Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:29]([CH2:30][CH3:31])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)=[CH:14][C:13]=3[F:28])[N:9]=[CH:10][C:5]=2[C:4](=[O:32])[C:3]=1[C:33]([NH2:35])=[O:34].CC[Cl:38]>CO.CCOCC>[ClH:38].[NH2:1][C:2]1[N:29]([CH2:30][CH3:31])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)=[CH:14][C:13]=3[F:28])[N:9]=[CH:10][C:5]=2[C:4](=[O:32])[C:3]=1[C:33]([NH2:35])=[O:34]
Reactant: CCCl
Agent: CCN1CCN(c2cc(F)c(Nc3ncc4c(=O)c(C(N)=O)c(N)n(CC)c4n3)c(OC)c2)CC1
Solvent: CO
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.08 g (0.18 mmol) of the product prepared in step 10.6 in 5 mL of methanol is added 0.53 mL (0.53 mmol) of 1.0 M hydrochloric ether. The mixture is stirred for 30 minutes at room temperature and then diluted with ether. The precipitate is drained by suction, rinsed with ether and with pentane, and dried under vacuum. 0.133 g of the expected product is obtained in the form of a beige-coloured solid. Yield (dihydrochloride)=77%. m.p. >260°C. M+H+=485.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.F[C:33]1([F:39])[CH2:38][CH2:37][NH:36][CH2:35]C1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:36]4[CH2:37][CH2:38][C@@H:33]([F:39])[CH2:35]4)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: FC1(F)CCNCC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: Fc1ccccc1-n1nnc(-c2nc(-c3ccc(CN4CC[C@@H](F)C4)cc3)no2)c1-c1ccncc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and 4,4-difluoropiperidine (168 mg; 0.97 mmol) to give Example 161 as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.72 (2H, dd, J=4.5, 1.7 Hz), 8.05 (2H, d, J=8.1 Hz), 7.63-7.52 (2H, m), 7.45 (2H, d, J=8.0 Hz), 7.40-7.34 (3H, m), 7.22-7.15 (1H, m), 3.61 (2H, s), 2.57 (4H, t, J=5.4 Hz), 2.07-1.94 (4H, m). LC/MS (Method C): 518 (M+H)+. HPLC (Method I) Rt 15.55 min (Purity: 97.6%).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=1)[CH:3]([CH3:5])[CH3:4].Br[CH2:23][C:24](=[O:38])[CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:12]([N:11]1[C:10](=[O:19])[C:9]([CH3:20])=[C:8]([CH3:21])[N:7]=[C:6]1[CH:2]([NH:1][CH2:23][C:24](=[O:38])[CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH:3]([CH3:4])[CH3:5])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Reactant: Cc1nc(C(N)C(C)C)n(Cc2ccccc2)c(=O)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(NCC(=O)CCN2C(=O)c3ccccc3C2=O)C(C)C)n(Cc2ccccc2)c(=O)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To 2-(1-Amino-2-methyl-propyl)-3-benzyl-5,6-dimethyl-3H-pyrimidin-4-one (0.66 g, 2.33 mmol) in DMF (15 mL) was added 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (0.69 g, 2.33 mmol, prepared as described in WO 89/10360) and N,N-diisopropylethylamine (0.301 g, 2.33 mmol). The reaction was stirred for 16 h at room temperature, concentrated under vacuum, dissolved in EtOAc/H2O, washed with water, dried (Na2SO4), and evaporated to give the title compound as a white foam (1.04 g, 89%). MS(ES+) m/e 501 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](N)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N([O-])=O.[Na+].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([Cu])#N>C(O)(=O)C.O.C(OCC)(=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: c1ccncc1
Agent: N#C[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccccn4)ccc32)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 37 mg of 2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (EXAMPLE 79) in acetic acid (1.0 mL) was added NaNO2 (7.7 mg) in H2O (0.5 mL). The mixture was stirred 1 h at 0° C. Pyridine (1 mL) was added followed by CuCN (9.8 mg). Gas evolution was observed. The reaction mixture was poured into ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated. The product mixture was purified by silica gel chromatography eluting with a gradient solvent system of 100% CH2Cl2 going to 10% MeOH CH2Cl2 giving 18.3 mg of the title compound. Mass spectrum (ESI): 293.3 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Li:15]>O1CCCC1>[C:1]1([Li:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]C
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
In a 300-cm3 four-necked flask in which the atmosphere was replaced with nitrogen, 7.4 g of fluorene were dissolved in 100 cm3 of tetrahydrofuran, followed by treating the solution with methyllithium, thereby obtaining a tetrahydrofuran solution of fluorenyllithium. Next, 50 cm3 of a tetrahydrofuran solution containing 5.2 g of previously synthesized 3,7-biscyclopentadienylidenebicyclo[3,3,0]octane were added dropwise to the tetrahydrofuran solution at -10° C. over 30 minutes. After completion of the addition, the reaction temperature was elevated up to room temperature, followed by stirring for 15 hours. Then, 100 cm3 of a 3.6% hydrochloric acid solution were poured thereinto to bring the reaction to an end. The resultant solid was collected by filtration, washed with ether, and then dried to obtain 7.6 g of white powdery 3,7-dicyclopentadienyl-3,7-difluorenylbicyclo[3,3,0]octane.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:37]2[CH2:38][CH2:39][N:34]([C:26]3[CH:27]=[C:28]([F:33])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[F:24])[CH2:35][CH2:36]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1cc(F)c(N2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)cc1F
Yield: 91.9 %

