Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1F
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1F

Procedure:
A mixture of 14.0 g (0.1 mole) of 2-fluorobenzoic acid and 30 ml of thionyl chloride (SOCl2) is refluxed in 70 ml of benzene for four hours. The mixture is cooled and concentrated under vacuum to give 2-fluorobenzoyl chloride as a liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[CH:39]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:40]([O:42][CH3:43])=[O:41]>CN(C=O)C>[C:44]1([CH:39]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]4[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=4)=[O:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]2)[C:40]([O:42][CH3:43])=[O:41])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCC(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of intermediate (10) (0.007 mol) and Na2CO3 (0.007 mol) in DMF (50 ml) was stirred at room temperature. Methyl 2-bromo-2-phenylacetate (0.007 mol) was added dropwise. The mixture was stirred for 3 hours. The solvent was evaporated. The residue was triturated under hexane, filtered off and dried, yielding 3.37 g of methyl α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-phenyl]-1-piperidineacetate (intermediate 11, mp. 138° C.).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7]3[CH:11]=[C:10](Br)[S:9][C:8]=3[C:13]3[CH:17]=[C:16](Br)[S:15][C:14]=3[C:4]=2[CH:3]=1.[CH:19]1[C:31]2[N:30]([C:32]3[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.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>[CH:19]1[C:31]2[N:30]([C:32]3[CH:37]=[CH:36][C:35]([C:2]4[S:6][C:5]5[C:7]6[CH:11]=[C:10]([C:35]7[CH:34]=[CH:33][C:32]([N:30]8[C:29]9[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=9[C:23]9[C:31]8=[CH:19][CH:20]=[CH:21][CH:22]=9)=[CH:37][CH:36]=7)[S:9][C:8]=6[C:13]6[CH:17]=[C:16]([C:35]7[CH:36]=[CH:37][C:32]([N:30]8[C:29]9[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=9[C:23]9[C:31]8=[CH:19][CH:20]=[CH:21][CH:22]=9)=[CH:33][CH:34]=7)[S:15][C:14]=6[C:4]=5[CH:3]=4)=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: Brc1cc2c(s1)c1cc(Br)sc1c1cc(Br)sc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2cc3c(s2)c2cc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)sc2c2cc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)sc32)cc1
Temperature: 95 °C

Procedure:
Under a nitrogen atmosphere, 2,5,8-tribromobenzo[1,2-b:3,4-b′:5,6-b″]trithiophene (33) (500 mg, 1.04 mmol) obtained in Example 4, 4-(N-carbazolyl)phenyl boronic acid (1.34 g, 4.66 mmol) and tripotassium phosphate hydrate (3.96 g, 18.6 mmol) were suspended in DMF (40 mL) and degassed by Ar bubbling for 30 minutes. Pd(PPh3)4 (179 mg, 0.155 mmol) was added and heated at 90-100° C. for 18 hours. After completion of the reaction, water (30 mL) was added. A precipitated solid substance was obtained by filtration, washed with water (50 mL) and acetone (10 mL) and dried under reduced pressure. Vacuum sublimation purification was performed to obtain a light yellow substance (47.7 mg, 5%). MS (MALDI-TOF,1,8,9-trihydroxyanthracene matrix) m/z=966.34
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:8][N:7]=[C:6]1[C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([O:23]COC)=[CH:16][C:15]=1[O:27]COC)([CH3:4])[CH3:3].C(=O)([O-])O.[Na+]>CO>[CH:20]([C:18]1[CH:19]=[C:14]([C:6]2[N:5]([CH:2]([CH3:4])[CH3:3])[C:9]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:8][N:7]=2)[C:15]([OH:27])=[CH:16][C:17]=1[OH:23])([CH3:21])[CH3:22]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(S(C)(=O)=O)n1C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(-c2nnc(S(C)(=O)=O)n2C(C)C)c(O)cc1O
Reaction time: 8 h
Yield: 75 %

