Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[N:9]=3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pental ene (1.34 g, 3 mmol), 4-Trifluoromethylphenylboronic acid (0.85 g, 4.5 mmol), Na2CO3 (2 M, 7 mL), and Pd(PPh3)2Cl2 (270 mg, 0.2 mmol) in toluene/ethanol (1:1, 18 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4′-Trifluoromethyl-biphenyl-4-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 35% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5](=[CH:9][C:10]1[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:13]=[CH:12][C:11]=1[O:31][CH3:32])[C:6](=O)[CH3:7])[CH3:2].Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][S:44][C:45](=[NH:47])[NH2:46])=[CH:39][CH:38]=1.C([O-])(=O)C.[Na+]>CN(C)C=O.CCOCC>[CH2:1]([O:3][C:4]([C:5]1[CH:9]([C:10]2[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:13]=[CH:12][C:11]=2[O:31][CH3:32])[N:46]=[C:45]([S:44][CH2:43][C:40]2[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)[NH:47][C:6]=1[CH3:7])=[O:33])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C=C(C(C)=O)C(=O)OCC
Reactant: COc1ccc(CSC(=N)N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C1N=C(SCc2ccc(OC)cc2)NC(C)=C1C(=O)OCC
Temperature: 70 °C

Procedure:
The reaction mixture containing 2-[[2-methoxy-6-pentadecyl phenyl]methylene]-3-oxobutanoic acid ethyl ester (3 g, 6.6 mmol), 2-((4-methoxyphenyl)methyl)-2-thiopseudourea hydrochloride (1.2 g, 6.6 mmol), and sodium acetate (0.6 g, 7 mmol) in dimethylformamide (30 mL) was heated at 70° C. for 4 h. The reaction was cooled to room temperature, diluted with ether, and filtered. The filtrate was washed with water, sodium bicarbonate, and brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the compound was obtained as brown viscous liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)[CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:19]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:30][CH:31]=1)[CH2:20][CH3:21]
Reactant: CCCOCc1ccc(CO)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCOCc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 68 h
Yield: 179.2 %

Procedure:
Into a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 4-(propoxymethyl)benzyl alcohol (502 mg) and triphenylphosphine (782 mg) in THF (10 ml) was added at 0° C. diethyl azodicarboxylate (a 40% solution in toluene) (1.30 g), and the resulting mixture was stirred at room temperature for 68 hours. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.15 g) as colorless crystals.
Reaction SMILES: [C:1]1([S:7]([C:10]2([CH2:15][CH2:16][CH2:17]O)[CH2:14][CH:13]=[CH:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:31][C:32]1[CH2:33][NH:34][CH2:35][CH2:36][C:37]=1[CH3:38].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[C:1]1([S:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:34]3[CH2:33][C:32]([CH3:31])=[C:37]([CH3:38])[CH2:36][CH2:35]3)[CH2:14][CH:13]=[CH:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)C1(CCCO)CC=CC1
Reactant: CC1=C(C)CNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=C(C)CN(CCCC2(S(=O)(=O)c3ccccc3)CC=CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(1-benzenesulphonylcyclopent-3-enyl)propan-1-ol (56 mg, 0.21 mmol) and triethylamine (41 μL, 0.29 mmol) in dichloromethane (5 ml) was cooled to 0° C. and treated with methanesulphonyl chloride (21 μL, 0.27 mmol). The mixture was allowed to warm to room temperature and stirred for 30 minutes, then diluted with water and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (5 ml), treated with 3,4-dimethyl-1,2,5,6-tetrahydropyridine (397 mg, 0.32 mmol) and potassium carbonate (58 mg, 0.42 mmol) and heated at 60° C. for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:13]([OH:15])=O)([O-:3])=[O:2].N1CCCCC1.CC(=O)[CH2:24][C:25](=[O:27])[CH3:26]>N1C=CC=CC=1.CCOCC>[C:25]([CH:26]1[C:13](=[O:15])[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[C:7]1=[O:9])(=[O:27])[CH3:24]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CC(=O)CC(C)=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: CCOCC
Product: CC(=O)C1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reaction time: 6 h
Yield: 76.1 %

