Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:11])[C:3](=[N:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO.S(OC)(O[CH3:18])(=O)=O>C(=O)([O-])[O-].[Na+].[Na+].O>[O:1]=[C:2]([CH3:11])[C:3](=[N:9][O:10][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(=NOC)C(C)=O
Yield: 82.7 %

Procedure:
In a solution of 13.3 g of sodium carbonate in 120 ml of water is dissolved 10 g of ethyl 3-oxo-2-hydroxyiminobutyrate, followed by addition of 30 ml of methanol. The mixture is cooled with ice and, under stirring, 15.8 g of dimethyl sulfate is added dropwise over a period of 3 minutes. After the dropwise addition has been completed, the ice-bath is removed and the mixture is stirred at room temperature for 40 minutes. The reaction mixture (pH 8 or higher) is extracted twice with ethyl acetate and the extracts are pooled, washed with water and dried. The solvent is then evaporated off under reduced pressure and the residue is subjected to distillation under reduced pressure. By the above procedure is obtained 9 g of ethyl 3-oxo-2-methoxyiminobutyrate as a pale-yellow oil boiling at 56°-61° C./0.3-0.4 mmHg.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:22])=O>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([Cl:22])=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Temperature: 79 °C
Yield: 98.3 %

Procedure:
59.8 g (233.4 mmol) of 4′-acetoxybiphenyl-4-carboxylic acid and 278 g (2.33 mol) of purified thionyl chloride were placed in a reactor and refluxed under heat (79° C.) for 4 hours. Thionyl chloride was distilled off under atmospheric pressure, 150 ml of toluene was added, and toluene and thionyl chloride were distilled off under reduced pressure, to give 63 g of an end compound (yield498%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]=5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:31])=[O:32])[CH:3]=2)[CH:47]=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 88 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 66C) (250 mg, 0.381 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (172 mg, 0.571 mmol) using Pd(PPh3)2Cl2 (14 mg, 0.019 mol) and sodium carbonate (121 mg, 1.143 mmol) in toluene/ethanol/water (20/10/4 ml) to afford 237 mg (88% yield) of the titled. MS: m/z=704.3 (M+1).
Reaction SMILES: [OH-].[Na+].C(OC([N:10]([C:27]1[C:32]([O:33][CH3:34])=[N:31][C:30]([CH3:35])=[CH:29][N:28]=1)[S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=O)C(C)C>CO.C(COC)OC>[CH3:34][O:33][C:32]1[C:27]([NH:10][S:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[N:28][CH:29]=[C:30]([CH3:35])[N:31]=1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1-c1ccc(C)cc1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
2 M Sodium hydroxide solution (0.6 ml) was added to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.232 g) in methanol (2.4 ml) and dimethoxyethane (2.4 ml) and the mixture was stirred for 2 hours. Volatile material was removed by evaporation and water (10 ml) was added to the residue. The mixture was acidified with 2M hydrochloric acid and extracted with ethyl acetate (2×10 ml). The extracts were washed with water (10 ml) and saturated sodium chloride solution (10 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue was recrystallised from ethanol to give N-(3-methoxy-5-methyl-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.1 g) m.p. 184-185° C.; 1H NMR (d6 -DMSO): 2.3 (s,3H), 2.4 (s,3H), 3.6 (s,3H), 7.05-7.3 (m,5H), 7.45-7.7 (m,3H), 8.1 (dd,1H), 9.35-9.45 (br s,1H); mass spectrum (-ve FAB, DMSO/Methanol/GLY): 368 (M-H)-.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[NH2:27]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:23][C:24]1[CH:25]=[C:26]([NH:27][C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH:28]=[C:29]([CH3:31])[CH:30]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)cc(NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 119.5 %

Procedure:
Commercially available Boc-L-proline (16, 2.3 g; 10.7 mmol) is dissolved in DCM (20 ml) and cooled to 0° C. followed by the addition of NEt3 (1.12 g; 11.22 mmol) and ethyl chloroformiate (1.22 g; 11.22 mmol) and finally commercially available 3,5-dimethylaniline (15) (1.36 g; 11.22 mmol). The reaction mixture is stirred at rt for 60 minutes. Brine (50 ml) is added and the organic layer is separated. The aq. layer is extracted with DCM (2×30 ml). The combined organic layers are dried over MgSO4, filtered and the solvent is removed under reduced pressure to give 4.07 g of crude (S)-tert-butyl 2-((3,5-dimethylphenyl)carbamoyl)pyrrolidine-1-carboxylate (17) which is used in the next step without further purification. LC-MS: tR=0.81 min; [M+H]+=319.11.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]1)=O)([CH3:4])([CH3:3])[CH3:2].[H-].COCCO[Al+]OCCOC.[Na+].[H-].C1(C)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][NH:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:18]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N1CCC(CNC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(CNC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a solution of N-[(R)-2-[(1-isopropylpiperidin-4-yl-methyl) amino]-1-phenyl-2-oxoethyl]carbamic acid tert-butyl ester (1.0 g, 2.6 mmol) in 15 mL of THF was added 65 wt % sodium bis(2-methoxyethoxy)aluminum hydride in toluene (2.4 mL, 7.7 mmol). The reaction mixture was heated at reflux for 3 h after which time the mixture was cooled to 0° C. and the reaction was quenched by the slow addition of a saturated solution of Rochelle's salt. The product was extracted into EtOAc; and the combined extracts were dried over sodium sulfate, filtered, and concentrated to afford, after purification (SiO2: 0 to 30% isopropylamine in 1:1 hexane:EtOAc), 0.9 g (94%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:32]=1)[C:18]1[C:17](Br)=[C:16]([O:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:9][CH:10]=1.[CH3:33][Sn](C)(C)C>O.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>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:32]=1)[C:18]1[C:17]([CH3:33])=[C:16]([O:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:9][CH:10]=1
Reactant: C[Sn](C)(C)C
Reactant: CC(C)(O)COc1ccc2c(c1Br)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1c(OCC(C)(C)O)ccc2c1[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 90 °C