Procedure:
5 N hydrochloric acid (0.5 mL) was added to a methanol solution (0.5 mL) of 4-isopropyl-3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-5-methylsulfonyl-4H-[1,2,4]triazole (an intermediate of Example 2-13 F63-05: 35 mg, 82 μmol) and the mixture was stirred for 8 hours. After cooling to ice cold conditions, it was neutralized by adding saturated aqueous sodium hydrogencarbonate. The solution was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure. The solids thus obtained were dried under reduced pressure to obtain 4-isopropyl-6-(4-isopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-benzene-1,3-diol (SFN-a21, white solids, 20.8 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=2)=[O:16])=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)CCc2oc(-c3ccccc3)nc2-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(CCc1oc(-c2ccccc2)nc1-c1ccc(Cl)cc1)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-[4-(4-chlorophenyl)-2-phenyl-5-oxazolyl]-N-[4-(ethoxycarbonyl)phenyl]propionamide (0.70 g), potassium hydroxide (0.26 g), ethanol (20 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 5 hrs and further stirred at 50° C. for 3 hrs. The reaction mixture was poured into water and acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a colorless powder. Recrystallization from chloroform-ethanol gave 4-({3-[4-(4-chlorophenyl)-2-phenyl-5-oxazolyl]propanoyl}amino)benzoic acid as colorless prism crystals (0.51 g, 75%). melting point: 243–244° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:41][C:15]3[N:16]=[C:17]([C:26]4[C:27]5[C:31]([CH:32]=[CH:33][CH:34]=4)=[N:30][N:29](C4CCCCO4)[CH:28]=5)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].CO.S(=O)(=O)(O)O>O>[NH:30]1[C:31]2[C:27](=[C:26]([C:17]3[N:18]=[C:19]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[C:14]4[CH:13]=[C:12]([CH2:11][N:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH2:7]5)[S:41][C:15]=4[N:16]=3)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cccc5nn(C6CCCCO6)cc45)nc3s2)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.2 %

Procedure:
4-(6-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-2-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine 21 (500 g, 0.836 mole) was charged to a sizable reactor, followed by methanol (9.5 L) and water (250 ml). The resulting slurry was cooled to 0° C. and stirred for 0.5 h. A cold solution of concentrated sulfuric acid (H2SO4, 5.54 ml, assay 95-98%, 1.004 mole, 1.20 equiv.) and water (250 ml) was slowly added while maintaining the temperature below 10° C. The mixture was allowed to warm up to the ambient temperature and stirred for 20 hours. The slurry was cooled to 5° C., filtered and rinsed with cold methanol (2 L). The cake was charged to a reactor and stirred in a mixture of methanol (9.5 L) and water (25 ml) at 50° C. for 3 hours. The slurry was cooled 0-5° C., filtered and rinsed with cold methanol (2 L). The cake was dried in a vacuum oven at 50° C. for 24 hours to afford 4-(2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine II sulfate salt as a light yellow solid (482 g, 94%). 1H NMR (300 MHz, DMSO-d6) δ 3.00-4.00 (br, 8H), 3.01 (s, 3H), 3.85-3.87 (m, 4H), 4.00-4.02 (m, 4H), 4.69 (s, 2H), 7.46-7.52 (t, 7.8 Hz, 1H), 7.70-7.73 (d, 8.3 Hz, 1H), 7.91 (br, 1H), 8.22-8.25 (d, 7.2 Hz, 1H), 8.82 (s, 1H). LCMS (ESI pos) m/e 514 (M+1).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].[CH3:14][C:15]([CH3:17])=[O:16].Cl>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1](=[O:9])[CH2:14][C:15](=[O:16])[CH3:17])[CH:3]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1cccnc1
Temperature: 25 °C

Procedure:
A cooled (0° C.) solution of ethyl nicotinate (3.00 g, 2.71 ml, 19.65 mmol) in THF (10 ml) was treated with sodium hydride (60%, 1.572 g, 39.3 mmol) followed by the dropwise addition of a solution of acetone (2.282 g, 39.3 mmol, 2.89 ml) in THF (10 ml). The mixture was heated at reflux for 3 hours and then allowed to cool to RT. The mixture was acidified to ˜pH5 with 2M HCl and partitioned between EtOAc and water. The organic phase was separated and washed with water, brine, dried (MgSO4) filtered and the solvent was removed in vacuo. Purification by chromatography on silica eluting with iso-hexane/EtOAc afforded the titled compound; 1H NMR (CDCl3, 400 MHz) δ 15.97 (1H, s), 9.10 (1H, s), 8.78 (1H, d), 8.22 (1H, d), 7.49 (1H, t), 6.21 (1H, s), 2.25 (3H, s). LCMS Rt=1.13 mins; [M+H]+ 164.21 Method LowpH_v002.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:29]4[CH:30]=[N:31][NH:32][CH:33]=4)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CNCCO2)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)cc1