Procedure:
To a solution of 100 g of 3-nitrophthalic acid in 100 mL of pyridine was added 0.8 mL of piperdine followed by 500 g of 2,4-pentanedione at room temperature. The mixture was stirred at 35°-40° C. for 6 hours and then diluted with 100 mL ether. The pyridine salt was filtered oft, washed with 100 ml of ether, dried, suspended in waer, and acidified with 400 mL of 6N HCl. The title compound was filtered off, dried,and recrystallized from ethanol to yield 84 g of yellow crystals, m.p. 148°-150°.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.C(OCC)C.[CH2:14]([O:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH3:25])[C:19]=1I)[CH3:15].[Li+].[Cl-].C(=O)C1C=CC=CC=1>C1COCC1.[Cl-].[NH4+]>[Br:24][C:21]1[C:20]([CH3:25])=[C:19]2[C:18](=[CH:23][CH:22]=1)[C:17](=[O:27])[O:16][CH:14]2[C:15]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)c1ccc(Br)c(C)c1I
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1C(c1ccccc1)OC2=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
3M PhMgBr in diethyl ether (1.7 mL, 5.07 mmol, 1.1 eq.) is added dropwise to the solution of 4-Bromo-2-iodo-3-methyl-benzoic acid ethyl ester (1.7 g, 4.61 mmol), LiCl (195 mg, 4.61 mmol) in dry THF (50 mL) at −10° C. The mixture is stirred at −10° C. for 2 hours. Benzaldehyde (0.977 g, 9.22 mmol) is slowly added to mixture at −10° C. This solution is stirred at room temperature for 16 hours and diluted with saturated aqueous ammonium chloride solution (100 mL). This solution is extracted with ethyl acetate (3×70 mL). The combined organic layers are washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue is purified by a silica chromatography to give the desire compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2cncc(F)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cncc(F)c2)n1
Yield: 55.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-amine (423 mg, 2.1 mmol), described in the previous step, and potassium carbonate (290 mg, 2.1 mmol) in anhydrous DCM (3.4 ml) was added dropwise phenyl chloroformate (0.61 ml, 4.8 mmol) as a solution in DCM (2 ml) to afford phenyl 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (411 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 1.28 (s, 9H), 6.47 (s, 1H), 6.95-7.41 (m, 7H), 7.72-7.82 (m, 1H), 8.40 (d, J=8 Hz, 1H); LC-MS (ESI) m/z 355 (M+H)+.
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]([CH3:12])[C:7](=[O:11])[CH2:8][NH:9][CH3:10].[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24](OCC)=[O:25])[O:23][C:19]=2[C:18]([F:29])=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16]=1[CH3:36])#[N:14].Cl>ClCCl>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:9]([CH2:8][C:7]([N:6]([CH3:12])[CH3:5])=[O:11])[CH3:10])=[O:25])[O:23][C:19]=2[C:18]([F:29])=[C:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:16]=1[CH3:36])#[N:14]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CNCC(=O)N(C)C
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CC(=O)N(C)C)nc2c1C#N
Reaction time: 0.58 h
Yield: 59.2 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 1.19 ml, 1.23 mmol) was dropwise added at room temperature to a dichloromethane (2 ml) solution of N,N-dimethyl-2-methylaminoacetamide (143 mg, 1.23 mmol), and stirred for 35 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (200 mg, 617 μmol) was dropwise added and stirred for 66.5 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate gave the entitled compound (144 mg, 59%) as an amorphous substance.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.O[C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].N1CCOCC1>CO.C(OCC)(=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:9]2[O:7][C:4]3([CH2:5][CH2:6][NH:1][CH2:2][CH2:3]3)[NH:13][C:11](=[O:12])[C:10]=2[CH:14]=1
Reactant: O=C1CCNCC1
Reactant: Cc1ccc(O)c(C(N)=O)c1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)NC1(CCNCC1)O2

Procedure:
A mixture of 26 mg (0.083 mmol) of N-[4,8-dimethoxyquinoline-2-yl)carbonyl]-4-piperidone (prepared as described in Example 44), 12.5 mg (0.083 mmol) of 2-hydroxy-5-methylbenzamide, and 0.020 mL of morpholine in 2 mL of methanol is refluxed for 20 hr. The reaction mixture is diluted with ethyl acetate, and washed with water, brine, and dried over Na2SO4. After solvent removal by rotoevaporation, the crude product is purified by preparative TLC to give 20 mg (0.045 mmol, 54% yield) of 1′-[4,8-dimethoxyquinoline-2-yl)carbonyl]-6-methylspiro-[2H-1,3-benzoxazin-2,4′-piperidin]-4-(3H)-one (Compound 137): 1H NMR (DMSO-d6): δ 2.28 (s, 3H), 3.95 (s, 3H), 4.06 (s, 3H), 6.98 (d, 1H), 7.19 (s, 1H), 7.23 (d of d, 1H), 7.33 (d of d, 1H), 7.52 (d of d, 1H), 7.56 (d, 1H), 7.68 (d of d, 1H), and 8.77 ppm (s, 1H). MS m/z: 448.1 (M+H)+, 470.0 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=[O:16].[O:20]1CCOCC1>>[ClH:1].[OH:20][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1Cl)OCO3
Product: Cl
Product: O=C(O)c1cnc2cc3c(cc2c1O)OCO3

