Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[C:6]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH2:5]2.C(O)(=O)C.N1CCCC1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]3[C:6]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:5]2)[CH2:13][CH2:14][C:15](=[O:17])[CH:16]=3)=[CH:9][C:10]=1[F:11]
Reactant: CCCCC1(CCC(C)=O)Cc2cc(N)c(F)cc2C1=O
Solvent: C1CCNC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCC12CCC(=O)C=C1c1cc(F)c(N)cc1C2
Temperature: 100 °C
Yield: 76.9 %

Procedure:
The diketone from step 1 (0.6 g, 2.14 mmol) was dissolved in toluene (15 mL) and treated with acetic acid (0.236 mL, 4.12 mmol) and pyrrolidine (0.344 mL, 4.12 mmol). The resulting solution was stirred and heated in an oil bath at 100° C. for 1.5 hours. After cooling to room temperature, the mixture was filtered through a pad of silica gel and the product was washed off with EtOAc. The filtrate and washings were concentrated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 4:1 to 3:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide 7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.45 g, 80%) as a yellow solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C:21]2=[CH:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].BrN1C(=[O:33])CCC1=O.Cl(O)(=O)(=O)=O.[OH-].[Na+]>O1CCOCC1.O.C(O)(=O)C>[C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@:21]42[O:33][C@H:20]4[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1CC[C@]2(C)C3=CC[C@]4(C)[C@@H](C(C)=O)CC[C@H]4[C@@H]3CC[C@H]2C1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)C[C@@H]4O[C@@]432)C1
Reaction time: 0.08 h

Procedure:
3α-Acetoxy-5α-pregn-9(11)-en-20-one (3 g.) was dissolved in dioxan (300 ml.) and water (75 ml.); N-bromosuccinimide (2.1 g.) was added followed by perchloric acid (60% w/v; 1.05 ml.) in water (30 ml.) and the reaction allowed to stand at room temperature under nitrogen for 5 min. The pH was adjusted to 11.7 with 2N sodium hydroxide and the reaction mixture was allowed to stand at room temperature under nitrogen for a further 15 min; the pH was adjusted to 6 with glacial acetic acid and the mixture was poured into water. The steroid was extracted with ether to give a crystalline solid (3.2 g.); crystallisation from ether-petrol followed by recrystallisation from aqueous methanol gave the title compound m.p. 133°-136°, [α]D + 105°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]1[NH:14][C:15]2[C:16]([N:25]=1)=[C:17]1[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]1.[H-].[Na+].I[CH3:29].[ClH:30]>CN(C=O)C.CO>[ClH:30].[CH3:29][N:14]1[C:15]2[C:16](=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[N:25]=[C:13]1[CH2:12][CH2:11][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: c1ccc2nc(CCc3nc4c(ccc5ncccc54)[nH]3)cnc2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(CCc2cnc3ccccc3n2)nc2c3cccnc3ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-(quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline (100 mg, 0.31 mmol) or 2-(2-(quinoxalin-2-yl)ethyl)-1H-imidazo[4,5-f]quinoline (60 mg, 0.18 mmol) in DMF (3 mL or 2 mL, respectively) cooled in an ice bath was added sodium hydride (12 mg, 0.31 mmol; or 7 mg, 0.18 mmol; respectively). After stirring for 30 minutes, iodomethane (44 mg, 0.31 mmol; or 25 mg, 0.18 mmol; respectively) was added and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water, washed with saturated sodium bicarbonate (10 mL), and extracted with DCM (20 mL×3). The combined organic layers were dried and concentrated to give a yellow solid as the free base. The free base may optionally be converted to a salt. For example, the free base was stirred in an HCl in methanol solution for 30 minutes to afford 3-methyl-2-(2-(quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline hydrochloride (20 mg) or 1-methyl-2-(2-(quinoxalin-2-yl)ethyl)-M-imidazo[4,5-f]quinoline hydrochloride (25 mg) as a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11]1[N:15]=[C:14]([CH3:16])[O:13][N:12]=1)([CH3:10])[CH3:9])(C)(C)C.O>C(OCC)(=O)C.Cl>[CH3:9][C:8]([CH3:10])([C:11]1[N:15]=[C:14]([CH3:16])[O:13][N:12]=1)[NH2:7]
Reactant: Cc1nc(C(C)(C)NC(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C(C)(C)N)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-ylcarbamate (5.38 g) was dissolved in in ethyl acetate (30 mL) saturated with hydrochloride and stirred at room temperature for 1 h. Then water (50 mL) was added. The aqueous phase was washed with ethyl acetate (2×30 mL) and the pH adjusted with 1 M sodium hydroxide solution to 9˜10. The solution was extracted with ethyl acetate (2×30 mL). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left the title compound (1.7 g, 54%) as colorless oil; MS: m/e 142.2 [M+H]+.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2CCCC[C:15]=2[CH:16]=1>CCCCCC.CCOCC>[Li:5][CH:1]1[C:10]2[N:9]=[CH:8][C:7]([CH3:6])=[CH:16][C:15]=2[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]C1CCCc2cc(C)cnc21
Reaction time: 1 h

