Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16].Br[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: BrCC1CCCO1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid (696 mg, 3.39 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of 2-bromomethyl-tetrahydro-furan (672 mg, 4.07 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. The excess solvent was removed in vacuo. The residue was diluted with water (50 mL) and was treated with a 1N aqueous hydrochloric acid solution until the solution was acidic. The resulting solution was extracted into ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate with glacial acetic acid) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid (692.3 mg, 70.8%) as a white solid: mp 100-102° C.; FAB-HRMS m/e calcd for C13H14Cl2O3 (M+H)+ 289.0399. found 289.0404.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:9]3[O:11][C@@:12]45[CH2:22][CH2:21][C@H:20]([OH:23])[C:19]([CH3:25])([CH3:24])[C@@H:18]4[CH2:17][CH2:16][C@H:15]([CH3:26])[C@@:13]5([CH3:27])[CH2:14][C:8]=3[C:7]([OH:28])=[CH:6][C:5]=2[C:4](=[O:29])[NH:3]1.[C:30]1(C)[CH:35]=CC(S([O-])(=O)=O)=C[CH:31]=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(O)CC>[OH:28][C:7]1[C:8]2[CH2:14][C@:13]3([CH3:27])[C@@H:15]([CH3:26])[CH2:16][CH2:17][C@H:18]4[C:19]([CH3:25])([CH3:24])[C@@H:20]([OH:23])[CH2:21][CH2:22][C@@:12]34[O:11][C:9]=2[C:10]2[CH:2]([O:1][CH2:31][CH2:30][CH3:35])[NH:3][C:4](=[O:29])[C:5]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(O)cc4c2C(O)NC4=O)C[C@]13C
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CCCOC1NC(=O)c2cc(O)c3c(c21)O[C@@]12CC[C@H](O)C(C)(C)[C@@H]1CC[C@H](C)[C@@]2(C)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 207.7 %

Procedure:
To a solution of Compound (30a) (33 mg, 0.08 mmol) in 3.0 ml of 1-propanol was added 6 mg of pyridinium p-toluenesulfonate, and the mixture stirred at room temperature for one hour. To the reaction was added 20 ml of ethyl acetate. The mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by a column chromatography (Merck, Lobar column, size A; ethyl acetate), and by crystallization from ethyl acetate to give 22 mg (60%) of Compound (30c).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1.[CH:22](OC)(OC)OC>CN(C=O)C.Cl.C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:22][N:9]([CH:10]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[C:3]=2[CH:4]=1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)ccc2N)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cnc3ccc(Br)cc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-((2-amino-5-bromophenyl)amino)pyrrolidine-1-carboxylate (320 mg, 0.938 mmol), HC(OCH3)3 (5 mL) in DMF (10 mL) was added concentrated HCl (two drops). The mixture was then stirred at room temperature for 16 h before concentration. The residue was then diluted with DCM (50 mL) and washed with saturated NaHCO3 solution (25 mL), water (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude desired product (250 mg, Yield 80%) which was used on the next step without further purification. LCMS (m/z): 366.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10]2)[CH3:3]>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]2)[CH3:1]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 103.8 %

Procedure:
Ethyl 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.87 g) was dissolved in a mixture of tetrahydrofuran (20 mL) and ethanol (20 mL), and 1M aqueous sodium hydroxide solution (9 mL) was added to the mixture. After stirring at 60° C. for 1 h, the mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was cooled to 0° C. and 1M hydrochloric acid (10 mL) was added. The resulting white suspension was filtered to collect a white precipitate. The precipitate was dissolved in ethyl acetate and the solution was dried over magnesium sulfate, filtered, and concentrated to give the title compound (1.81 g, 100%) as a white amorphous solid. MS 390 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.Br[CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1
Reactant: ClCCBr
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCN(CCCl)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 3-piperidylcarboxylate (100 g, 0.64 mole) in acetone (600 ml) was treated with 1-bromo-2-chloroethane (54 ml, 0.64 mole) and anhydrous potassium carbonate (138 g, 1.00 mole) and the mixture stirred at room temperature for 24h. The mixture was concentrated in vacuo and the residue treated with water (400 ml) and extracted with ether (2×200 ml). The combined ether extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was purified by chromatography on silica gel eluting with 50% ether/60-80 petrol to give the title compound (D18) as a pale yellow oil (50.0 g, 36%).
Reaction SMILES: Br[CH:2]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=2[CH3:22])=[N:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:25][CH2:26][OH:27]>>[CH2:26]([O:27][CH:2]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=2[CH3:22])=[N:8][CH:7]=1)[CH2:3][CH2:4][CH3:5])[CH3:25]
Reactant: CCO
Reactant: CCCC(Br)c1cnc(-c2c(C)ccc(O)c2C)c2ccccc12
Product: CCCC(OCC)c1cnc(-c2c(C)ccc(O)c2C)c2ccccc12