Procedure:
Ethyl 4-chloro-6,7-methylenedioxyquinoline-3-carboxylate (18.5 g, 66.2 mmol) was dissolved in dioxane (100 mL) and treated with 50 mL 5 NNaOH and heated at reflux for 2 hour. After this time the solution was concentrated on a rotary evaporator, cooled and extracted with dichloromethane (2×100 mL). The remaining aqueous solution was then acidified with concentrated HCl and the precipitate collected and dried to afford 7 g of crude 4-hydroxy-6,7-methylenedioxyquinoline-3-carboxylic acid hydrochloride.
Reaction SMILES: [O:1]1[C@@H:3]2[C@H:4](O)[C@@H:5]3[C@@H:14]([C@@:15]4([CH3:27])[CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19][C@@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[C@@H:7]2[CH2:29][C@@H:8]2[C:9]1=[O:28].[Cl:31]CCl.ClC(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1>[Cl:31][C@@H:4]1[C@H:3]2[O:1][C@:2]32[C@:15]([CH3:27])([CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19]3)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:28])[C@H:8]2[CH2:29][C@@H:7]12
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 169 g of 5,6β-epoxy-7β-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one in a mixture of respectively 340 ml of dichloromethane, tetrachloromethane, and pyridine is combined with 200 g of triphenylphosphine and stirred for 2 hours at room temperature. The reaction solution is washed with water, dried over sodium sulfate, and evaporated to dryness under vacuum. The residue is stirred up with 310 ml of ethanol and filtered. The filter cake is washed with 175 ml of ethanol and dried under vacuum, thus obtaining 139.2 g of 7α-chloro-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one. An analytical sample, recrystallized from acetone-hexane, has a melting point of 228° C. [α]D =-100° (chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[NH:21]1[C:30]2[CH2:29][CH2:28][CH2:27][C:26](=O)[C:25]=2[CH:24]=[CH:23][C:22]1=[O:32].C1C=CC=CC=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH:26]1[CH2:27][CH2:28][CH2:29][C:30]3[NH:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]1=3)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: NCCCNc1c2c(nc3cc(Cl)ccc13)CCCC2
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=c1ccc2c([nH]1)CCCC2NCCCNc1c2c(nc3cc(Cl)ccc13)CCCC2
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a flask was added N1-(6-chloro-1,2,3,4-tetrahydro-acridin-9-yl)-propane-1,3-diamine (116 mg, 0.40 mmoL), 7,8-dihydro-1H,6H-quinoline-2,5-dione (85 mg, 0.52 mmoL), benzene (4 mL) and one drop of acetic acid, and the resulting mixture as heated to reflux under nitrogen. The water generated from the reaction was removed by Dean-Stark apparatus. After refluxing for 24 h, the benzene was distilled off and methanol (2 mL) was added, followed by sodium borohydride (30 mg, 0.80 mmoL). After stiring at room temperature for 24 h, the reaction was stopped and concentrated. The mixture was treated with saturated sodium bicarbonate and methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride twice. The combined methylene chloride extract was combined, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by preparative TLC using 15% MeOH/1% ammonium hydroxide in methylene chloride to give the desired product (102 mg, 0.23 mmoL, 58%).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C@H:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(O)C.C(Cl)Cl>[CH2:1]([N:8]([CH2:12][C@@H:13]1[CH2:14][CH2:15][C:16](=[O:18])[NH:17]1)[CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CC[C@@H](CN(CCO)Cc2ccccc2)N1
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)(=O)OCCN(Cc1ccccc1)C[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
To a solution of (S)-(+)-5-((benzyl(2-hydroxyethyl)amino)methyl)pyrrolidin-2-one (3.5 g, 14.1 mmol) in ethanol-free CHCl3 (55 ml), TEA (2.85 g, 28.22 mmol) and methanesulfonyl chloride (3.23 g, 28.22 mmol, in 10 ml of CHCl3) were added at 0° C. The mixture was allowed to warm to room temperature and left stirring for 20 hours, then it was diluted with DCM (60 ml) and washed with a saturated solution of NaHCO3 (3×50 ml). After drying (Na2SO4) and removal of the solvent, the crude was purified by flash chromatography (DCM/abs EtOH/Petroleum Ether/33% NH4OH/Et2O 300/180/900/9.9/360 respectively) to afford the title compound (2.9 g, 63% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=O)([O-:3])=[O:2].[CH3:14][C:15]1[O:16][C:17](=[O:25])[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.CN1CCCC1=O>O>[CH3:14][C:15]1[N:20]([C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]([OH:25])=[O:16])[C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])=[N:8][N:9]=1
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1nc2ccccc2c(=O)o1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nnc(-c2ccccc2[N+](=O)[O-])n1-c1ccccc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 1.8 g of 2-nitrobenzoic hydrazide, 1.6 g of 2-methylbenzo[d][1,3]oxazin-4-one and 5 ml of N-methylpyrrolidone was heated to 80° C. with stirring for 2 hours. After cooling, the mixture was admixed with water to slight cloudiness and stirred for a further 1 hour, during which time a solid precipitated out which was filtered off with suction, recrystallized from ethanol and dried under reduced pressure.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:19][O:18]1>CS(C)=O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:19][CH2:4][O:18]1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc(C2(Cn3cncn3)CCO2)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
101 mg (4.2 mmole) of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to 10 ml of dimethyl sulfoxide, and the resulting mixture was stirred at 80° C. for 30 minutes. At the end of this time, the mixture was cooled, 928 mg (4.2 mmole) of trimethylsulfoxonium iodide were added thereto and the reaction temperature was allowed to rise to room temperature. The mixture was then stirred for 30 minutes, after which 501 mg (2.11 mmole) of 2-(2,4-difluorophenyl)-2-[(1H-1,2,4-triazol-1-yl)methyl]-oxirane was added, and the mixture was stirred at 50° C. for a further 16 hours. At the end of this time, the reaction mixture was cooled, poured into 50 ml of ice-water and extracted with 100 ml of ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 2:3 by volume mixture of hexane and ethyl acetate, to afford 238 mg (yield 45%.) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.Cl.[CH3:15][CH:16]1[O:21][CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.[CH2:23]=O.O>C(O)C.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:23][N:18]1[CH2:19][CH:20]([CH3:22])[O:21][CH:16]([CH3:15])[CH2:17]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CC1CNCC(C)O1
Reactant: C=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCC(CN1CC(C)OC(C)C1)C2=O

