Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[C:2](=[C:4](\[CH:6]=O)/[Cl:5])/[Cl:3].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C1C=CC=CC=1>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:6]2[O:9][C:1](=[O:8])[C:2]([Cl:3])=[C:4]2[Cl:5])=[CH:11]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Solvent: c1ccccc1
Product: O=C1OC(c2c[nH]c3ccccc23)C(Cl)=C1Cl
Temperature: 25 °C
Yield: 16.5 %

Procedure:
A stirred mixture of 20.3 g (0.12 mole) of mucochloric acid, 14.1 g (0.12 mole) of indole and 125 ml of benzene was heated for approximately twenty hours at reflux temperature. The reaction mixture was cooled to ambient temperature and a dark brown solid which had separated was collected by filtration. This solid was purified by two successive recrystallizations from benzene at approximately 60° C., with the aid of decolorizing charcoal. After the second recrystallization, the purified product was dried at 60° C. in vacuo to obtain 5.3 g of the known 5-(3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula VI: R=R1 =Y=H), a pale green-colored solid, which first melted at 174° C., then turned black and finally decomposed at 182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)[C:3]=1[C:4]#[N:5].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:16][N:17]([CH3:19])[CH3:18])=[C:13]([CH3:15])[N:12]=[CH:11]2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1cn(-c2cccc(Cl)c2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2cccc(Cl)c2C#N)c1CN(C)C
Yield: 29 %

Procedure:
As described for example 84b, 2-chloro-6-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 5 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) afforded the title compound as a white solid (yield: 29%). MS: m/e=275.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9](Cl)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na]>CN(C=O)C.CCOCC>[O:22]([C:9]1[O:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Agent: [Na]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc(Oc2ccccc2)nc1C(F)(F)F
Reaction time: 1 h

Procedure:
The compound of Example 5, ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate (4.87 g; 0.02 mol) was added to a mixture of sodium phenol in 100 ml DMF. The reaction was allowed to progress at ambient temperature for 1 hour. Gas chromatographic analysis, at this point, indicated the completion of the reaction. The dark brown liquid was then slurried in ether and washed 5 times with NaOH (5%) and H2O. The resulting brown liquid was dried (MgSO4) and concentrated in vacuo to yield 5.2 g of a brown semi-solid. Bulb to bulb distillation at 75° C./25 mm gave 1.7 g of a colorless oil. Further distillation at 130° C./0.25 mm gave 2.8 g of a white solid. Recrystallization from methylcyclohexane gave 1.08 g of pure white solid, ethyl 2-phenoxy-4-trifluoromethyl-5-oxazolecarboxylate, mp 75°-77° C., yield 18%.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5([C:29]([O:31]CC)=[O:30])[CH2:28][CH2:27][CH2:26]5)=[O:24])[CH2:19][CH2:18]4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5([C:29]([OH:31])=[O:30])[CH2:26][CH2:27][CH2:28]5)=[O:24])[CH2:19][CH2:18]4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1
Reactant: CCOC(=O)C1(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)C2(C(=O)O)CCC2)CC1
Yield: 67.1 %

