Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])(O)=O.[Na+].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:17])=[C:12]([CH:16]=1)[C:13]([NH2:15])=[O:14].[C:18]1([CH:28]=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>CN(C)C(=O)C>[CH3:6][O:7][C:8]1[CH:16]=[C:12]2[C:11](=[CH:10][CH:9]=1)[N:17]=[C:28]([C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=1)[NH:15][C:13]2=[O:14]
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: O=Cc1cccc2ccccc12
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2nc(-c3cccc4ccccc34)[nH]c(=O)c2c1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
Sodium hydrogen sulfite (0.8 g, 7.5 mmol) was added to a solution of 5-methoxy-2-aminobenzamide (9) (1.2 g, 7.3 mmol) and 1-naphthaldehyde (14) (1.1 g, 7.3 mmol) in N,N-dimethylacetamide (DMAC) (20 mL). The mixture was heated with stirring at 150° C. for 3 h and poured into ice water (200 mL). The precipitate was collected, washed with water, and dried in vacuo. After purification by column chromatography (silica gel; chloroform) and then recrystallization from EtOH, 6-methoxy-2-(naphthalen-1-yl)-4-quinazolinone (17) was obtained (1.5 g, 70%) as pale yellow needles. The method used to prepare 17 was used with the indicated substituted benzaldehyde and benzamide to afford 18-31. Compounds 17-31 were further analyzed by the method as described in “General materials and method”. The properties of Compounds 17-31 were respectively described as below.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(=[O:4])=[O:3].[O:23]1[C:27](=O)[CH2:26][NH:25]C1=O.Cl.N>C(Cl)Cl>[CH3:1][S:2]([CH2:5][CH2:6][N:7]1[C:8]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:25][CH2:26][C:27]1=[O:23])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)CCNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C1CNC(=O)O1
Agent: Cl
Agent: N
Solvent: ClCCl
Product: CS(=O)(=O)CCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
To a solution of 0.5 g of 2-(β-methylsulfonylethyl) amino-5-chlorobenzophenone in 20 ml of dry methylene chloride is added 0.5 g of oxazolidine-2,5-dione. To the mixture is added 20 ml of ethereal hydrogen chloride under cooling. The mixture is stirred at room temperature. After completion of the reaction, the mixture is poured into ice water, basified with aqueous ammonia and extracted with methylene chloride. The extracts are combined and dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The residue is added with isopropyl alcohol to form crystals. Recrystallization from acetone gives 1-(β-methylsulfonylethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one as colorless leaflets, m.p. 218° - 219° C.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[Br:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[Br:19][C:20]1[CH:24]=[CH:23][N:22]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Brc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(Br)n2)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 25.2 %

Procedure:
A mixture of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (0.837 g, 3.00 mmol), 3-bromo-1H-pyrazole (0.441 g, 3.02 mmol), and cesium carbonate (2.94 g, 9.02 mmol) in DMF (10 mL) stirred for 5 h at 100° C. The reaction mixture was cooled to room temperature and poured ethyl acetate (50 mL). The mixture was washed with water (3×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue purified via column chromatography on silica gel (eluting with 10% dichloromethane/methanol to afford tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.25 g, 25%) as a white solid. MS (ESI, pos. ion) m/z 330, 332 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][S:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[S:9][CH2:8][C:7]1[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CSc2ncccn2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(CSc2ncccn2)cc1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To 2-[(4-nitrobenzyl)sulfanyl]pyrimidine (8.0 g) was added 85% ethanol solution (160 ml), and then, calcium chloride (1.8 g) and reduced iron (9.0 g), and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[(2-pyrimidinylsulfanyl)methyl]aniline (2.5 g).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([OH:18])=O)[CH2:2][CH3:3].[Cl-].[NH4+].C([N:23](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>O.CN(C=O)C>[CH2:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([NH2:23])=[O:18])[CH2:2][CH3:3]
Reactant: CCN(CC)CC
Reactant: CCCNc1cc(-c2ccncc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1cc(-c2ccncc2)sc1C(N)=O
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
A mixture of 3-(propylamino)-5-(pyridin-4-yl)thiophene-2-carboxylic acid (0.477 g, 1.82 mmol), ammonium chloride (0.974 g, 18.2 mmol), triethylamine (2.56 mL, 18.2 mmol) and DMF (11 mL) was stirred for 5 min. Then, 1-hydroxybenzotriazole (0.743 g, 5.50 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g, 5.50 mmol) were added and stirring was continued for 3 days. The mixture was then poured into sat. aqueous sodium hydrogen carbonate (100 mL) and water (60 mL). Extraction with ethyl acetate-tetrahydrofuran (3:1, 2×100 mL), washing with sat. aqueous sodium hydrogen carbonate and brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a yellow solid. This solid was triturated with dichloromethane, and the precipitate was collected by filtration to afford the title compound (0.374 g, 79%) as a yellow solid:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[OH-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=1.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[C:25]#[N:26])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#CCc1ccc(F)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: N#CC(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 5 h