Procedure:
A solution of 15% w/w n-butyl lithium in hexane (51 ml.) ca. 0.12 m) was added portionwise to a solution of 3-methyl-5,6,7,8-tetrahydroquinoline (14.7 g., 0.1 m) in ether (100 ml.) and the mixture allowed to stand at room temperature for 1 hour to form 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline. The solution was then added dropwise to a cooled, stirred solution of methylchloroformate (9.45 g., 0.1 m) in ether (100 ml.). The mixture was further treated as described in Example 25 of copending U.S. Ser. No. 460,265 to give methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate.
Reaction SMILES: [C:1]12([S:11][C:12]3[C:13](=[O:20])[O:14][C:15]([CH3:19])=[CH:16][C:17]=3[OH:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:21]O>C(O)(=O)C>[C:1]12([S:11]([C:12]3[C:13](=[O:20])[O:14][C:15]([CH3:19])=[CH:16][C:17]=3[OH:18])=[O:21])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: OO
Reactant: Cc1cc(O)c(SC23CC4CC(CC(C4)C2)C3)c(=O)o1
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)C23CC4CC(CC(C4)C2)C3)c(=O)o1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
To a solution of 2.0 g. (0.0068 mole) of 3-(1-adamantylthio)-4-hydroxy-6-methyl-2-pyrone in 50 ml. of glacial acetic acid was added 0.78 g. (0.0070 mole) of 30% hydrogen peroxide and the solution allowed to stand at room temperature for 19 hours. The solution was then poured into ice water, and the resulting white solid precipitate was collected on a filter and recrystallized from ethanol to give the pure product 3-(1-adamantylsulfinyl)-4-hydroxy-6-methyl- 2-pyrone as 1.67 g. (80 percent) of colorless needles, m.p. 174.5°C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=1)[CH3:24]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(NC(C)=O)c1
Temperature: 100 °C

