CCCC1>[CH3:31][O:26][C:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:14]2[O:13][C:12]3[C:28]([Cl:30])=[CH:29][C:9]([NH:8][CH2:5][CH2:4][Cl:3])=[CH:10][C:11]=3[CH2:17][S:16](=[O:18])(=[O:19])[C:15]=2[CH:20]=1)=[O:27]
Reactant: O=C([O-])O
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Reactant: O=C(O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reaction time: 1 h

Procedure:
Sodiumborohydride (1.77 g, 46.78 mmol) was added portionwise to a stirred solution of chloro-acetic acid (7.71 g, 81.59 mmol) in benzene (270 mL) and dry tetrahydrofuran (30 mL) under nitrogen atmosphere at 15° C. The reaction mixture was stirred for 1 h, treated with the methyl ester of Example 35j (5 g, 13.61 mmol) and refluxed for 0.5 h. The reaction mixture was treated with 10% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified by crystallization (ethyl acetate/hexane) to obtain the title compound as a white solid. Yield: 5.25 g, (90%); mp: 224-225° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H, CH3), 3.45 (t, 2H, CH2), 3.75 (t, 2H, CH2), 3.92 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 6.53 (t, 1H, NH), 6.65-6.79 (m, 2H, Ar), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar). MS: m/e (ES+) 431 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.OC1C(C#N)=CNC(=O)C=1.CS(O[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1)(=O)=O.CS(OC1CCN(C2N=CC(CCC)=CN=2)CC1)(=O)=O>>[Cl:1][C:2]1[C:3]([O:18][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: N#Cc1ccc(-n2cc(Cl)c(O)cc2=O)cc1F
Agent: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Agent: N#Cc1c[nH]c(=O)cc1O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1

Procedure:
The intermediate was prepared according to the procedures described in Example 221 substituting 4-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile for 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate for 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate in Step B. MS (ESI) 392 (M+H).
Reaction SMILES: CC1C=C(C(F)(F)F)C2C(=CC=C(O)C=2)N=1.[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28]C)[CH:26]=2)[N:21]=[C:20]([CH3:30])[CH:19]=1>>[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=2)[N:21]=[C:20]([CH3:30])[CH:19]=1
Reactant: COc1ccc2nc(C)cc(Br)c2c1
Agent: Cc1cc(C(F)(F)F)c2cc(O)ccc2n1
Product: Cc1cc(Br)c2cc(O)ccc2n1

Procedure:
Synthesized as per 2-Methyl-4-trifluoromethyl-quinolin-6-ol using 4-Bromo-6-methoxy-2-methyl-quinoline as starting material. ESI-MS(M+H+): 238.00/240.00.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10].Cl.[H][H]>CO.C(OCC)(=O)C.CCCCCC>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10]
Reactant: CCC(=O)COc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(O)COc1cccc(C(F)(F)F)c1
Reaction time: 69 h

