Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1)[CH3:2].C(N(CC)CC)C.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: CCc1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
6-Ethyl-4-pyrimidinol (Intermediate 11, 0.93 g, 7.49 mmol) was treated with triethylamine (1.044 mL, 7.49 mmol) and phosphorus oxychloride (3.49 mL, 37.5 mmol) and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, evaporated under reduced pressure and the residue was poured into 2M aqueous hydrochloric acid solution (10 mL). This solution was extracted with DCM (×2). The DCM layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (552 mg);
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[C:16]([CH:18]=[C:19]([O-])[CH3:20])#[N:17].[Na+].[NH2:23]/[C:24](/[CH3:32])=[CH:25]\[C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27].C(O)(=O)C>CC(O)C>[C:16]([C:18]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:14])=[CH:5][C:4]3=[O:15])[C:25]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[C:24]([CH3:32])[NH:23][C:19]=1[CH3:20])#[N:17]
Reactant: CCCOC(=O)/C=C(/C)N
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Reactant: CC([O-])=CC#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1ccc(F)c2c(=O)cc(C)oc12

Procedure:
A solution of 100 mg (0.49 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 50.96 mg (0.49 mmol) of sodium 1-cyanoprop-1-en-2-olate, 69.45 mg (0.49 mmol) of propyl 3-aminocrotonate and 0.04 ml (0.73 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The beige-colored crystals are filtered off with suction and dried at 40° C. in a vacuum drying oven. 112.9 mg (58.7% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[O:37]1[CH2:38][CH2:39][N:34]([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]4[O:20][C:21]([C:24]5[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=5)=[CH:22][N:23]=4)=[O:18])=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[CH2:35][CH2:36]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCOCC5)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.6 %

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (31 mg, 0.070 mmol) and morpholine (0.012 mL, 1.4 mmol) were dissolved in dichloroethane (2 mL) and NaBH(OAc)3 (31 mg, 15 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 7 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 50-100% EtOAc/hexanes) to furnish methyl 6-(2-(3-(4′-(morpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a light yellow oil (21 mg, 58%): 1H NMR (CDCl3, 600 MHz) δ 8.12 (d, 1H, J=7.7 Hz), 8.04-8.02 (m, 2H), 7.97 (t, 1H, J=7.8 Hz), 7.52 (d, 4H, J=8.0 Hz), 7.38 (d, 2H, J=8.0 Hz), 7.34 (d, 2H, J=8.0 Hz), 4.04 (s, 3H), 3.73 (t, 4H, J=4.5 Hz), 3.54 (s, 2H), 3.51 (t, 2H, J=7.6 Hz), 3.16 (t, 2H, J=7.6 Hz), 2.48 (s, 4H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.8, 139.3, 139.0, 138.2, 136.7, 129.6, 128.9, 128.0, 127.1, 126.8, 125.2, 123.3, 67.0, 63.1, 53.6, 53.1, 40.6, 29.3; HR ESI-TOF m/z 512.2173 (M+H+, C30H29N3O5, requires 512.2180).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)CI>CN(C=O)C>[F:5][CH:4]([F:7])[CH2:2][N:25]1[CH2:26][CH2:27][C:21]2[C:22](=[N:23][C:18]([N:15]3[CH2:16][CH2:17][CH:12]([O:11][C:10]4[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:9]=4[F:8])[CH2:13][CH2:14]3)=[C:19]([NH:28][CH:29]([CH3:31])[CH3:30])[N:20]=2)[CH2:24]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Agent: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(CC(F)F)CC2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (50 mg, 0.080 mmol) and Cs2CO3 (92 mg, 0.281 mmol) in DMF (0.5 mL) was added 1,1-difluoro-2-iodoethane (0.071 mL, 0.804 mmol) at 23° C. The reaction mixture was stirred at 80° C. for 18 h. The resulting crude material was filtered, rinsed with DMSO (2×0.5 mL), and purified by HPLC Method B using a 30% to 70% ACN gradient to give the title compound as a TFA salt (6.1 mg, 13%) as a yellow film. