Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:20])[F:19])[C:10]1=[O:22])[CH2:5][CH2:6][S:7][CH3:8].O.[OH-].[Li+]>O1CCCC1.O>[CH3:8][S:7][CH2:6][CH2:5][C@H:4]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:20])([F:21])[F:19])[C:10]1=[O:22])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](CCSC)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSCC[C@@H](C(=O)O)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A solution of (S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (134 mg, 0.39 mmol) in tetrahydrofuran/water (6 mL, 1:1) was treated with lithium hydroxide monohydrate (33 mg, 0.78 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 2 h. After this time, the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran. The resulting material was then diluted with a 1N aqueous hydrochloric acid solution and then extracted with ethyl acetate. The organic layers were combined and then dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated in vacuo to afford (S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyric acid (126 mg, 97%) as a white foam: HR-ES(+) m/e calcd for C14H14NO3SF3 [M+H]+ 334.0719, observed 334.0717; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.07 (d, J=7.46 Hz, 1H), 7.83 (d, J=7.67 Hz, 1H), 7.59-7.71 (m, 1H), 5.25 (dd, J=4.48, 10.44 Hz, 1H), 4.79 (d, J=17.47 Hz, 1H), 4.56 (d, J=17.47 Hz, 1H), 2.41-2.66 (m, 3H), 2.20-2.35 (m, 1H), 2.13 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C:23]4=[O:35])=[CH:18][CH:17]=3)[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[NH:36][C:37]([C:39]1[S:43][C:42]2[CH2:44][CH2:45][CH2:46][CH2:47][C:41]=2[CH:40]=1)=[O:38].CO.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]4=[O:35])=[CH:20][N:21]=3)[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[NH:36][C:37]([C:39]1[S:43][C:42]2[CH2:44][CH2:45][CH2:46][CH2:47][C:41]=2[CH:40]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3cc(-c4ccc(F)c(NC(=O)c5cc6c(s5)CCCC6)c4)n[nH]c3=O)nc2)C(=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2cc(Nc3ccc(N4CCNCC4=O)cn3)c(=O)[nH]n2)ccc1F)c1cc2c(s1)CCCC2
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A 10-mL single-neck round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 2h (75 mg, 0.129 mmol), methanol (2 mL) and 4 M HCl in dioxane (2 mL) and the mixture stirred for 2 h. After this time, ethyl acetate (20 mL) and water (20 mL) were added. The pH was adjusted to 6.5 with aqueous 10% potassium carbonate. The aqueous layer was separated and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine (20 mL) and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to a residue which was purified by column chromatography to afford a 56% yield of 21 (40 mg) as a white solid: mp 285-287° C.; 1H NMR (500 MHz, DMSO-d6) δ13.21 (s, 1H), 10.07 (s, 1H), 9.50 (s, 1H), 8.36 (d, 1H, J=2.5 Hz), 8.04 (dd, 1H, J=7.5, 2.0 Hz), 7.71 (s, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 7.53 (d, 1H, =9.0 Hz), 7.41 (t, 1H, J=9.0 Hz), 3.63 (t, 2H, J=5.5 Hz), 3.42 (s, 2H), 3.04 (t, 2H, J=5.0 Hz), 2.78 (t, 2H, J=5.0 Hz), 2.62 (t, 2H, J=5.5 Hz), 1.78 (m, 4H); MS (ESI+) m/z 560.0 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:16])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[Li+].[OH-].O>C1COCC1.CO.O>[CH3:16][N:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2ccccc2)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(-c2ccccc2)cc1C(=O)O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl-4-bromo-1-methyl-1H-pyrrole-2-carboxylate (2.5 g, 11.5 mmol) in DMF (35 mL) under argon were added sequentially Pd(PPh3)4 (0.66 g, 0.58 mmol) and phenyl boronic acid (3.46 g, 28.4 mmol). The reaction mixture was heated to 70° C., and Na2CO3 (11 g, 104 mmol) dissolved in water (30 mL) was added. The reaction mixture was heated to 110° C. (14 h), cooled to room temperature, diluted with water (250 mL), and extracted with diethyl ether (250 mL×3). The combined organic layers were dried and concentrated in vacuo. The residue was purified by silica chromatography (eluted with petroleum ether:ethyl