Procedure:
Using a steel capillary, 87.9 g of 1-(3-trifluoromethylphenoxy)butan-2-on, dissolved in 130 ml of methanol and 0.641 g of Ru2Cl4 [(R)-2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl]2 [N(C2 H5)3 ]=Ru2Cl4 [(R)-BINAP]2 [N(C2 H5)3 ] and 1.2 ml of 1N hydrochloric acid are transferred in succession into a steel autoclave under an argon atmosphere. In 3 cycles (20 bar, atmospheric pressure), the argon inert gas is displaced by hydrogen, and the mixture is subsequently hydrogenated at 20° C. under a hydrogen pressure of 80 bar. After 69 hours, the hydrogen uptake has ended. The reaction mixture is removed from the steel autoclave and evaporated on a rotary evaporator. The residue obtained is dissolved in ethyl acetate/n-hexane 1/4 and filtered through a short silica gel column to remove the catalyst. After the collected fractions have been evaporated, the desired product is obtained in a yield of 87.9 g (99% of theory); refractive index nD22 1.4611; [α]36520 -18.7+0.2° (c=1.0 in methanol).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH2:11][Cl:12])=[CH:7][CH:6]=1)(=O)C.[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>C(O)C>[ClH:12].[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:10][CH2:11][N:16]2[CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)=[CH:13][CH:14]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(=O)Oc1ccc(C=CCCl)cc1
Solvent: CCO
Product: Cl
Product: Oc1ccc(C=CCN2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
The process for preparing this compound will be given below along with its physical properties. A solution of 4.6 grams of p-acetoxycinnamyl chloride in 30 milliliters of ethanol is added dropwise to a solution of 6.49 grams of isoindoline in 20 milliliters of ethanol, and the resulting mixture is stirred overnight at room temperature. The precipitated crystals are collected by filtration and recrystallized from methanol to obtain 3.16 grams (yield 50%) of N-(p-hydroxycinnamyl)-isoindoline hydrochloride as crystals having a melting point of 213°-214° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH:32]([O-])=O.[NH4+]>[Pd].C(O)C>[F:31][C:2]([F:1])([F:30])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:32])=[O:25])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: COC(=O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
10% Palladium on carbon (0.536 g, 0.50 mmol) was added to methyl 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (1.096 g, 2.52 mmol) and ammonium formate (1.587 g, 25.17 mmol) in ethanol (50 mL). The resulting mixture was stirred at 78° C., with further portions of ammonium formate being added every 5 hours until the reaction was complete. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was evaporated to dryness, redissolved in DCM (100 mL) and the solution was washed with water (50 mL) followed by brine (50 mL), then the solvents were evaporated to give crude product. The crude product was purified by flash silica chromatography, eluting with a gradient of 50 to 80% EtOAc in isohexane. Pure fractions were evaporated to afford ethyl 2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (0.820 g, 72.2%) as a gum.
Reaction SMILES: C[C:2](P(OC)(O)=O)([C:4]([O-:6])=[O:5])[CH3:3].[H-].[Na+].[Cl:14][C:15]1[CH:16]=[CH:17][C:18](C=O)=[C:19]2[C:23]=1[O:22][CH:21]=[CH:20]2.[CH3:26]OCCOC>>[CH3:26][O:6][C:4](=[O:5])[CH:2]=[CH:3][C:18]1[C:19]2[CH:20]=[CH:21][O:22][C:23]=2[C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: COCCOC
Reactant: O=Cc1ccc(Cl)c2occc12
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C=Cc1ccc(Cl)c2occc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Trimethylphosphonoacetate (363 mg) in dry DME (1 ml) was added dropwise to a suspension of sodium hydride (60%; 329 mg) in dry DME (20 ml) at 0° under nitrogen. The resulting white precipitate was stirred for 40 mins at room temperature, then a solution of 7-chloro-benzofuran-4-carbaldehyde (intermediate 2) (1.238 g) in dry DME (15 ml) was added at room temperature over 1 min. The mixture was heated under reflux for 2 h, cooled to room temperature, then partitioned between water (150 ml) and ether (100 ml). The. combined organic extracts were washed with brine (100 ml) and dried (MgSO4). The solvent was evaporated to give the title compound as a colourless solid (1.59 g)
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: Nc1cc(F)c(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
4-amino-5-chloro-2-fluorobenzoic acid (Intermediate 176; 500 mg, 2.64 mmol), 4-amino-1-methylpiperidine (452 mg, 3.96 mmol) and diisopropylethylamine (1.38 ml, 7.91 mmol) were stirred in DMF (5 mL) and HATU (1.50 g, 3.96 mmol) added. The reaction mixture was stirred for 3 hours at room temperature. The mixture was absorbed on to an SCX column, which was washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated to give a crystalline solid that was suspended in diethyl ether and filtered to yield the title compound as a pale brown solid (572 mg, 76%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:14][C:15]=1[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1F
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added 3-fluorobiphenyl-4-ylboronic acid (1.623 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(0) (0.334 g), and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization (THF/diisopropyl ether) to give the title compound (1.528 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10](OB(O)O)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.Br[C:18]1[N:19]=[C:20]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH3:35])[CH2:30][CH2:29]2)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:34]([N:31]1[CH2:30][CH2:29][N:28]([C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:27]=[C:18]([C:10]3[CH:11]=[CH:12][C:7]([C:2]4([CH3:1])[O:6][CH2:5][CH2:4][O:3]4)=[CH:8][CH:9]=3)[N:19]=2)[CH2:33][CH2:32]1)[CH3:35]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CC1(c2ccc(OB(O)O)cc2)OCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3ccc(C4(C)OCCO4)cc3)cc3ccccc23)CC1

Procedure:
4-(2-Methyl-1,3-dioxolan-2-yl)phenylboric acid (0.41 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.62 g) were reacted in the presence of tetrakistriphenylphosphinepalladium(0) (0.11 g) in toluene (50 ml) and a 10% aqueous solution of sodium carbonate (30 ml) in nitrogen atmosphere at 120° C. for 30 min. The organic layer was separated, washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methyl-1,3-dioxolan-2-yl)phenyl]isoquinoline.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1C=CC=C[CH:3]=1.[CH3:10][NH2+:11][CH3:12].O.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:10][N:11]([CH3:12])[C:14]1[CH:19]=[CH:18][C:17]2[CH:2]([CH3:3])[C:1](=[O:8])[O:9][C:16]=2[CH:15]=1
Reactant: c1ccccc1
Reactant: C[NH2+]C
Reactant: O=C([O-])c1ccccc1
Solvent: O
Product: CC1C(=O)Oc2cc(N(C)C)ccc21