Procedure:
To a stirred and warmed (30° C) mixture of 105 parts of 1-chloro-4-nitro-2-(trifluoromethyl)benzene, 10 parts of N,N,N-triethylbenzenemethanaminium chloride, 900 parts of sodium hydroxide solution 50% and 135 parts of tetrahydrofuran is added dropwise a mixture of 67.5 parts of 4-fluorobenzeneacetonitrile and 450 parts of tetrahydrofuran (exothermic reaction: temperature rises to 50° C). Upon completion, stirring is continued for 5 hours at 60° C. After cooling, the reaction mixture is poured onto crushed ice and the whole is acidified with a concentrated hydrochloric acid solution, while cooling. The product is extracted with methylbenzene. The extract is washed with water, dried filtered and evaporated. The residue is suspended in a mixture of 2,2'-oxybispropane and petroleumether. The product is filtered off, yielding α-(4-fluorophenyl)-4-nitro-2-(trifluoromethyl)-benzeneacetonitrile; mp. 68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of the corresponding acrylic acid derivative of Example 5 (1.0 g.) and palladium-on-charcoal (0.25 g. of 10%) in ethanol (50 ml.) was shaken in an atmosphere of hydrogen until uptake of hydrogen had ceased. Removal of the catalyst by filtration, evaporation of the filtrate and recrystallisation of the residue gave 0.25 g. of the title compound.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:36]([CH3:38])[CH3:37])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[Cl:35])[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C>O1CCCC1>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[Cl:35])[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:36]([CH3:37])[CH3:38])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (207) (125 mg, 0.22 mmol) in tetrahydrofuran (5 mL) were added triphenyl phosphine (117 mg, 0.45 mmol) and diisopropyl azodicarboxylate (0.09 mL, 0.45 mmol) at room temperature, a yellow clear solution was formed, after 5 min it turned into a light yellow hazy solution. The solution was stirred for 2 h at room temperature. Silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.3). The mixture was concentrated under reduced pressure to get a crude product, which was purified by a CombiFlash column (eluted at 2-5% methanol in dichloromethane) to get 9-benzyloxy-6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (208) (40 mg, 33.07%) as a white sticky solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:26])[NH:11][C:12]1([C:15]2[N:16]=[N:17][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)[CH3:9])(C)(C)C.O1CCOCC1.[ClH:34]>C(Cl)Cl>[ClH:34].[ClH:34].[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1([C:15]2[N:16]=[N:17][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)=[O:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ccc(-c3cn[nH]c3)nn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)C(=O)NC1(c2ccc(-c3cn[nH]c3)nn2)CC1
Reaction time: 1.5 h

Procedure:
((S)-1-{1-[6-(1H-pyrazol-4-yl)-pyridazin-3-yl]-cyclopropylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester was dissolved in CH2Cl2 (1.0 mL) and 4M HCl dioxane (2 mL, 8 mmol) was added. After 1.5 h, the solvents were removed at 50° C. under a stream of N2. This material was dried under vacuum to yield 73 mg of the title compound, m/z 273.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)sc1C(C)C
Yield: 90.4 %