Procedure:
2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-morpholine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst to give the title compound. LCMS (PS-A3) Rt 6.88 min [M+H]+ 340. 1H NMR (Me-d3-OD) δ 2.84-2.88 (2H, m), 3.32-3.36 (1H, m), 3.45-3.49 (1H, m), 3.69-3.72 (2H, m), 7.31 (2H, d), 7.40 (4H, apparent d), 7.56 (2H, d), 7.92 (2H, br.s).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]([N:21]2[CH2:26][C@@H:25]([CH3:27])[NH:24][CH2:23][C@@H:22]2[CH3:28])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:31](Br)[CH:32]=[CH2:33].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:33]([N:24]1[CH2:23][C@@H:22]([CH3:28])[N:21]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:30][CH:29]=2)[CH2:26][C@@H:25]1[CH3:27])[CH:32]=[CH2:31]
Reactant: C[C@@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1C[C@@H](C)N(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Yield: 99.5 %

Procedure:
The purified benzhydrylpiperazine (41.0 g, 83.7 mmol) was dissolved in 500 mL of dry tetrahydrofuran with 7.3 mL (84 mmol) of allyl bromide and 22 g (200 mmol) of sodium carbonate and heated at reflux overnight under nitrogen. The cooled reaction solution was filtered and the solvent removed to give 44.1 g of crude (±)-trans-1-allyl-4-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a brown oil. NMR (200 MHz, CDCl3): δ 0.15 (s,6H) 0.95 (m,12H); 1.15 (2 overlapping d,J=6 Hz,3H); 1.8 (m,1H); 2.1 (m,1H); 2.35-2.65 (m,3H); 2.7-2.9 (m,2H); 3.35 (dd,J1 =5 Hz,J2 =12 Hz,1H); 5.0-5.2 (m,3H); 5.85 (m,1H); 6.6-7.5 (m,8H).
Reaction SMILES: 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.[C:34](O)(=[O:36])[CH3:35].[Cl:38][C:39]1[C:40]([F:68])=[C:41]([NH:45][C:46]2[C:55]3[C:50](=[CH:51][C:52]([O:66][CH3:67])=[C:53]([CH2:56][N:57]([CH3:65])[C:58]4([C:62]([NH2:64])=[O:63])[CH2:61][NH:60][CH2:59]4)[CH:54]=3)[N:49]=[CH:48][N:47]=2)[CH:42]=[CH:43][CH:44]=1>ClCCl>[C:34]([N:60]1[CH2:61][C:58]([N:57]([CH2:56][C:53]2[CH:54]=[C:55]3[C:50](=[CH:51][C:52]=2[O:66][CH3:67])[N:49]=[CH:48][N:47]=[C:46]3[NH:45][C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([Cl:38])[C:40]=2[F:68])[CH3:65])([C:62]([NH2:64])=[O:63])[CH2:59]1)(=[O:36])[CH3:35]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
Diisopropylethylamine (0.11 ml, 0.63 mmol) and then HATU (95 mg, 0.25 mmol) were added to a solution of acetic acid (18 μl, 0.31 mmol) in dichloromethane (1 ml). After 10 minutes, the hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide (100 mg, 0.21 mmol Example 74) was added and the mixture stirred overnight at room temperature. After removal of the solvent, the resulting product was dissolved in dimethylformamide and purified on preparative HPLC (standard basic conditions) to give the title product as a powder (52 mg, 51%); 1H NMR Spectrum: (CDCl3) 1.92 (d, 3H), 2.38 (s, 3H), 3.70 (d, 1H), 3.83 (d, 1H), 3.98 (s, 3H), 4.18-4.27 (m, 3H), 4.55 (d, 1H), 5.80 (brs, 1H), 6.94 (brs, 1H), 7.15 (m, 2H), 7.29 (s, 1H), 7.96 (brs, 2H), 8.34 (brs, 1H), 8.72 (s, 1H); Mass Spectrum: (M+H)+ 487.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])OC(CCl)C[O:16]2)[C:5]([C:29]#[N:30])=[CH:4][N:3]=1>CO.Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15](=[O:16])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:5]([C:29]#[N:30])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)nc1-c1ccc(Cl)cc1C1(c2ccccc2F)OCC(CCl)O1
Agent: Cl
Solvent: CO
Product: N#Cc1cnc(N)nc1-c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
A solution of 0.2 g (0.448 mmole) of the end product of Example 9 in 20 ml of methanol and 10 ml of 3N hydrochloric acid was refluxed for 20 mins and the solvent was evaporated. The residue was partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer was dried, concentrated and filtered through 15 g of Florisil. The column was eluted with 200 ml of ether which was concentrated, filtered and recrystallized from dichloromethane/ether/petrol to give white prisms, mp 153°-157° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([NH:21][CH3:22])[CH:13]=1.[OH-].[Na+]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][C:14]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: O=CO
Reactant: CNc1cc(C)ccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1ccc(C)cc1N(C)C=O
Reaction time: 1.5 h