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.4 Hz, 6H), 1.82-1.93 (m, 2H), 2.03-2.10 (m, 2H), 2.79-2.98 (m, 4H), 3.24-3.32 (m, 2H), 3.33-3.75 (m, 4H), 4.05-4.18 (m, 3H), 4.52-4.55 (m, 1H), 5.76-5.82 (m, 1H), 6.39-6.72 (m, 1H), 7.00-7.04 (m, 1H), 7.25-7.34 (m, 2H); ESI-MS m/z [M+H]+ 468.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]1[CH:19]=[C:18]([C:20](=[O:28])[NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:17]=[CH:16][C:15]=1[CH:29]([NH2:31])[CH3:30])[CH:10]=[CH:9][CH:8]=2)=[O:4].[Li+].[OH-:33].[CH3:34][OH:35]>C1COCC1>[C:11]([O:33][C:34]([NH:31][CH:29]([C:15]1[CH:16]=[CH:17][C:18]([C:20](=[O:28])[NH:21][C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:19][C:14]=1[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:2])=[O:4])[NH:6]2)[CH3:30])=[O:35])([CH3:14])([CH3:12])[CH3:10]
Reactant: CO
Reactant: [OH-]
Reactant: COC(=O)c1cc2c(-c3cc(C(=O)Nc4ccncc4)ccc3C(C)N)cccc2[nH]1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc2[nH]c(C(=O)O)cc12
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[2-(1-amino-ethyl)-5-(pyridin-4-ylcarbamoyl)-phenyl]-1H-indole-2-carboxylic acid methyl ester (600 μmol) in THF (2.4 ml) and MeOH (2.4 ml) was added a 1N LiOH solution (2.4 ml). The reaction mixture was stirred at 40° C. for 6 hours. The reaction mixture was diluted with 1N LION and extracted with EtOAc. The aqueous layer is acidified with a 20% citric acid solution and extracted again with EtOAc. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:5]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:4][C:3]=1Br.[Cu][C:34]#[N:35].N.[CH3:37][N:38](C=O)C>>[CH2:20]([O:19][C:5]1[CH:4]=[C:3]([C:34]#[N:35])[C:2](=[CH:7][C:6]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:37]#[N:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCOc1cc(Br)c(Br)cc1OCCOCCOCCOC
Agent: N
Product: CCCCCCCCCCCCOc1cc(C#N)c(C#N)cc1OCCOCCOCCOC
Temperature: 150 °C
Reaction time: 48 h

Procedure:
A mixture of 1,2-dibromo-4-dodecyloxy-5-(1,4,7,10-tetraoxaundecyl)benzene (4.5 g, 7.7 mmole) and copper (I) cyanide (2.1 g, 23 mmoles) in anhydrous DMF (50 ml) was heated and stirred at 150° C. for 48 h under a nitrogen atmosphere. The mixture was carefully poured into rapidly stirred concentrated aqueous ammonia solution (300 ml). After 1 h, the precipitate was filtered and washed with ammonia solution (50 ml) and water (200 ml). The resultant solid was dried and then passed down a silica column (ethyl acetate/petrol, 2:5) to give 4-dodecyloxy-5-(1,4,7,10-tetraoxaundecyl)-phthalonitrile as white needles (1.7 g, 47%), m.p. 38°-40° C.(recrystallised from methanol/water), (Found C, 68.20; H, 9.00; N, 6.10, C27H42 N2O5 requires C,68.32; H, 8.92; N, 5.90); MS (CI) m/e 492 (M+ +NH4+); δH (200 MHz, CDCl3) 0.85(t, 3H), 1.23(br s, 18H), 1.83(q, 2H), 3.35 (s, 3H), 3.63 (m, 8H), 3.89 (t, 2H), 4.03 (t, 2H), 4.23(t, 2H), 7.12 (s, 1H), and 7.23 (s, 1H) and 4-dodecyloxy-5-(1,4,7,10-tetraoxaundecyl)phthalimide (0.27 g, 6%) as small white needles, m.p. 73°-74° C. (recrystallised from methanol/water), (Found C, 65.70; H, 8.78; N, 2.70, C27H43 NO7 requires C,65.69; H, 8.78; N, 2.70); MS (CI) m/e 511 (M+ +NH4+); δH (200 MHz, CDCl3) 0.85(t, 3H), 1.27(br s, 18H), 1.85(q, 2H), 3.38 (s, 3H), 3.66 (m, 8H), 3.93 (t, 2H), 4.09 (t, 2H), 4.27(t, 2H), 7.27 (s, 1H), 7.30 (s, 1H) and 7.34 (s, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C.CCOC(C)=O>CCO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Brc1ccc(NN=C2CCCCC2)cc1