Procedure:
A solution of ethyl 1-[(4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]cyclobutane-carboxylate from example 14 (0.050 g, 0.086 mmol), 5 N NaOH (10 ml) and ethanol (4 ml) was stirred at 90° C. for 3 hrs. The reaction was evaporated to dryness and residue was suspend in water (10 ml) and neutralized with 1N HCl. The aqueous layer was extracted with ethyl acetate (3×10 ml). The organic layer was dried using magnesium sulfate and concentrated down to form a white oil (0.032 g, 67%). 1H NMR (300 MHz, CDCl3) δ 7.68 (d, 1H), 7.27 (m, 8H), 4.63 (m, 1H), 3.84 (m, 1H), 3.41 (m, 1H), 3.25-2.95 (m, 4H), 2.87 (m, 1H), 2.58 (s, 3H), 2.45-2.20 (m, 4H), 2.05 (m, 2H), 1.89 (m, 8H), 1.63 (m, 5H), 1.61 (s, 2H). HRMS C34H42N4O3 m/z 555.3335 (M+H)Cal.; 555.3320 (M+H)Obs..
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[C:7]1=[O:17].Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:7]1=[O:17]
Reactant: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)c(OC)c1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3cccc(OCCCN4CCOCC4)c3C2=O)c(OC)c1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
A mixture of 2-(2,4-dimethoxy-benzyl)-4-hydroxy-isoindole-1,3-dione (313 mg, 1.00 mmol), 4-(3-chloropropyl)morpholine (160 mg, 1.11 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (5 mL) was heated at 60° C. for 18 hours. The mixture was diluted with ethyl acetate and extracted twice with 1N hydrochloric acid. The aqueous extracts were made basic with solid potassium carbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4) and concentrated to give a yellow solid which was recrystallised from methanol/petrol then ethyl acetate/chloroform/petrol to give the title compound (298 mg, 68%) as an off-white solid. 1H NMR (methanol-d4) 7.72 (1H, t), 7.41 (1H, d), 7.39 (1H, d), 7.02 (1H, d), 6.51 (1H, d), 6.43 (1H, dd), 4.72 (2H, s), 4.27 (2H, t), 3.81 (3H, s), 3.76 (3H, s), 3.68 (4H, t), 2.61 (2H, t), 2.50 (4H, m), 2.05 (2H, qn). MS: [M+H]+ 441.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1>C(OCC)C>[Br:1][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1cccc(Cl)c1
Solvent: CCOCC
Product: O=C(CBr)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (5.17 g, 32.3 mmol) was slowly added dropwise to a solution of 1-(3-chlorophenyl)ethanone (5.00 g, 32.3 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure, and the desired product was obtained quantitatively as an oil.
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[F:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[F:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Reaction time: 7 h
Yield: 95 %

Procedure:
To a mixed solution of 0.5 ml of 4N hydrochloric acid and 0.5 ml of acetic acid was added 235 mg of ethyl 1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 7 hours. After adding 1 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 182 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[CH:7]1[C:12]([CH:13]=O)=[CH:11][C:10]2[O:15][CH2:16][O:17][C:9]=2[CH:8]=1>>[CH:4]1([C:2]([CH:1]=[CH:13][C:12]2[CH:7]=[CH:8][C:9]3[O:17][CH2:16][O:15][C:10]=3[CH:11]=2)=[O:3])[CH2:6][CH2:5]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)C1CC1
Product: O=C(C=Cc1ccc2c(c1)OCO2)C1CC1