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (500 mg) and 4-chlorobenzenesulfonyl chloride (694 mg), respectively, to provide 1-(4-chlorobenzenesulfonyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (811 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[CH3:31][C:32]1([CH3:40])[C:34]([CH3:36])([CH3:35])[CH:33]1[C:37](O)=[O:38]>CCOC(C)=O.C1COCC1.CCN(CC)CC>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:37]([CH:33]3[C:34]([CH3:36])([CH3:35])[C:32]3([CH3:40])[CH3:31])=[O:38])[S:8][C:4]=2[CH:3]=1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)C(C(=O)Nc2nc3ccc(F)cc3s2)C1(C)C

Procedure:
A mixture of 6-fluoro-benzothiazol-2-ylamine (1 equiv), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1 equiv), 1-hydroxybenzotniazole, triethylamine (1.1 equiv), and 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.8 equiv) in 3:1 THF/Et3N (1 M) and were stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. Puried by silica gel chromatography afforded the title compound. MS (ESI+) m/z 293 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC=C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.8 %

Procedure:
In THF (14.0 ml)/methanol (14.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methyl-2-butenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.70 g). To the solution was added 1N sodium hydroxide (7.0 ml), and the mixture was stirred at room temperature for 24 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=6/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methyl-2-butenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.46 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][S:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCSCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-thiomorpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J7) (189 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (170 mg, 0.56 mmol) according to the general procedure M. Obtained as a yellow solid (302 mg).
Reaction SMILES: Br[C:2]1([CH:15]([Br:33])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=3)[CH:17]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[OH-].[Na+]>CO>[Br:33][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][N:24]=2)[CH:17]=1)=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)(C(Br)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=C(Br)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 40 °C
Reaction time: 14 h
Yield: 55.2 %

Procedure:
To a solution of tert-butyl 4-bromo-4-(bromo(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methyl)piperidine-1-carboxylate (890 mg, 1.50 mmol) in MeOH (5 mL) was added 2N NaOH (3 mL). The reaction was stirred at 40° C. for 14 h. The reaction was concentrated and the residue was dissolved in ethyl acetate. Water was added and the pH was adjusted to 2 using concentrated HCl. The organic layer was concentrated and the residue was purified by silica gel column chromatography (0-5% MeOH/CH2Cl2) to afford the title compound (425 mg, 55% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:18])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.[Cl-].[Cl:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:20][CH:21]=[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:9]([CH3:18])[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: CC(C(=CCl)c1cccnc1)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone and chloromethyltriphenylphosphonium chloride there is obtained 3-(α-chloromethylene-2,4-dichloro-β-methylphenethyl)-pyridine as an isomer-pure compound in the form of a yellow oil;
Reaction SMILES: [C:1]([C:4]1[CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][C:8]=2[CH:9]=1)(=O)[CH3:2].Cl.[NH2:22][OH:23]>CCO.N1C=CC=CC=1>[C:1](=[N:22][OH:23])([C:4]1[CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][C:8]=2[CH:9]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)C1=Cc2cc(Oc3ccccc3)ccc2OC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)C1=Cc2cc(Oc3ccccc3)ccc2OC1
Reaction time: 48 h