Temperature: 105 °C
Yield: 91.4 %

Procedure:
A 250-mL round-bottomed flask was charged with 1-(4-bromophenyl)hydrazine hydrochloride (10 g, 45.05 mmol, 1.00 equiv) in EtOH (120 mL). To this was added cyclohexanone (8.8 g, 89.80 mmol, 2.00 equiv) and acetic acid (2.7 g, 45.00 mmol, 1.00 equiv). The resulting mixture was heated to 105° C. in an oil bath for about 1 hour. The reaction progress was monitored by TLC (EtOAc:PE=1:1). Upon completion, the reaction mixture was cooled down to room temperature and filtered off to obtain 1-(4-bromophenyl)-2-cyclohexylidenehydrazine as a yellow solid (11 g, 92%).
Reaction SMILES: [Br:1]Br.Cl[C:4]1[CH:18]=[CH:17][C:7]([C:8]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:9])=C[CH:5]=1.Cl[CH2:20][Cl:21]>>[Br:1][CH:10]([C:8](=[O:9])[C:7]1[CH:17]=[CH:18][CH:4]=[CH:5][C:20]=1[Cl:21])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: BrBr
Reactant: COC(=O)CCCC(=O)c1ccc(Cl)cc1
Reactant: ClCCl
Product: COC(=O)CCC(Br)C(=O)c1ccccc1Cl
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Bromine (46.5 g) was added dropwise to a dichloromethane (400 ml) solution of methyl 4-(4-chlorobenzoyl)butyrate (70.0 g). After stirring for 15 minutes, the reaction mixture was washed with water, dried (MgSO4), and concentrated to obtain methyl 4-bromo-4-(chlorobenzoyl)butyrate (89.5 g, 96%) as an oily substance. NMR (δ ppm in CDCl3): 2.3-2.7(4H,m), 3.71(3H,s), 5.33(1H,dd,J=8&5.5Hz), 7.48(2H,d,J=8.5Hz), 7.98(2H,d,J=8.5Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([NH:19][C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:29]([C:30](=[O:31])[NH:32][CH3:33])=[CH:34][CH:35]=[CH:36][C:37]=4[F:38])[C:24]([Cl:39])=[CH:23][N:22]=3)=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: COCCOC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCOC)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 2-methoxy-ethyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (80 mg, 52%). LCMS (m/e) 545 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.95-8.73 (m, 1H), 8.09 (s, 1H), 7.41-7.15 (m, 4H), 7.14-6.87 (m, 3H), 6.30-6.13 (m, 1H), 4.40-4.18 (m, 2H), 4.13-3.97 (m, 2H), 3.82-3.61 (m, 2H), 3.57-3.39 (m, 3H), 3.34-3.22 (m, 2H), 2.97-2.86 (m, 3H), 2.13-2.00 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](NC2N=CN=C(NC(C3CC3)=O)C=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29](F)C=3)(C)[NH:23][C:24](=[O:25])[C:3]=12.[C:34](=O)([O-])[O-].[Cs+].[Cs+].[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][SH:49])=[CH:44][CH:43]=1>CC(O)C>[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][S:49][C:6]2[C:5](=[O:21])[N:4]3[C:22]4([CH2:27][CH2:32][CH2:31][CH2:30][CH2:29]4)[NH:23][C:24](=[O:25])[C:3]3=[C:2]([CH3:34])[CH:7]=2)=[CH:44][CH:43]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Reactant: COc1ccc(CS)cc1
Agent: [Cs+]
Solvent: CC(C)O
Product: COc1ccc(CSc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