Procedure:
2-(3,4-Methylenedioxyphenyl)vinyl cyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 8.4 g. of cyclopropyl methyl ketone and 15 g. of piperonal according to the procedure described above in Preparation A1 affording 21.5 g., m.p. 85°-87° C. when recrystallized from ethanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:2]=1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:25][C:21]1[N:20]=[C:19]([NH:17][C:14]2[N:15]=[CH:16][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ncc(-c2cccnc2)c2cccnc12
Reactant: Cc1cccc(Br)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cccc(Nc2ncc(-c3cccnc3)c3cccnc23)n1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
5-Pyridin-3-yl-[1,7]naphthyridin-8-ylamine (0.1 g, 0.45 mmol) and 2-bromo-6-methylpyridine (0.14 g, 0.8 mmol) were dissolved in 4 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (52 mg, 0.09 mmol), cesium carbonate (0.23 g, 0.72 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (47 mg, 0.045 mmol) were added and the reaction mixture was stirred for 20 hrs at 130° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1->0:100 gradient). The desired product was obtained as a light yellow solid (66 mg, 47%), MS: m/e=314.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:26].O>C(O)(=O)C>[NH2:1][C:2]1[N+:3]([O-:26])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:16])[F:17])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1cc(-c2ccc(N)nn2)ccc1OC(F)F
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc(-c2ccc(N)[n+]([O-])n2)ccc1OC(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
8.9 g (31.6 mmol) of 3-amino-6-(4-difluoromethoxy-3-ethoxyphenyl)pyridazine in 60 ml of glacial acetic acid are heated with 10.9 g (63.2 mmol) of m-chloroperoxybenzoic acid with stirring at 60° C. for 2 h. After cooling, the solution is stirred into 100 ml of water, the solution is exhaustively extracted with ethyl acetate, and the organic extract is dried over magnesium sulfate, concentrated in vacuo and chromatographed on neutral silica gel first with ethyl acetate and then with ethyl acetate/methanol 8:2. The appropriate fractions are concentrated, the residue is taken up in a little ethyl acetate, petroleum ether (b.p. 40°-70° C.) is added to incipient opalescence, and the product is crystallized by cooling. The crystals are filtered off with suction, washed with petroleum ether and dried at 80° C. in vacuo. 5.7 g (60.7%) of the title compound of m.p. 202°-3° C. are obtained.
Reaction SMILES: [C:1]([O:7]C)(=O)[CH2:2][C:3]([CH3:5])=O.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[C:18]1[CH:22]=[N:21][NH:20][C:19]=1[NH2:23].C(O)C>C(O)(=O)C>[CH3:5][C:3]1[NH:23][C:19]2[N:20]([N:21]=[CH:22][C:18]=2[C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:9])[C:1](=[O:7])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(C)c(-c2cn[nH]c2N)c(C)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2cnn3c(=O)cc(C)[nH]c23)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Methyl acetoacetate (0.7 ml) was added to a solution of 4-(2,4,6-Trimethyl-phenyl)-2H-pyrazol-3-ylamine (1.120 g, 5.57 mmol) in 5 ml of acetic acid and the resulting mixture was heated at reflux for two days. Reaction mixture cooled and a white solid formed. Ethanol (6 ml) was added and stirred at room temperature overnight, filtered to give white solid which was recrystallized from ethanol to give 673 mg(45.2%) of the title compound as white crystals. 1H NMR (DMSO-d6) ä 11.9(s, 1H), 7.7(s, 1H), 6.95(s, 2H), 5.55(s, 1H), 2.25(s, 3H), 2.20(s, 3H), 2.0(s, 6H)ppm.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH3:22]CO>>[Br:3][C:4]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=2)=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: COc1ccc(COc2cccc(C=O)c2Br)cc1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1ccc(COc2cccc(CO)c2Br)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
NaBH4 (0.38 g, 10 mmol) was added to a solution of 2-bromo-3-(4-methoxy-benzyloxy)-benzaldehyde (1.59 g, 4.95 mmol) in EtOH (15 mL) at 0° C. (bath temp). The mixture was stirred at 0° C. (bath temp) for 1.5 h and then concentrated in vacuo. H2O (10 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The organic fractions were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound as white solid: yield 1.50 g (94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:4]=1[CH2:5][N:6]([CH3:16])[C:7]2=[O:15]>CO.CCOC(C)=O.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[C:7](=[O:15])[N:6]([CH3:16])[CH2:5]2
Reactant: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(N)c2c1CN(C)C2=O
Reaction time: 8 h

Procedure:
Pd/C (7.67 mg, 0.0720 mmol) was added to a solution of 4-methoxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one in MeOH (2 mL) and EtOAc (2 mL) and the mixture was hydrogenated at stp overnight. The solution was filtered and the title compound was not further purified. MS (ES+): m/z 193.14 (100) [MH+]; HPLC: tR=0.65 min (UPLC, analytical).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)Cc1ccccc1
Yield: 56.4 %

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with phenacetyl chloride (0.045 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.500 mL) to obtain 0.0205 g (56%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][NH:15][CH2:16][C@@H:5]23)[CH:10]=1
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: Clc1cccc(Cl)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CC2