Procedure:
To a solution of N-(3-hydroxy-phenyl)-acetamide (0.5 g, 3.3 mmol) in acetone (5 ml) was added K2CO3 (0.46 g, 3.3 mmol), ethyl bromoacetate (0.67 g, 4.0 mmol) and 10 4 A molecular sieves. The reaction mixture was then heated in the microwave for 1 h at 100° C. (150 W, 200 psi). The reaction mixture was filtered and the acetone layer evaporated in vacuo. This residue was dissolved in EtOAc (10 ml) and washed with 2M KOH (5 ml×2). The organic layer was dried (Na2SO4), filtered and the solvent removed in vacuo to give the title compound as a colourless oil which solidified upon standing.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]2[C@@H:11]([C:19]([OH:21])=O)[O:10]1.[CH2:22]([NH2:24])[CH3:23].C(OCC)C>ClCCl.CN(C)C=O>[CH2:22]([NH:24][C:19]([C@@H:11]1[C@@H:12]2[C@@H:13]([O:14][C:15]([CH3:17])([CH3:18])[O:16]2)[C@H:9]([O:8][CH3:7])[O:10]1)=[O:21])[CH3:23]
Reactant: CO[C@@H]1O[C@H](C(=O)O)[C@@H]2OC(C)(C)O[C@@H]12
Reactant: CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
Oxalyl chloride (14.0 ml, 160 mmol) was added dropwise to a stirred solution of (3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (J. Amer. Chem. Soc., 80, 5168–5173 (1958)) (23.30 g, 107 mmol) in anhydrous dichloromethane (120 ml) and N,N-dimethylformamide (2 drops) and the mixture stirred at room temperature for 3 hours until gas evolution had ceased. TLC analysis showed that some starting material still remained and therefore further N,N-dimethylformamide (2 drops) was added and stirring continued for 1 hour. The solvent was removed under reduced pressure and the residue azeotroped with anhydrous dichloromethane (×2). The residue was dissolved in anhydrous dichloromethane (200 ml) and the solution treated dropwise with ethylamine (2 M solution in tetrahydrofuran, 140 ml, 280 mmol). This solution was allowed to stand at room temperature for 48 hours. Diethyl ether (250 ml) was added and the mixture stirred for 15 minutes. The mixture was filtered and the solvent removed from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane gradually changing to dichloromethane:ethyl acetate (44:66, by volume) to afford the title compound as a yellow solid (24.70 g).
Reaction SMILES: [C:1]1([S:7][C:8]([CH:22]2[CH2:27][O:26][C:24](=[O:25])[CH:23]2[C:28](=[O:43])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:30]=2)([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:44][C:45](OC(C)=O)=[O:46].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[C:45]([O:43][C:28](=[C:23]1[CH:22]([C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:27][O:26][C:24]1=[O:25])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1)(=[O:46])[CH3:44]
Reactant: O=C1OCC(C(Sc2ccccc2)(Sc2ccccc2)c2ccccc2)C1C(=O)c1cccc(OCc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(=C1C(=O)OCC1C(Sc1ccccc1)(Sc1ccccc1)c1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the ketone from Step 1 (1.91 g) in CH2Cl2 (20 mL) was added Ac2O (1.5 mL), Et3N (2.3 mL) and DMAP (40 mg). The reaction mixture was stirred at r.t. for 18 hr then diluted with Et2O and a saturated solution of NH4Cl. The organic phase was extracted, washed with H2O, brine, dried over MgSO4, and the solvent evaporated to afford the title product as a foam which was used as such in the next step.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:17]1[C:11]2[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:5][CH2:6]3)=[N:13][C:12]=2[CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc2c(c1)Cc1ccccc1C(N1CCNCC1)=N2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCN(C2=Nc3ccccc3Cc3ccccc32)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
A mixture of 2.77 g of 6-(1-piperazinyl)-11H-dibenz[b,e]azepine, 2.00 g of ethyl bromoacetate and 1.38 g of potassium carbonate in 14 ml of N,N-dimethylformamide was stirred at 70° C. for 3 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The etheral layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (2:1 and 1:1) as eluents to give 2.91 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless prisms, mp 107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:41]1([CH2:47][C:48]([NH2:50])=[O:49])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([CH2:47][C:48]([NH2:50])=[O:49])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)OC)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, 4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-methoxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H44N5O4Cl2 [(M+H)+] 680.2765, observed 680.2767.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]([CH3:30])[CH:24]=[N:25]2>>[CH3:30][N:23]1[C:22]2[C:26](=[N:27][CH:28]=[N:29][C:21]=2[NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)[N:25]=[CH:24]1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Cn1cnc2ncnc(Cl)c21
Product: Cn1cnc2ncnc(NCC3CCN(S(=O)(=O)CCc4ccccc4)CC3)c21

Procedure:
EXAMPLE 85 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 6-chloro-7-methyl-7H-purine (6-chloro-7-methyl-7H-purine was prepared according to G. B. Eilon, J. Org. Chem., 27:2478–2491(1962): MS (m+1)=415.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][S:27]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1)(=[O:29])=[O:28].N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:39]/[C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: CS(=O)(=O)n1cc(C=O)c2ccccc21
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(C)(=O)=O)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (2 mL) was added with 1-(methanesulfonyl)-1H-indole-3-carboxaldehyde (0.0641 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(6-hydroxy-2-{[1-(methylsulfonyl)-1H-indol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.104 g, 66%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[NH2:26][NH2:27]>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([NH:26][NH2:27])=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a suspension of methyl 4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (200 mg, 0.61 mmol) in EtOH (3.5 mL) was added hydrazine hydrate (0.5 mL). After stirring for 15 hrs at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×1 mL) and water (3×1 mL), and drying under vacuo at 70° C. for 1 hr gave 130 mg of the title compound (65%) as a white solid in 95.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=O)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Oc1cc(F)ccc1NC2=O
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(s1)Oc1cc(F)ccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 8-fluoro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][Cl:14])(=O)=O)=CC=1.[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([OH:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH2:11][CH2:12][CH2:13][Cl:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Yield: 99.5 %