6′-Bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (1, 2.0 g, 6.42 mmol) was dissolved in 2-propanol (20 mL). To this mixture was added cesium carbonate (6.28 g, 19.28 mmol), followed by (4-methoxyphenyl)methanethiol (1.18 g, 7.71 mmol). The reaction mixture was stirred at 70° C. for 16 h. After completion, solvent was evaporated under reduced pressure and the crude was washed with water (50 mL) followed by diethyl ether and then dried under reduced pressure to afford 6′-((4-methoxybenzyl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3) as grey solid. Yield: 2.15 g, 87%; MS (ESI) m/z 385.5 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].O>C(OCC)(=O)C.CC(C)=O.[Cu](Br)Br>[C:17]([CH:19]([CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10])[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccccc1F
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 124 %

Procedure:
To a solution of 2′-fluoroacetophenone (28.6 g) in ethyl acetate (400 mL), copper (II) bromide (92.6 g) was added, and the mixture was heated under reflux for 4 hr. The reaction mixture was cooled to room temperature and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give crude 1-bromo-1-(2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassium carbonate (88 g) was added to ethyl cyanoacetate (168 g), and the mixture was stirred at 45° C. for 1 hr. A solution (360 mL) of crude 1-bromo-1-(2-fluorophenyl)ethanone (90.5 g) in acetone was added dropwise over 20 min. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr. To the reaction mixture water (300 mL) and ethyl acetate (300 mL) were added, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium dihydrogenphosphate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. An excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1→4:1) to give the title compound as an oil (yield 64.0 g, about 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[C:2]1=[O:11].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(NC(=O)CCl)C=CC=CC=1>>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[C:2]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: ClCc1ccccc1
Agent: O=C(CCl)Nc1ccccc1
Product: O=C1C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
Indoline-2,3-dione (I-D) is either N-alkylated with benzylchloride (I-E) or N-phenyl-2-chloro-acetamid (I-F) to yield the 1-benzylindoline-2,3-dione (I-G) or with the 1-phenylcarbamoylmethylindoline-2,3-dione (I-H), respectively.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1.CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])[CH2:5][CH2:6][N:7]([C:37]([N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)=[O:38])[CH2:8][CH2:9]1)#[N:3]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)N2CCC(C#N)(NC(=O)C(CC3CCCCC3)NC(=O)N3CCOCC3)CC2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride and 4-methyl-piperzine carbonyl chloride in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]=[C:9]1[NH:28][C:12]2=[N:13][C:14]3[CH:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:18][C:19]=3[CH:20]=[C:11]2[NH:10]1>>[O:8]=[C:9]1[NH:28][C:12]2=[N:13][C:14]3[CH:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:27])=[CH:18][C:19]=3[CH:20]=[C:11]2[NH:10]1
Reactant: CN1CCNCC1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: CN1CCN(C(=O)CCCOc2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1

Procedure:
Reaction of N-methylpiperazine and 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid (2 g) analogously to the procedure of Example 4 gave the title compound as the hydrated dihydrochloride salt; yield 2.85 g (92%), m.p. 286°-288° C. (dec.).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CC(C)([O-])C.[K+].CS(O[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:29][CH2:28][C:27]3[CH:30]=[CH:31][S:32][C:26]=3[C:25](=[O:33])[C:24]=2[CH:34]=1)(=O)=O>C(O)C>[O:33]=[C:25]1[C:24]2[CH:34]=[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:3]([OH:4])[CH3:2])[CH:21]=[CH:22][C:23]=2[O:29][CH2:28][C:27]2[CH:30]=[CH:31][S:32][C:26]1=2