Procedure:
The title compound was prepared by Example 305, Step A, from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate and the corresponding 2,6-dichlorobenzeneboronic acid followed by hydrolysis of the resultant BOC protected amine adduct by the procedure of Example 305, Step B. 1H NMR (CDCl3, 300 MHz) δ7.38 (dd, 2H), 7.15 (t, 1H), 6.80 (d, 1H), 6.73 (d, 1H), 3.69 (td, 1H), 3.57-3.30(m, 3H), 3.28-3.00 (m, 3H), 3.00-2.83 (m, 3H), 2.20 (bs, 2H), 2.00-1.81 (m, 2H). MS (CI): 346 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([CH2:7][OH:8])=[N:3]1.[H-].[Na+].Cl[C:12]1[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[N:19][N:20]=2)[N:17]=1>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[N:5][C:4]([CH2:7][O:8][C:12]2[C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[N:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:20]=3)[N:17]=2)=[N:3]1
Reactant: Cn1cnc(CO)n1
Reactant: Clc1nn2c(-c3cnccn3)nnc2cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(COc2nn3c(-c4cnccn4)nnc3cc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210; 0.044 g, 0.39 mmol) in dimethyl formamide (10 ml) was added sodium hydride (0.016 g of a 60% dispersion in oil, 0.390 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 0.5 h. After this time, the product from Example 1 step e) (0.1 g, 0.325 mmol) was added and the reaction mixture stirred for 2.5 h. The solvent was removed under high vacuum. Water (5 ml) was added to the residue and the solid produced was collected by filtration. The solid was recrystallised from ethyl acetate/ethanol to give the required product (0.049 g, m.p. 256.9-257.8° C.). 1H NMR (360 MHz, CDCl3) δ 3.94 (3H, s), 5.62 (2H, s), 7.47 (3H, m), 7.67 (2H, m), 8.04 (1H, s), 8.10 (1H, s), 8.70 (1H, s), 8.84 (1H, s), 9.80 (1H, s) (ES+) m/e 386 [MH+].
Reaction SMILES: [C:1]1(=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[N:11]O.[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C.[Zn]>[O:13]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:11][C:14](=[O:16])[CH3:15]
Reactant: O=C1C(=NO)CCc2ccccc21
Reactant: CC(=O)O
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
Zinc powder (24 g, 367 mmol) was added to a solution of 3,4-dihydro-[1,2]naphthoquinone 2-oxime (21.5 g, 123 mmol) in acetic acid (200 mw) and acetic anhydride (150 ml), and the solution was stirred at room temperature for 12 hours. After filtration and removal of the solvents under reduced pressure, the residue was partitioned between water and chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was washed with ethyl acetate and dried to afford N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (16.5 g, 81 mmol, 66%) as brown crystals.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1>>[N:29]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33][CH:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1
Reactant: C1CC(C2CCNCC2)CCN1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Product: c1cncc(-c2cc3c(-c4cccc(N5CCC(C6CCNCC6)CC5)n4)n[nH]c3cn2)c1

Procedure:
Following the procedures of Example 143, and starting with 3-(6-Fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 4,4′-bipiperidine, 273 was obtained and purified via reverse phase HPLC using a gradient of MeCN in water with 0.1% HCOOH to afford 25 mg (20%) over two steps. ESI MS m/z 440.2 (M+1). 1H NMR (400 MHz, DMSO): 9.23 (s, 1H), 8.97 (s, 1H), 8.61 (s, 1H), 8.39 (s, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J=7.3 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 4.54 (d, J=11.1 Hz, 2H), 2.97 (s, 2H), 2.66 (s, 2H), 1.88-1.71 (m, 4H), 1.46 (s, 1H), 1.31 (s, 5H)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F
Yield: 74.7 %

Procedure:
A mixture of 0.073 g (0.38 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 ml of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 112 mg of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 75%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.ClCCl>[C:29]([NH:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc(N(C)c2nc(N)nc3ccccc23)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C)c2nc(NC(C)=O)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-amino-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (20 mg, 0.07 mmol), triethylamine (0.02 ml, 0.14 mmol), acetyl chloride (0.01 ml, 0.14 mmol) and DMAP (1 mg) in 2 ml of dichloromethane similar to example 28 to give 3 mg (13.6%) of white solids. 1H NMR (CDCl3): 7.88 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.52-7.47 (m, 1H), 7.15-7.12 (m, 2H), 6.95-6.86 (m, 4H), 3.85 (s, 3H), 3.55 (s, 3H), 2.68 (s, 3H).