acetate=40:1) to afford methyl-1-methyl-4-phenyl-1H-pyrrole-2-carboxylate as a white crystalline solid (0.257 g). The ester (0.26 g, 1.2 mmol) was then combined with LiOH/H2O (0.15 g, 3.6 mmol) in THF (5 mL), CH3OH (5 mL) and H2O (2.5 mL) and was stirred at 40° C. (4 h). Water (25 mL) was added and the mixture was washed with DCM (15 mL). The pH of the aqueous phase was adjusted to 5-7 using HCl (1N). The water was removed and the residue was dissolved in MeOH (100 mL) and then filtered. The filtrate was concentrated in vacuo to give 1-methyl-4-phenyl-1H-pyrrole-2-carboxylic acid as white solid. (0.419 g) 1H-NMR (CDCl3, 400 MHz): δ 4.01 (s, 3H), 7.16 (d, J=1.6 Hz, 1H), 7.23 (t, J=7.2 Hz, 1H), 7.38 (m, 3H), 7.53 (dd, J=7.2, 8.4 Hz, 2H)
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1.[CH2:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]1[O:21][CH2:20]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:23]([O:22][CH2:18][CH:19]([OH:21])[CH2:20][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:3]2[CH:2]=[CH:1][C:6]([O:7][CH2:20][CH:19]([OH:21])[CH2:18][O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:5][CH:4]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1)[CH2:24][CH2:25][CH3:26]
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCCCOCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOCC(O)COc1ccc(S(=O)(=O)c2ccc(OCC(O)COCCCC)cc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
4,4'-Dihydroxydiphenyl sulphone (125.0 g; 0.5 mole), butyl glycidyl ether of epoxide content 7.45 equiv./kg (134.2 g; 1 equiv.), and benzyltrimethylammonium chloride (1.0 g) were stirred together and heated at 100° C. for 1 hour, at 120° C. for 2 hours, and then at 130° C. for 4 hours. The mixture was cooled, and was found to have an epoxide content of 0.03 equiv./kg, indicating that the reaction was substantially complete.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].C1C(=O)N([Br:22])C(=O)C1.COC(C)(C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:22])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1[N+](=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 43.8 %

Procedure:
To a stirred solution of 4-methyl-2-nitro-benzoic acid methyl ester (108.5 g, 555.7 mmol) in acetonitrile (750 mL), was added NBS (97.9 g, 550.1 mmol). The mixture was heated to a gentle reflex with a 200 W light bulb on for 5.5 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate (1500 mL). The solution was washed with water (2×600 mL) and brine (300 mL), dried over magnesium sulfate, and concentrated to give a brown oil. To the oil, was added t-butyl methyl ether (300 mL). The mixture was heated at 70° C. for 15 minutes. The mixture was allowed to cool to about 53° C. over one hour, then to 45° C., and then at 20-25° C., while blowing nitrogen with a glass pipette overnight. The suspension was filtered via a medium pore-sized funnel. The solid was washed with a pre-cooled 10° C. mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to give 4-bromomethyl-2-nitro-benzoic acid methyl ester as an off-white solid (66 g, 43% yield). The solid was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1I.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][C:14]=2[Cl:16])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: Clc1ccc(I)c(Cl)c1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1ccc(Sc2ccc(Br)cc2)c(Cl)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 2,4-dichloroiodobenzene (0.72 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-(4-bromo-phenylsulfanyl)-2,4-dichloro-benzene (0.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[F:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:29][CH2:28][N:27]([CH2:26][C:25]2[CH:34]=[CH:35][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:31][CH2:32]1)=[O:20])[CH3:2]
Reactant: Fc1ccc(CN(CCCl)CCCl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (5 g, 16.9 mmol) and (4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (5.8 g, 20.1 mmol) 5.3 g of the product was isolated. Yield 5.3 g (67%); Brown oil; MS: 474 (M+H)+.