Procedure:
A mixture of 18.2 g (0.1 mole) of 4-methyl-3-(3-oxobutyl)-maleic acid anhydride and 17.5 g (0.15 mole) of dimethylammonium benzoate in 400 ml of benzene is heated under reflux using a water separator for 42 hours. The benzene is removed in vacuo and the residue that remains is partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product remaining after drying and after removal of the methylene chloride is chromatographed over silica gel with petroleum ether/ether. Subsequent recrystallisation from ether/petroleum ether yields 6-dimethylamino-3-methylbenzofuran-2(3H)-one having a melting point of from 87° to 89° C.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[N:32][CH:31]=[N:30]1>O>[N+:1]([C:4]1[O:8][C:7]([C:9]([NH:37][CH2:36][CH2:35][CH2:34][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: NCCCn1cncn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCn1cncn1)c1ccc([N+](=O)[O-])o1
Reaction time: 3 h

Procedure:
A mixture of about 4.71 g of 5-nitro-2-furoic acid, about 4.86 g of 1,1'-carbonyldiimidazole and about 100 ml of dry tetrahydrofuran was stirred in a 250 ml round bottom flask with a drying tube for about 3 hours. An approximately 4.0 g portion of 1H-1,2,4-triazole-1-propanamine was added and the mixture was stirred overnight at room temperature. The mixture was refluxed for about 3 hours, about 15 ml of water was added, refluxing continued for about 2 hours, then the mixture was concentrated to remove the solvents. An approximately 200 ml portion of methylene chloride and about 30 ml of 1N sodium hydroxide were added, the mixture was shaken and the organic layer separated and washed with two about 50 ml portions of water, then dried, filtered and evaporated to a solid. This solid was recrystallized from ethanol, giving about 290 mg of the desired product as beige crystals, mp 176°-177° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[C:13]1([CH:19]2[CH2:23][CH2:22][CH:21](O)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OC(=O)C)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:22]2[CH2:21][CH2:20][CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Reactant: OC1CCC(c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(=O)n(C2CCC(c3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (1.6 g, 6.8 mmol), 3-phenylcyclopentanol (1.32 g, 8.15 mmol) and triphenylphosphine (2.7 g, 10.2 mmol) in dry THF (15 mL) was slowly added diethyl azodicarboxylate (1.8 g, 10.2 mmol) at RT. The resulting yellow solution was stirred at room temperature for 17 h. The mixture was diluted in ethylacetate, washed with water, brine, dried over MgSO4, and chromatographed on silica gel using hexanes to 3:1 hexanes:ethylacetate, to afford the title compound. MS m/z: 376 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]([CH3:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:22])[CH:16]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Cs+].[C:29]([O:32][CH2:33]Br)(=[O:31])[CH3:30]>CC(C)=O>[C:29]([O:32][CH2:33][O:12][C:11](=[O:13])[C:10]([NH:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:22])[CH:16]=1)(=[O:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NNC(C)(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CC(=O)OCBr
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(=O)OCOC(=O)C(C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Temperature: 44 °C
Reaction time: 16 h

Procedure:
To a suspension of compound 102 (170 mg, 0.5 mmol) and cesium bicarbonate (99 mg, 0.5 mmol) in acetone was added bromomethyl acetate (170 mg, 0.5 mmol) and the mixture stirred at 44° C. temperature for 16 h. After removing the solvent under reduced pressure, the residue was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated, dried over MgSO4 and concentrated to afford the crude product, which was used in the next reaction without further purification.
Reaction SMILES: C([Li])CCC.[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[C:12]1([S:18](C2CC(Cl)CC2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:28]1[CH2:29][CH:30]([C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:18]([N:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])(=[O:19])=[O:20])[CH2:31][CH2:32]1
Reactant: O=S(=O)(c1ccccc1)C1CCC(Cl)C1
Reactant: CCCCCC
Reactant: O=C1CCCN1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCCN1S(=O)(=O)c1ccccc1C1CCCC1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
8 cm3 of a 1.5M solution of n-butyllithium in n-hexane is poured into a solution comprising 1.02 g, or 0.9 cm3 of 2-pyrrolidinone in 50 cm3 of tetrahydrofuran, cooled to -70° C. without the temperature exceeding -60° C. After 15 minutes, 3 g of benzenesulphonyl-4-cyclopentyl chloride in solution in 12 cm3 of tetrahydrofuran is added, maintaining the temperature between -65° and -70° C. After allowing to return to ambient temperature over 2 hours and evaporating to dryness, the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 2.6 g of expected product is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([SH:13])[CH3:12].[H-].[Na+]>O1CCCC1>[CH2:11]([S:13][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:12]
Reactant: CCS
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1ccc([N+](=O)[O-])cn1
Yield: 86.1 %

Procedure:
2-Ethylthio-5-nitropyridine (5.0 g) is prepared in substantially the same manner as in the first paragraph of Reference Example 4, using 5.0 g of 2-chloro-5-nitropyridine, 2.0 g of ethyl mercaptan, 1.4 g of sodium hydride (about 60%, in oil), and 20 ml of dry tetrahydrofuran.