Procedure:
A vial was charged with (S)-1-(2-amino-1′-bromo-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-2′-yloxy)-2-methylpropan-2-ol (150 mg, 0.302 mmol), tetrakis(triphenylphosphine)palladium(0) (34.9 mg, 0.030 mmol), TEA (168 μL, 1.209 mmol), and tetramethyltin (617 μL, 4.53 mmol). The vial was sealed and heated in a 90° C. oil bath 16 h. The mixture was cooled to RT, diluted with water, and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in methanol and filtered through a 0.2 micron filter. The filtrate was purified by reverse-phase HPLC (10-40% CH3CN/H2O with 0.1% TFA). The fractions containing product combined in saturated aq. sodium bicarbonate solution with the aid of methanol and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-1-(2-amino-1′-methyl-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-2′-yloxy)-2-methylpropan-2-ol as a white solid. MS m/z=432.0. Calc'd for C25H26N3O4: 432.19.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][N:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+].O>CS(C)=O>[CH3:28][O:29][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][N:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Fc1cccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.5 %

Procedure:
{2-[4-(6-Fluoropyridin-2-yloxy)-phenyl]-ethyl}-pteridin-4-ylamine (200 mg, 0.55 mmol) was dissolved in 4 mL dry DMSO and treated with sodium methoxide (300 mg, 5.5 mmol, 10 eq) and stirred for 20 h at 25° C. The mixture was poured into H2O (15 mL) and extracted with CH2Cl2 (2×25 ml). The pooled CH2Cl2 extracts were washed with H2O and brine, dried (Na2SO4), filtered, and evaporated. The gummy residue was dissolved in a minimum quantity of CH2Cl2 and treated with hexane to precipitate the product as a solid that was collected by suction filtration, washed with hexane and dried in vacuo to afford {2-[4-(6-methoxypyridin-2-yloxy)-phenyl]-ethyl}-pteridin-4-yl-amine (139 mg) as a tan solid: mp 152-153° C.; 1H NMR (DMSO-d6) δ 9.09 (s, 1H), 9.00 (t, J=5.9 Hz, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.51 (d, J=8.0 Hz, 2H), 6.36 (d, J=7.7 Hz, 2H), 3.83 (m, 2H), 3.65 (s, 3H), 3.00 (m, 2H); ESIMS m/z 375 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>CC(C)=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:37]2[CH2:38][CH2:39][N:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)[CH2:35][CH2:36]2)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Yield: 85.4 %

Procedure:
To a compound of N1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-chloroacetamide (500 mg, 1.46 mmol) in dry acetone (20 mL) was added anhydrous potassium carbonate (1 g, 7.30 mmol) and 1-(2-pyridyl)piperazine (238 mg, 1.46 mmol). The reaction mixture was refluxed for 24 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. The potassium carbonate was then removed by suction filtration and the solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product 6a (585 mg, 86% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:15]3[NH:29][N:28]=[N:27][N:16]=3)[N:14]=2)[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(Cl)ccc1COc1ccc(Cl)cc1Cc1cccc(-c2nnn[nH]2)n1
Reaction time: 11 h
Yield: 28.7 %

Procedure:
A mixture of 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)-methyl]-2-pyridinecarbonitrile (93 mg), sodium azide (51 mg), ammonium chloride (42 mg) and dimethylformamide (1 ml) was stirred at 120° for 11 hours. After cooling, water (5 ml) was added and the mixture extracted with ethyl acetate (2×5 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (29.7 mg, 29%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[NH:10][C:11](=O)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[N:10]=1
Reactant: COc1ccnc(-c2cc3ccccc3c(=O)[nH]2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccnc(-c2cc3ccccc3c(Cl)n2)c1