Procedure:
A mixture of acetic anhydride (23.3 ml) and formic acid (15.9 ml) was stirred at 50 to 60° for 90 minutes and then cooled to 0 to 5° in an ice/salt bath. 4'-Methyl-2'-(methylamino)acetophenone (17.25 g) was added and the solution stirred at 20° for 3 hours. The reaction mixture was cooled to 0° and water (80 ml) added dropwise whilst maintaining the temperature below 8°. Aqueous sodium hydroxide (specific gravity 1.5, 60 ml) was added dropwise whilst maintaining the temperature below 10°. The mixture was extracted with dichloromethane (3×30 ml). The combined extracts were washed with aqueous sodium chloride (6M, 100 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the residue purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (100:1) to give the novel compound 2'-acetyl-5'-methyl-N-methylformanilide, m.p. 58°-60°.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:19])[C:10]=2[C:9]2[C:4](=[CH:5][C:6]([NH:20][C:21](=[O:27])[CH2:22][C:23]([O:25]C)=[O:24])=[CH:7][CH:8]=2)[C:3]1=[O:28].[OH-].[Na+].Cl>CO.CN(C)C=O.O.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:19])[C:10]=2[C:9]2[C:4](=[CH:5][C:6]([NH:20][C:21](=[O:27])[CH2:22][C:23]([OH:25])=[O:24])=[CH:7][CH:8]=2)[C:3]1=[O:28]
Reactant: COC(=O)CC(=O)Nc1ccc2c3c(n(C)c(=O)c2c1)-c1ccccc1C3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(NC(=O)CC(=O)O)cc3c1=O)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 3-[(6-methyl-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl)amino]-3-oxopropanoate (10, 158 mg, 0.42 mmol) was dissolved in methanol (20 mL) and dimethylformamide (2 mL). A solution of sodium hydroxide (103 mg) in water (2 mL) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Concentrated hydrochloric acid (1 mL) was added and the solution diluted with chloroform (30 mL). A dark-red precipitated was formed between the two phases. The solid was filtered and the organic and water layers discarded. The solid was washed with water (10 mL) and ether (2×10 mL). The solid was dried and compound 15 was obtained as a reddish-brown solid (93 mg, 61%): mp 262° C. (dec). IR (KBr) 3447, 3323, 1731, 1695, 1573, 1529, 1433, 1317, 1195, 1054, 899, 763 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 10.5 (s, 1H), 8.45 (s, 1H), 8.31 (d, J=8.6 Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.46-7.38 (m, 3H), 3.86 (s, 3H), 3.39 (s, 2H); 13C NMR (125 MHz, DMSO-d6) δ 190.1, 169.5, 165.1, 162.4, 155.7, 138.1, 137.5, 134.5, 133.8, 131.2, 127.6, 125.7, 124.1, 123.6, 122.7, 117.0, 116.9, 106.9, 44.4, 32.4; MALDIMS m/z (rel intensity) 363 (MH+, 100); ESIMS (m/z, relative intensity) 361 [(M-H+)−], 100); HRESIMS calcd for C20H14N2O5 361.0824 [(M-H+)−]. found 361.0828 [(M-H+)−]; negative ion; HPLC purity: 99.4% (MeOH, 100), 98.6% (MeOH—H2O, 95:5).
Reaction SMILES: [B-](F)(F)(F)F.C1[N+](=S(F)F)CC[O:8]C1.[C:15]1([CH2:21][CH2:22][CH2:23][OH:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:25](#[N:27])[CH3:26]>>[C:15]1([CH2:21][CH2:22][CH2:23][OH:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:25]([NH:27][CH2:23][CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[CH3:26]
Reactant: FS(F)=[N+]1CCOCC1
Reactant: CC#N
Agent: F[B-](F)(F)F
Agent: OCCCc1ccccc1
Product: CC(=O)NCCCc1ccccc1
Reaction time: 1.5 h
Yield: 25 %