Procedure:
6-Methoxy-1,2,3,4-tetrahydronaphthalen-1-one (17.6 g, 0.1 mol), 2,6-dimethylmorpholine hydrochloride (15.1 g, 0.1 mol), and paraformaldehyde (6.0 g, 0.2 mol) were refluxed together in ethanol (50 ml) with concentrated hydrochloric acid (0.25 ml) as a catalyst for 3 hours. The reaction was cooled and poured into water containing concentrated hydrochloric acid (5 ml) and extracted with ether (200 ml). The aqueous solution was cooled in ice and neutralised with sodium hydroxide solution (10%) then extracted with ether (2×200 ml) dried over magnesium sulphate and evaporated under reduced pressure to give a residue which was recrystallised from petrol (60°-80°) to give 6-methoxy-2-(2,6-dimethylmorpholinomethyl)-1,2,3,4-tetrahydronaphthalen-1-one a white crystalline solid (10 g, 33% yield) melting at 110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:13][C:7]=3[C:6]=2[CH:21]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([Cl:29])=[O:28])=[CH:25][CH:24]=1>>[ClH:29].[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[CH:12]1[CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=4)=[CH:21][C:6]=3[C:7]=2[CH2:13]1)[CH2:16][CH3:17]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCN(CCC)C1CCc2oc3ccc(N)cc3c2C1
Product: CCCN(CCC)C1CCc2oc3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Product: Cl
Yield: 87.6 %

Procedure:
Beginning with 0.072 gm (0.20 mMol) 8-amino-1,2,3,4-tetrahydro-2-dipropylaminodibenzofuran and 0.032 gm (0.20 mMol) 4-fluorobenzoyl chloride, 0.078 gm (87%) of the title compound were recovered as an off-white solid by the procedure described in Example 17.