Procedure:
The ketone (2.53 g, 9.5 mmol) is dissolved in 90 ml of an EtOH/pyridine mixture (1:1), and treated with hydroxylamine hydrochloride (0.99 g, 14.3 mmol). The mixture is stirred for 2 days. The reaction mixture is partitioned between ether and water, and the aqueous layer is extracted twice with ether. The combined organic layer is then washed twice with 2N HCl and water, dried (MgSO4), and evaporated. The residue is purified by flash chromatography (10% EtOAc/hexane) to give 3-acetyl-6-phenoxy-2H-1-benzopyran oxime as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(#N)C>[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([NH:20][C:21]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)=[O:22])=[O:19]
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(-c2ccc(Cl)cc2)cn1
Reaction time: 15 h

Procedure:
5-(4-Chlorophenyl)-2-pyridylamine (2 grams) was dissolved in 90 ml acetonitrile and then reacted with 2,6-difluorobenzoyl isocyanate (2.6 grams) under nitrogen at room temperature. A solid formed immediately which, after stirring for about 15 hours, was collected and identified as the desired product by NMR analysis, yield 3.4 grams, m.p. 229°-234° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[S:15][C:14]([C:16]2[CH:17]=[C:18]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][C:21]=2F)=[CH:13][CH:12]=1>CS(C)=O>[Cl:10][C:11]1[S:15][C:14]([C:16]2[CH:17]=[C:18]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][C:21]=2[O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(F)c(-c2ccc(Cl)s2)c1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(OC2CCOCC2)c(-c2ccc(Cl)s2)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Tetrahydro-pyran-4-ol (1.01 g, 5.01 mmol) was added dropwise at 0° C. to a suspension of sodium hydride (200 mg, 5.01 mmol) in DMSO (10 ml). After stirring for 30 min at 10° C., a solution of the product obtained from step 1 (850 mg, 3.34 mmol) in DMSO (2 ml) was added dropwise and stirring was continued for 1 h at RT. The reaction was quenched with ice/water (50 ml). Ethyl acetate (50 ml) was added and the aqueous phase was extrated with ethyl acetate (2×30 ml). The combined organic phases were washed with brine (2×50 ml), dried over sodium sulphate, filtered, and evaporated. The product was obtained in quantitative yield and used in the next step without further purification.
Reaction SMILES: C(O[C@H:5]1[C@H:10]2[C:11]([CH2:14]OC(=O)C)=[CH:12][CH2:13][C@@H:9]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][O:6]1)(=O)C.[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:14][CH:11]1[C@H:10]2[CH2:5][O:6][CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[C@H:9]2[CH2:13][CH2:12]1
Reactant: COC(=O)C1=CO[C@@H](OC(C)=O)[C@H]2C(COC(C)=O)=CC[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)C1=COC[C@@H]2C(C)CC[C@H]12
Yield: 81.5 %