Procedure:
The resulting 3-(4-methoxypyridin-2-yl)isoquinolin-1-one (0.85 g) was reacted with phosphorus oxychloride (10 ml) according to the method of Example 10-2, to give 1-chloro-3-(4-methoxypyridin-2-yl)isoquinoline. The resulting compound was reacted, as it was, with N-ethylpiperazine (2.5 ml) at 100° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The resulting ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.40 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:18]=[C:17]2[C:5]([C:6](=[O:20])[C:7]3[N:16]2[C:15](=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=3)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CN1C(=O)CCC1>C(Cl)(Cl)Cl>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:18]=[C:17]3[C:5]([C:6](=[O:20])[C:7]4[N:16]3[C:15](=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=4)=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=C1c2ccc(Cl)cc2-n2c1nc1ccccc1c2=O
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc3c(c2)-n2c(nc4ccccc4c2=O)C3=O)CC1
Yield: 53 %

Procedure:
9-Chloroindolo[2,1-b]quinazoline-6,12-dione (Example 31, 155 mg, 0.55 mmol), N-methylpiperazine (75 μL, 0.68 mmol) and 3 mL of NMP were stirred at at 70° C. for 1 h. Chloroform (50 mL) was added and the mixture was washed with water (3×100 mL), dried (Na2SO4), filtered and solvent removed in vacuo to give the crude product. Silica gel chromatography purification of the residue using (95:5) chloroform:methanol as eluent gave 101 mg (53%) of the title compound: mp 214° C. (dec); 1H NMR(CDCl3) δ 2.40 (s, 3H), 2.55-2.65 (m, 4H), 3.60-3.70 (m, 4H), 6.68-6.74 (dd, 1H), 760-7.70 (t, 1H), 7.73-7.80 (m, 1H), 7.80-7.86 (m, 1H), 7.99-8.05 (d, 1H), 8.10-8.14(d, 1H), 8.36-8.42 (d, 1H); MS (M+H)+ 347.2.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([C:13]1[N:14]=[CH:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[CH3:12].[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:15]1[O:16][C:17]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)=[C:13]([CH2:11][CH3:12])[N:14]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCc1ncoc1-c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
LiHMDS (1.0 M in THF, 26 mL, 26 mmol) was added dropwise to a solution of Example 43A (5.75 g, 23.8 mmol) in THF (100 mL) at −78° C. After 30 min solid hexachloroethane (6.21 g, 26.2 mmol) was added in one portion, and the reaction mixture was allowed to proceed for 18 hr with gradual warming to ambient temperature. The reaction was quenched with saturated aq NH4Cl solution (50 mL), and the mixture was partitioned between H2O and Et2O. The aqueous phase was extracted once with Et2O, and the combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified on silica gel (Analogix® Intelliflash 280™; SF40-150 g column; 100% hexane 7 min, then 0% to 20% EtOAc/hexanes eluant, 23 min) which yielded 6.23 g (95%) of the title compound as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.87 (d, J=8.5, 2H), 7.79 (d, J=8.5, 2H), 2.77 (q, J=7.5, 2H), 1.23 (t, J=7.5, 3H). MS (DCI+) m/z 276 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:16]N(C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[O:29]1CCCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:16][OH:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(Cl)cc2)cc1OC
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.60 g (17.2 mmol) of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-chlorophenyl)acrylamide, 80 ml of 5% hydrochloric acid and 100 ml of tetrahydrofuran were mixed and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 4.46 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl)acrylamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([OH:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:26][CH3:27].CO>CN(C=O)C.C(Cl)Cl>[CH2:26]([O:13][C:11]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:12]=1)[CH3:27]
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of D1 (9.6 g, 38 mmol, 1.0 eq.) and K2CO3 (6.8 g, 50 mmol, 1.3 eq.) in dry DMF (100 mL) was added at RT iodoethane (4.0 mL, 7.8 g, 50 mmol, 1.3 eq.). After stirring for 72 h at RT the mixture was cooled to 0° C. MeOH (5 mL) was added, the mixture was diluted with DCM (200 mL) and washed with water and phosphate buffer. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the product D2 as a brown solid which was used without further purification in the subsequent step. MS (ES) C14H15FN2O3 requires: 278. Found: 279 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24]O>>[CH3:24][O:20][C:19](=[O:21])[CH2:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([Cl:22])=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2, 50 mg, 0.16 mmol) and 10% HCl in methanol (3 ml) was stirred for 3 h at room temperature. The mixture was concentrated and the residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:5) to afford 23 mg (44%) of the title compound as white solids.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: C1CCNC1
Reactant: COc1cc([N+](=O)[O-])c(N)cc1C(=O)O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(N)cc1C(=O)N1CCCC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.24 g of 5-amino-2-methoxy-4-nitrobenzoic acid in 30 ml of N,N-dimethylformamide was added 3.24 g of N,N'-carbonyldiimidazole at room temperature. After 30 minutes, 5 ml of pyrrolidine was added, and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound, m.p. 159°-162° C., yield of 4.16 g.