Reactant: CNO
Reactant: CS(=O)(=O)OCCCCc1ccc2c(c1)C(=O)c1sccc1CO2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CN(O)CCCCc1ccc2c(c1)C(=O)c1sccc1CO2
Temperature: 25 °C
Yield: 51.1 %

Procedure:
To a stirring solution of 4.77 g of N-methylhydroxylamine hydrochloride in 100 ml of absolute ethanol was added 6.38 g of potassium tert-butoxide. To the resulting suspension was added 6.98 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol methanesulfonate, and an additional 150 ml of absolute ethanol. The suspension was allowed to reflux for 24 hours and was then cooled to room temperature. The suspension was filtered to remove potassium chloride and the filter cake was washed with absolute ethanol. The resulting solution was concentrated in vacuo to a waxy solid. The solid was dissolved in 300 ml of methylene chloride and partitioned against 200 ml of water. The organic phase was dried with 200 ml of saturated aqueous sodium chloride, collected, dried again (Na2SO4), filtered, and concentrated in vacuo to an oil. The oil solidified upon standing, and was recrystallized from isopropanol to give 3.09 g of 4-(4,10-dihydro-10 -oxothieno[3,2-c][1]benzoxepin-8-yl)-N-hydroxy-N-methyl-1-butylamine, m.p. 107°-108° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2)nc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 61b (760 mg, 4.49 mmol), NBS (878 mg, 4.93 mmol) and DBPO (54 mg, 0.23 mmol) in carbon tetrachloride according to Method A. Crude product was purified by flash chromatography on silica-gel using hexane/ethyl acetate (8:1) as eluent. White solid. Yield: 297 mg, 73%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.54 (s, 2H), 7.42-7.53 (m, 3H), 7.71-7.77 (m, 1H), 7.80-7.85 (m, 1H), 7.98-8.04 (m, 2H), 8.72-8.76 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=29.7, 120.6, 127.0, 128.4, 128.8, 130.1, 137.6, 138.5, 149.6, 157.36; (ESI): m/z=249.66 [M+H]+.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)=[O:16])[CH2:12]1)(C)(C)C.CCN(CC)CC.ClC[C:40](Cl)=[O:41].C([O-])([O-])=O.[K+].[K+].Br[C:50]1[N:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[N:51]1[CH:52]=[CH:53][CH:54]=[N:55][C:50]=1[N:7]1[CH2:8][CH2:9][N:10]([CH:11]2[CH2:14][N:13]([C:15]([C:17]3[S:21][C:20]4[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:19]=4[CH:18]=3)=[O:16])[CH2:12]2)[C:40](=[O:41])[CH2:6]1
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2cc3ccc(C(F)(F)F)cc3s2)C1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc2ccc(C(F)(F)F)cc2s1)N1CC(N2CCN(c3ncccn3)CC2=O)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 22.3 %

Procedure:
To a solution of 1g (30 mg, 0.068 mmol) and Et3N (0.04 mL, 0.28 mmol) in CH2Cl2 (3 mL) at 0° C. was added chloroacetyl chloride (11.5 mg, 0.10 mmol). The reaction was stirred at 0° C. for 1.5 h, and was then quenched with aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. The resulting residue was stirred with TFA (0.5 mL) in CH2Cl2 (2 mL) for 1.5 h. The solution was concentrated, and the residue was stirred in aq. NaHCO3 (2 mL) and THF (3 mL) for 24 h. To the resulting intermediate 1h in this mixture of aq. NaHCO3 and THF was added K2CO3 (28 mg, 0.20 mmol) and 2-bromopyrimidine (32 mg, 0.20 mmol). The reaction mixture was heated to reflux for 16 h, and was then extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 3% MeOH/CH2Cl2) gave Cpd 23 as a white solid (7 mg). MS 462 (M+H+).