Procedure:
After methyl (1S, 4aS, 7aR)-1-acetoxy-7-(acetoxymethyl)-1, 4a, 5, 7a-tetrahydrocyclopenta[c]pyran-4-carboxylate (100 mg, 0.0003 mol) obtained in Example 21 was dissolved in 5 mι of ethyl acetate, 20% Pd(OH)2 --C (5 mg) was added to the solution, and the reaction mixture was stirred for 24 hours in a hydrogen gas atmosphere of 1 atm. The catalyst was removed by celite filtration and the filtrate was concentrated. The residual substance was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=2:8 eluent was distilled, and a colorless oily substance was obtained, i.e., methyl (4aS, 7aR)-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran-4-carboxylate (48 mg, yield=30.4%). This methyl (4aS, 7aR)-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran-4-carboxylate had the following physicochemical properties.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].I[C:30]1[CH:31]=[N:32][N:33]([CH:35]2[CH2:50][CH2:49][C:38]3([CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]3)[CH2:37][CH2:36]2)[CH:34]=1>>[NH2:28][C:14]1[N:15]=[CH:16][C:17]([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:50][CH2:49][C:38]4([CH2:41][N:40]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:39]4)[CH2:37][CH2:36]3)[CH:34]=2)=[CH:18][C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CCC(n3cc(I)cn3)CC2)C1
Product: C[C@@H](Oc1cc(-c2cnn(C3CCC4(CC3)CN(C(=O)OC(C)(C)C)C4)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared as a off-white solid from (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine and tert-butyl 7-(4-iodo-1H-pyrazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate under the conditions described in Step 6 of Example 3.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[S:13][C:14]([Cl:19])=[CH:15][C:16]=1[CH2:17][OH:18].C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[S:13][C:14]([Cl:19])=[CH:15][C:16]=1[CH:17]=[O:18]
Reactant: OCc1cc(Cl)sc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cc(Cl)sc1Br
Reaction time: 0.5 h

Procedure:
To a solution of DMSO (2.10 mL, 29.7 mmol) in dichloromethane (50 mL) at −78° C. was added oxalyl chloride (1.90 mL, 26.8 mmol) dropwise and the mixture was stirred for 30 min. at the temperature. To it was then added (2-bromo-5-chloro-3-thienyl)methanol from Example 1, Step 2 (4.50 g, 19.8 mmol, crude) in dichloromethane (25 mL) via a cannula and the resultant solution was stirred for 30 min. Triethylamine (6.40 mL, 45.5 mmol) was added in one portion and the mixture was stirred at −78° C. for 30 min. and allowed to warm slowly in air. The mixture was concentrated in vacuo and then resuspended in ether and then filtered. The filtrate was concentrated in vacuo to give the desired product. The crude was used directly without further purification.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(O)nc1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(Cl)nc1Cc1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared as described in Example 7, but employing a solution of ethyl 2-hydroxy-4-benzylpyrimidine-5-carboxylate (1.1 g, 4.3 mmol) and POCl3 (16 g, 107 mmol) resulting in a 37% yield (0.44 g); 1HNMR (DMSO-d6) δ 9.00 (s, 1H), 7.6-7.4 (m, 5H), 4.55 (s, 2H), 4.25 (q, 2H), 1.14 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O-:9])=[O:8])[CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][O:3]1.Cl>C(O)C.[OH-].[Na+]>[O:1]=[C:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][O:3]1
Reactant: O=C([O-])C1C(=O)OCC1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1C(=O)OCC1c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A mixture of ethyl (4R*,5R*)-5-[3-t-butyldiphenylsilyloxy)propyl]-2-oxo-4-phenyltetrahydro-3furancarboxylate (2.43 g) in ethanol (40 ml) and 1N aqueous sodium hydroxide (9.16 ml) was stirred at 50° C. for 2 hours. 1N HYdrochloric acid (10 ml) was added to the reaction mixture and the organic solvent was evaporated in vacuo. The aqueous solution was extracted with ethyl acetate, and the'extract was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo to give (4R*,5R*)-5-[3-t-butyldiphenylsilyloxy)propyl]-2-oxo-4-phenyltetrahydrofuran-3-carboxylic acid (2.20 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:1]([CH2:7][C:6]1[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cccc2c1C(=O)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NCCc2cccc(N(Cc3ccccc3)Cc3ccccc3)c21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1.466 g (9.039 mmol) 8-amino-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 15 ml DMF and combined with 3.226 g (23.340 mmol) potassium carbonate and with 3.808 ml (31.420 mmol) benzylbromide. This reaction mixture is stirred for 16 h at 50° C. The reaction mixture is diluted with ethyl acetate and extracted with sodium hydrogen carbonate solution. The organic phases are dried and the solvent is eliminated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=425.1 [M+H]+.