Procedure:
To a stirred suspension of morpholinodifluorosulfinium tetrafluoroborate (362 mg, 1.5 mmol) in acetonitrile (3.0 mL) at room temperature was added 3-phenylpropanol (131 μL, 1.0 mmol). After 1.5 h, the reaction mixture was quenched at room temperature with a 5% aqueous sodium bicarbonate solution, stirred for 15 minutes, and the resulting mixture was extracted twice using dichloromethane. The organic phases were combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents were evaporated and the resulting crude material was purified by silica gel flash chromatography using DCM/MeOH (100/1) to provide 3-phenylpropanol (25 mg, 19%) and N-acetyl-3-phenylpropylamine (33 mg, 25%) as clear oils. Characterization for the latter: 1H NMR (CDCl3, 300 MHz) δ 7.31-7.08 (m, 5H), 5.60 (brs, 1H), 3.25 (q, J=6.8 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.91 (s, 3H), 1.76 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 170.1, 141.4, 128.5, 128.3, 126.0, 38.3, 33.3, 31.1, 23.3.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([CH:16]=[N:17]O)[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2].O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]#[N:17])[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2]
Reactant: CCn1c(=O)c2cc(C=NO)cn2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCn1c(=O)c2cc(C#N)cn2c2ccccc21
Yield: 77.4 %

Procedure:
A mixture of 2.5 g (9.8 mmole) of the product of Step A in 40 ml of acetic acid anhydride was refluxed for 3 hours and was then poured into a mixture of water-sodium carbonate-ethyl acetate. The decanted organic phase was washed once with water, dried, filtered and evaporated to dryness. The residue was triturated with ether to obtain 1.8 g of 4,5-dihydro-5-ethyl-4-oxopyrrolo-[1,2-a]-quinoxaline-2-carbonitrile in the form of buff needles melting at 237°-239° C.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[O:5].[OH-].[K+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23]>O.CC(C)=O>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[O:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4](=[O:5])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(C(=O)c2ccccc2O)cc1
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=S)Oc1ccccc1C(=O)c1ccc(C#N)cc1
Temperature: 50 °C
Yield: 83.4 %

Procedure:
15 g (0.0672 mol) of the 4-(2-hydroxybenzoyl)benzonitrile obtained in Preparation IVb are suspended in a mixture of 150 cm3 of water and 100 cm3 of acetone, 4.15 g (0.0735 mol) of potassium hydroxide are then added and the resulting reaction mixture is stirred and heated for 20 minutes at 50° C. (a red coloration appears, followed by complete dissolution). The solution obtained is cooled to 0° C., a solution of 9.14 g (0.074 mol) of dimethylthiocarbamoyl chloride in 80 ml of acetone is added and the resulting mixture is stirred at room temperature for 3 hours. The reaction medium is hydrolyzed. The precipitate formed is filtered off and then triturated in ether. 17.4 g of the expected product are obtained in the form of a beige solid (yield: 84%).