Procedure:
A mixture of 102.4 g (411.7 mmol) of 3-chloropropyl p-toluene sulfonate, 75 g (411.7 mmol) of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 75.7 g (547.5 mmol) of potassium carbonate, and 1.66 g (4.1 mmol) of methyl-tricapryl ammonium chloride in 900 ml of acetone was stirred rapidly at reflux for 18 hr. The mixture was filtered and the solvent was removed giving 106 g of the tile compound after recrystallization from a chloroform-hexane mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>C1COCC1>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:13][CH2:14]2)=[O:34])=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C=Nc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and 4-benzyloxyphenyl isocyanate (68 mg, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a yellow solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[OH:16].Cl.[CH:18](OCC)(OCC)OCC>CO>[CH3:8][C:7]1[C:2]2[N:1]=[CH:18][O:16][C:3]=2[CH:4]=[CH:5][C:6]=1[NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14]
Reactant: CCOC(OCC)OCC
Reactant: Cc1c(NC(=O)C(F)(F)F)ccc(O)c1N
Agent: Cl
Solvent: CO
Product: Cc1c(NC(=O)C(F)(F)F)ccc2ocnc12
Temperature: 90 °C
Yield: 76.7 %

Procedure:
A solution of 2-amino-3-methyl-4-trifluoroacetamidophenol (4.25 g, 18.15 mmol) and concentrated hydrochloric acid (45 mL) in methanol (5.2 mL) is treated with triethyl orthoformate (2.98 mL, 27.2 mmol). A simple distillation apparatus is attached and the mixture is heated with an oil bath to 90° C. and methanol is distilled from the reaction. The reaction mixture is cooled to room temperature and distributed between ethyl ether (200 mL) and water (20 mL). The ether layer is washed with a 0.1 M aqueous solution of sodium hydroxide (20 mL), dried over magnesium sulfate and concentrated under reduced pressure to yield 3.40 g of 4-methyl-5-trifluoroacetamidobenzoxazole as an orange solid.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.BrN1C(=O)CCC1=O.N(CCCC#N)=NCCCC#N.[N-:32]=[N+:33]=[N-:34].[Na+].[BH4-].[Na+]>C(Cl)(Cl)(Cl)Cl>[N:32]([C@@H:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:1]([OH:11])[CH2:2][CH2:3]1)=[N+:33]=[N-:34]
Reactant: O=C1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: N#CCCCN=NCCCC#N
Agent: O=C1CCC(=O)N1Br
Agent: [BH4-]
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=N[C@H]1CC[C@@H](O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-tetralone (2.92 g, 20 mmol), N-bromosuccinimide (3.56 g, 20 mmol) and azodibutyronitrile (80 mg) in carbon tetrachloride (80 mL) was refluxed for 1.25h, then evaporated in vacuo. The resulting oil was dissolved in DMF (8 mL), treated with sodium azide (2.6 g, 40 mmol) and stirred at RT for 2h. The reaction mixture was partitioned between Et2O (200 mL) and H2O (50 mL). The resulting organic layer was dried (MgSO4), filtered and evaporated in vacuo. The resulting oil was dissolved in EtOH (100 mL), cooled to 0° C. under argon and treated with sodium borohydride (0.76 g, 20 mmol). The reaction mixture was stirred at RT for 1h, concentrated in vacuo to approx. 50 mL and partitioned between H2O and Et2O. The aqueous layer was extracted with DCM (100 mL) and EtOAc (100 mL) and the combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified by FCC using 0-30% cyclohexane/diethyl ether to give the title compound at Rf 0.2 as a dark red oil (1.5 g, 40%). 1H NMR (300 MHz, CDCl3): 7.57-7.52 (1 H, m), 7.43-7.28 (3 H, m), 4.81-4.72 (1 H, m), 4.55-4.49 (1 H, m), 2.13-1.99 (3 H, m), 1.79 (1 H, m).