Procedure:
A mixture of 3-[4-(1-bromo-butyl)-isoquinolin-1-yl]-2,4-dimethyl-phenol (110 mg, 0.29 mmol) and c-HCl (30 uL) in EtOH (12 ml) is heated at reflux for 18 h. After removal of solvent, the residue is diluted with DCM and neutralized with 1N—NaOH. The layers are separated and the aqueous layer is extracted with DCM. The combined organic layers are dried over Na2SO4 and concentrated. The residue is chromatographed on silica gel to give 19 mg of 3-[4-(1-Ethoxy-butyl)-isoquinolin-1-yl]-2,4-dimethyl-phenol along with the unreacted starting material (80 mg).
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=1.[C:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)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>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:25]3[CH:26]=[CH:27][C:22]([CH2:21][C:19]#[N:20])=[CH:23][CH:24]=3)=[CH:3][N:4]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: COc1nccc2c1c(I)cn2C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(CC#N)cc1)cn2C1CCOCC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridine (20.0 mg) obtained in Step A of Example 16 in DMF (2 mL)/water (0.20 mL) were added (4-(cyanomethyl)phenyl)boronic acid (13.5 mg), tetrakis(triphenylphosphine)palladium(0) (6.45 mg) and potassium carbonate (15.4 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 2/1) to give the title compound (12.0 mg) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:4]([OH:30])([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[O:1]=[C:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:4]([OH:30])([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:3]1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)=O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@]4(O)CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
A solution of 750 mg of the 3β ,5α -25-trihydroxy-cholestane (VI) in 300 ml of acetone was treated dropwise with 10cc of Jones reagent. The reaction mixture was treated with 10 ml of methanol, left for 15 minutes at room temperature and concentrated in vacuum. The residue was extracted with ether and washed with water. The ether extract was evaporated in vacuo and the residue was crystallized from benzene to give 570 mg of 3-keto-5α,25-dihydroxy-cholestane (VII) m.p. 215°-217°. Nmr δ 0.70 (s, 3H), 1.15 (s, 3H), 0.95 (d, J=5Hz, 1H), 1.22 (s, 3H) Anal. Calcd for C27H46O2 : C, 77.5; H, 11.1%. Found: C, 77.0; H, 10.5%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>CCOCC>[CH2:13]([N:3]1[C:2]([CH3:12])([CH3:1])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]1([CH3:11])[CH3:10])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1
Solvent: CCOCC
Product: CCCCN1C(C)(C)CS(=O)(=O)CC1(C)C

Procedure:
38.2 g (0.2 mole) of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is heated with 13.7 g of n-butylbromide for 120 hours at 95°-100° C. After cooling, the contents of the flask are taken up in 300 ml of ether. The difficultly soluble hydrobromide of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is separated by filtration, and the ether solution extracted twice with 100 ml of water each time, in order to remove the last traces of starting product or its hydrobromide. The ether solution is dried over sodium sulphate and then fully concentrated by evaporation. The residue is crystallised from ligroin to obtain 1-butyl-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide, M.P. 180° C (3).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][OH:36])[CH2:22][CH2:21]4)=[N:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3cnc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: OCCBr
Product: CN(C)C(=O)c1cc2cnc(Nc3cnc(N4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 54.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.114 mmol) and 2-bromo ethanol (25 mg, 0.20 mmol) to give 7-cyclopentyl-2-[4-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 54%). MS(ESI) m/z 480.6 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11](COCC[Si](C)(C)C)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])[C:8]2=[CH:7][N:6]=1.[H-].[Na+].C1(C)C=CC(S([O:46][CH2:47][CH:48]2[CH2:52]OC(C)(C)[O:49]2)(=O)=O)=CC=1>CN(C=O)C>[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:52][CH:48]([OH:49])[CH2:47][OH:46])=[CH:16][C:15]=3[CH3:21])[C:8]2=[CH:7][N:6]=1
Reactant: Cc1cc(O)ccc1-c1nn(COCC[Si](C)(C)C)c2nc(Oc3ccc(F)cc3F)ncc12
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(O)CO)ccc1-c1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 85 °C
Yield: 15.4 %

Procedure:
4-[6-(2,4-Difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3-methyl-phenol (0.125 g, 0.26 mmol) from Example 12 was placed in a microwave tube together with dry DMF (3.0 mL) and sodium hydride (0.021 g of 60% suspension in mineral oil, 0.31 mmol). 2,2-Dimethyl-1,3-dioxolan-4-ylmethyl p-toluene sulfonate (0.91 g, 0.31 mmol) was added, and the tube was sealed and heated to 85° C. for five minutes via microwave. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic phase was separated, and the aqueous phase was washed twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The resulting residue was dissloved in 3 mL of 4 N HCl in dioxane, transferred to a sealed tube, and heated to 90° C. for 90 minutes. The reaction mixture was cooled, partitioned between water and ethyl acetate, and made basic by addition of aqueous sodium bicarbonate (to pH 9). The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC plate using methylene chloride/MeOH 93:7 to yield 0.016 g (0.04 mmol, 14.5%) of 3-{4-[6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3-methyl-phenoxy}-propane-1,2-diol. Mass Spec. M+H=429.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].O>CN(C)C=O>[C:20]1(=[O:30])[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[O:7][C:8]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=3[CH:10]=2)[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)c1ccc2cc(CCCCBr)oc2c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(CCCCN3C(=O)c4ccccc4C3=O)oc2c1