Reaction SMILES: N1C=CC=CC=1C1NC2C=CC=CC=2N=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.[Cl:27][C:28]1[CH:33]=[C:32](I)[CH:31]=[CH:30][C:29]=1[C:35]1[S:36][C:37]([N:40]2[CH2:47][C@@H:46]3[C@@H:42]([CH2:43][N:44]([CH3:48])[CH2:45]3)[CH2:41]2)=[N:38][N:39]=1>CCOC(C)=O.CO.[Cu]I.CN(C=O)C>[Cl:27][C:28]1[CH:33]=[C:32]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:31]=[CH:30][C:29]=1[C:35]1[S:36][C:37]([N:40]2[CH2:41][C@@H:42]3[C@@H:46]([CH2:45][N:44]([CH3:48])[CH2:43]3)[CH2:47]2)=[N:38][N:39]=1
Reactant: CN1C[C@@H]2CN(c3nnc(-c4ccc(I)cc4Cl)s3)C[C@@H]2C1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C[C@@H]2CN(c3nnc(-c4ccc(-n5ccnc5)cc4Cl)s3)C[C@@H]2C1
Temperature: 60 °C
Reaction time: 72 h
Yield: 16.9 %

Procedure:
DMF (0.75 mL) was added to a nitrogen flushed flask containing copper(I) iodide (13 mg, 0.067 mmol), 2-(2-pyridyl)benzimidazole (13 mg, 0.067 mmol) and cesium carbonate (273 mg, 0.839 mmol). The resulting suspension was heated at 60° C. for 1 hour. 1H-Imidazole (23 mg, 0.336 mmol) and 2-(2-chloro-4-iodophenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole (150 mg, 0.336 mmol) were added and the mixture was heated at 90° C. for ˜18 hours. The reaction mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford a green oil. The crude material was taken up in MeOH (30 mL) and SiliaMetS-DMT (0.61 mmol/g, 1.098 g, 0.67 mmol) was added. The resulting suspension was stirred at room temperature for 72 hours then the SiliaMetS-DMT was removed by vacuum filtration and the filtrate was concentrated in vacuo to afford the crude product as a yellow oil. The crude material was purified by mass directed preparative HPLC under acidic conditions (TFA modified). The product containing fractions were combined, loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a white solid (22 mg, 17% yield). LC-MS: Rt 0.52 min; MS m/z 387.0 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 8.15 (d, J=8.59 Hz, 1H), 8.06 (d, J=2.02 Hz, 1H), 7.91 (s, 1H), 7.83 (dd, J=8.59, 2.53 Hz, 1H), 7.15 (s, 1H), 3.72 (dd, J=10.36, 8.34 Hz, 2H), 3.37 (dd, J=10.36, 2.78 Hz, 2H), 3.00 (br. s., 2H), 2.56 (br. s., 4H), 2.26 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:14][C:15]1[N:20]=[C:19](S(C)(=O)=O)[N:18]=[C:17]([NH:25][C:26]2[NH:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[CH:16]=1>CC(O)(C)C>[Cl:14][C:15]1[N:20]=[C:19]([S:13][C:4]2[CH:5]=[C:6]3[C:11](=[C:2]([F:1])[CH:3]=2)[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[N:18]=[C:17]([NH:25][C:26]2[NH:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[CH:16]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Reactant: Cc1ccc2cc(S)cc(F)c2n1
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3cc(F)c4nc(C)ccc4c3)n2)[nH]n1
Temperature: 90 °C
Yield: 49.2 %

Procedure:
To a stirred solution of 8-fluoro-2-methylquinoline-6-thiol (1.21 g, 6.27 mmol) in tBuOH (25 ml) was added 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (1.5 g, 5.22 mmol). The reaction mixture was degassed three times (vacuum/N2) before being heated to 90° C. for 18 hours. The crude mixture was partially concentrated in vacuo. The resulting solid was filtered and washed with ethyl acetate and an aqueous solution of K2CO3. The solid was dried in a pistol under vacuo to afford the title compound as an off-white solid (1.029 g, 49% yield). 1H NMR (DMSO D6, 400 MHz) δ1.42 (3H, br s), 2.73 (3H, s), 4.95 (1H, br s), 6.47 (1H, br s), 7.61 (1H, d), 7.78 (1H, dd), 8.14 (1H, s), 8.39 (1H, d), 10.32 (1H, br s), 11.75 (1H, br s); MS (ES+) 401, (ES−) 399.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19]Br)=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1>C1COCC1>[Br:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1
Reactant: OCC1CC1
Reactant: CC(C)n1nc(Br)c2ccc(CBr)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1nc(Br)c2ccc(COCC3CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
Cyclopropyl-methanol (0.05 ml, 0.67 mmol) was dissolved in THF (1 ml). To this was added NaH (60%, 0.028 g, 0.72 mmol) in a single portion. The mixture was stirred at RT for 5 min then 4-bromo-7-bromomethyl-2-isopropyl-2H-phthalazin-1-one (0.2 g, 0.56 mmol) in THF (1 ml) was added in one portion and the reaction mixture was stirred for 1 hour. Whereupon LC-MS indicated complete consumption of starting material, the solvent was removed under vacuum and the residue was purified by flash column chromatography (elution: 80% heptane, 20% EtOAc) to give the title compound (0.17 g, 87% yield) as a light yellow oil. Tr=1.80 min, m/z (ES+) (M+H)+ 351 & 353
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=4)[CH2:17][CH2:16]3)=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(C4CC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(C4CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.3 %

Procedure:
To a solution of methyl 4-((4-(((trans-2-(4-cyclopropylphenyl)cyclopropyl)amino)methyl) piperidin-1-yl)methyl)benzoate (118 mg, 0.282 mmol) in methanol (3 mL) was added sodium hydroxide (1M, 2 mL, 2 mmol), and the mixture was stirred at room temperature for 6 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 46 mg of product (HCl salt) as white solid. MS: (M+H)+=405.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.54-0.72 (m, 2H), 0.84-1.01 (m, 2H),1.15-1.29 (m, 1H), 1.51-1.71 (m, 3H), 1.82-2.12 (m, 4H), 2.96 (br. s., 4H), 3.12 (br. s., 1H), 4.33 (br. s., 2H), 6.94-7.14 (m, 4H), 7.74 (d, J=8.08 Hz, 2H), 8.01 (d, J=8.34 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.[CH3:18][C:19]1C=CC(S(O)(=O)=O)=C[CH:24]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[C:19]([CH3:24])([CH3:18])[O:8][C:5]2=[CH:6][CH:7]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(Br)cc2-c2[nH]c3ccccc3c21
Temperature: 150 °C
Yield: 391.7 %

Procedure:
To the solution of 4-bromo-2-(1H-indol-2-yl)phenol (200 mg, 0.69 mmol) in acetone (5 mL) was added PTSA (26 mg, 0.14 mmol), it was stirred at 150° C. in a sealed tube. Then the solvent was removed and the crude product was purified using prep-TLC to provide the desired product of 2-bromo-6,6-dimethyl-6,11-dihydrochromeno[4,3-b]indole (180 mg, yield: 79.3%). MS (M+H)+: 327/329.