Procedure:
A solution of ethyl 2-(4-bromobutyl)benzofuran-6-carboxylate (3.25 g., 0.01 mole) and potassium phthalimide (2.04 g., 0.011 mole) in dimethylformamide (25 ml.) is stirred at 25°-27° C. for 18 hours. The solution is poured into water. The precipitated ethyl 2-(4-phthalimidobutyl)benzofuran-6-carboxylate is collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:23]1[CH2:28][CH2:27][CH:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][CH:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:27][CH2:28]1)=[O:6]
Reactant: C1CC(OCCN2CCOCC2)CCN1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCOCC2)CC1
Reaction time: 1 h
Yield: 16.6 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1)(0.2 g, 0.67 mmol), 4-(2-(piperidin-4-yloxy)ethyl)morpholine (79) (0.144 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white foam (0.055 g, 16.6% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.60-1.48 (1H, m), 1.83-1.64 (2H, m), 1.94-1.88 (1H, m), 2.59-2.57 (4H, m), 2.64 (2H, t), 3.14-3.05 (1H, m), 3.49-3.37 (1H, m), 3.58-3.51 (1H, m), 3.66-3.60 (3H, m), 3.74-3.72 (4H, m), 4.06-3.94 (1H, m), 4.28 (2H, s), 7.01 (1H, t), 7.32-7.26 (2H, m), 7.77-7.70 (3H, m), 8.48-8.44 (1H, m), 10.77 (1H, s); m/z (LC-MS, ESI+), RT=1.57 (M+H 495).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[I-:17].[Na+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][I:17]
Reactant: COC(=O)CCCCCCCCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCCCCCI
Yield: 97 %

Procedure:
12-Bromododecanoic acid methyl ester (5.65 g, 19.3 mmol) was dissolved in acetone (50 ml). Sodium iodide (14.4 g, 96 mmol) was added and the reaction was refluxed under nitrogen for 20 h. The sample was concentrated under vacuum. Water (100 ml) was added, and the mixture was extracted with AcOEt (2×100 ml). The organic extracts were pooled and washed with water plus a small amount of sat. NaCl and sat. NaCl (100 ml each), dried over MgSO4, and concentrated to yield a light yellow oil (6.37 g, 97%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]3[N:17]=[CH:18][CH:19]=[CH:20][C:8]=3[N:7]=2)=[CH:2]1.[H-].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][C:8]2[CH:20]=[CH:19][CH:18]=[N:17][C:9]1=2
Reactant: c1cnc2c(c1)N=C(c1ccsc1)c1ccccc1N2
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2ccsc2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(3-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:11]=2)[C:6](=[O:19])[C:7]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)=[CH:8]1
Reactant: C1CCNC1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Product: Cn1nnnc1-c1cn(C)c2cc(N3CCCC3)ccc2c1=O

Procedure:
In a similar way to that described in Example 30, 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5 g) was boiled under reflux with pyrrolidine (50 ml) for 20 hours to give 1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-7-pyrrolidino-4-quinolone, m.p. 267°-270° (from industrial methylated spirit:water 5:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 8-methoxy-9-[4-(piperazin-1-yl)phenyl]thieno[2,3-c]quinolin-4(5H)-one (89 mg, 0.23 mmol) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.42 mL, 0.68 mmol) and methanesulfonyl chloride (45 μL, 0.27 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with water and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered, concentrated and the residue was purified by preparatory HPLC (C18 silica, acetonitrile/water w/0.05% TFA gradient) to afford the desired product (72 mg, 68%) as a brown solid: ESI MS m/z 470 [C23H23N3O4S2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: N#Cc1cc(Cl)c(C(=O)Nc2c(F)cncc2F)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: N#Cc1cc(Cl)c(C(Cl)=Nc2c(F)cncc2F)c(Cl)c1
Temperature: 85 °C
Reaction time: 56 h

Procedure:
A stirred suspension of 2,6-dichloro-4-cyano-N-(3,5-difluoropyridin-4-yl)-benzamide (1.35 g, 4.12 mmol) in thionyl chloride (14 mL) was heated at 85° C. for 5 hours and then at 80° C. for 56 hours under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure to afford the title compound as an orange solid (1.5 g, quantitative). LCMS (Method D): RT=4.01 min, m/z: 346 [M+H+].