Reaction SMILES: [C:1](OC)(=[O:3])[CH3:2].[CH3:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>C(OCC)C>[CH3:2][C:1](=[O:3])[CH2:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COC(C)=O
Reactant: CCCCCC(C)=O
Agent: Cl
Solvent: CCOCC
Product: CCCCCC(=O)CC(C)=O
Temperature: 0 °C
Yield: 64 %

Procedure:
To a stirred solution of methyl acetate 15 (27.8 ml; 25.9 g; 350 mmol) in diethyl ether (200 ml) NaH (60% w/w; 4.80 g; 200 mmol) was added and resulted slurry was brought to boiling. Then a solution of 2-heptanone 16 (24.4 ml; 20.0 g; 175 mmol) in diethyl ether (150 ml) was added dropwise over 3 h. Refluxing was maintained for next 5 h. Then 10% aqueous solution of HCl with crushed ice (ca. 100 ml) was added carefully and organic phase was separated. Water phase was extracted with diethyl ether (150 ml) and combined organic phases were washed with saturated aqueous solution of NaHCO3 (50 ml), dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to give 15.6 g (99.7 mmol; 64% yield) of 17. 1H NMR (500 MHz, CDCl3) δ 0.90 (3H, m), 1.31 (2H, m), 1.60 (2H, m), 2.05 (2.1H, s), 2.13 (0.3H, s), 2.17 (0.3H, s), 2.24 (0.3H, s), 2.26 (1.4H, t, J=7.5 Hz), 2.42 (0.15H, t, J=7.5 Hz), 2.50 (0.25H, t, J=7.4 Hz), 3.57 (0.25H, s), 5.49 (0.7H, s); 13C NMR (126 MHz, CDCl3) δ 14.0, 22.5, 22.6, 23.1, 25.0, 25.5, 30.9, 31.2, 31.5, 38.3, 43.8, 58.0, 69.1, 191.5, 194.4, 202.2, 204.3, 204.6; MS (EI) m/z 157 ([M+H]+, 52), 156 (M+, 9), 141 (8), 113 (17), 100 (45), 85 (100); exact mass calculated for C9H16O2 156.1150. found 156.1151.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([OH:13])[N:6]=[CH:7]2.[CH3:14][Zn]C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1.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>[F:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:14])=[C:3]2[C:8]=1[CH:7]=[N:6][C:5]([OH:13])=[CH:4]2
Reactant: Oc1cc2c(Br)ccc(F)c2cn1
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)c2cnc(O)cc12

Procedure:
A solution of 5-Bromo-8-fluoroisoquinolin-3-ol (76.5 mg, 0.316 mmol), 2.0 M of dimethylzinc in toluene (0.40 mL, 0.80 mmol), and Pd(PPh3)4 (22 mg, 0.019 mmol) in THF in a microwave reactor tube was heated in the microwave reactor to 80° C. for 60 min. The reaction solution was poured into sat. aq. NH4Cl, and the resulting mixture was extracted with DCM (3×25 mL). The combined DCM extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with Et2O. The resulting light greenish-yellow solid was washed with Et2O and dried in vacuo to give the title compound as light greenish-yellow solid. It was used in the next step without further purification. MS(ES+): m/z=178.17 (100) [MH+]. HPLC: tR=2.36 min (polar—5 min, ZQ2).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:26])=[CH:20]4)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:27][CH3:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:28][O:27][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)[N:13]=[CH:12][N:11]=[C:10]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[CH:20]2
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCN(C)CC1
Yield: 32 %

Procedure:
A solution of 7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (150 mg, 0.38 mmol), (prepared as described in Example 73), in 1-methylpiperazine (2 ml) was heated at 100° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and aqueous 5% sodium hydrogen carbonate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on an isolute column eluting with methanol/ethyl acetate/methylene chloride (1/4/5 followed by 1/9/0) and 3M ammonia in methanol/methanol/methylene chloride (5/10/80). After removal of the solvent under vacuum, the solid was dissolved in the minimum of methylene chloride and ether/petroleum ether was added. The precipitate was collected by filtration, and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(4-methypiperazin-1-yl)propoxy)quinazoline (55 mg, 32%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])O[C:14](=[O:29])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]=[N+:27]=[N-:28])[CH:17]=2)=[CH:3]1.[OH-].[NH4+:32]>CN(C=O)C.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:32][C:14](=[O:29])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]=[N+:27]=[N-:28])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(OCCCN=[N+]=[N-])c3)C(=O)OC2=O)c2ccccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C2=C(c3cccc(OCCCN=[N+]=[N-])c3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
To a solution of 3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]furan-2,5-dione (1.0 g) in DMF (7 mL) was added and ammonium hydroxide (50 mL). The reaction mixture was heated at 140° C. for 3.5 h, then cooled to room temperature and diluted with water. The precipitates were filtered and dried to give 3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]-1H-pyrrole-2,5-dione (0.58 g). MS (EI): M+ 401.