Procedure:
The aforementioned ester (46 mg, 0.121 mmol) was hydrolyzed with sodium hydroxide in a conventional manner, and extraction and recrystallization were performed to obtain the title compound (40, 40 mg, 91%) as colorless prisms.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].CCN(CC)CC.[CH3:14][O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24](OS(C(F)(F)F)(=O)=O)=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17]>CN(C=O)C.[Cu]I.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>[CH3:14][O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2cc(C#C[Si](C)(C)C)ccc12
Reaction time: 15 h

Procedure:
A solution of 15.6 ml (113 mMol) ethynyl-trimethylsilane (Fluka; Buchs/Switzerland) and 15.7 ml (113 mMol) Et3N in 250 ml degassed DMF is added to 34 g (102 mMol) 6-trifluoromethanesulfonyloxy-naphthalene-1-carboxylic acid methyl ester, 1.0 g (5.2 mMol) CuI and 5.0 g (7.1 mMol) Pd(PPh3)2Cl2 in 250 ml of degassed DMF. After 15 h at rt, the mixture is concentrated partially in vacuo at 40° C. and the residue re-dissolved in sat. NaHCO3 solution and EtOAc. The aq. phase is separated off and extracted twice with EtOAc. The organic layer is washed twice with sat. NaHCO3 solution, water/sat. NaHCO3 solution 1:1 and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/EtOAc 199:1) gives the title compound as an oil: MS: [M+1]+=283; TLC(hexane/EtOAc 19:1): Rf=0.22.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:15])[N:6]=1)[NH2:4].C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[C:28]([C:30]([CH3:32])=O)[CH:27]=[CH:26][CH:25]=1>C(O)C>[CH3:15][C:7]1[N:6]=[C:5]([NH:3][N:4]=[C:30]([C:28]2[CH:29]=[C:24]([CH3:23])[CH:25]=[CH:26][CH:27]=2)[CH3:32])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: CC(=O)c1cccc(C)c1
Reactant: Cc1nc(NN)c2ccccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=NNc1nc(C)nc2ccccc12)c1cccc(C)c1

Procedure:
The title compound was prepared from 4-hydrazino-2-methylquinazoline dihydrochloride (250 mg, 1.01 mmol), triethylamine (0.35 mL, 2.02 mmol) and 3-methylacetophenone (0.35 mL, 2.63 mmol) in ethanol (5 mL) by a procedure similar to Example 4, step 4 yielding 11 mg (4%) of a yellow solid. HPLC Purity: 95%.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:22][C:23]1[CH:50]=[CH:49][C:48]([CH2:51][CH2:52]Br)=[CH:47][C:24]=1[C:25]([NH:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:22][C:23]1[CH:50]=[CH:49][C:48]([CH2:51][CH2:52][N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[CH:47][C:24]=1[C:25]([NH:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(CCBr)ccc1OCc1ccccc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCN(CCc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-Ethylpiperazine (0.065 mL) and potassium carbonate (0.042 g) were added to an acetone (1.2 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethyl)benzamido)-4-phenylbenzoate (0.060 g), followed by stirring at room temperature for 6 hours. 1-Ethylpiperazine (0.065 mL) was added to the reaction mixture, followed by stirring at room temperature for 9 hours. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.062 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(4-ethylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH2:6][CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][C:9]=12.S(=O)(=O)(O)O.[OH-].[NH4+]>>[N+:1]([C:15]1[CH:14]=[CH:13][C:12]2[N:8]3[CH2:7][CH2:6][N:5]=[C:9]3[S:10][C:11]=2[CH:16]=1)([O-:4])=[O:2]
Reactant: c1ccc2c(c1)SC1=NCCN12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)SC1=NCCN12
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 Parts of 2,3-dihydroimidazo[2,1-b]benzothiazole mononitrate are added portionwise to 55.2 parts of concentrated sulfuric acid at 0° C. Upon completion, stirring is continued for 30 minutes at room temperature. The reaction mixture is poured onto crushed ice and the whole is alkalized with ammonium hydroxide at a temperature below 20° C. The product is extracted with a mixture of trichloromethane and methanol (90:10 by volume). The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 160 parts of 1-butanol. The product is filtered off and dried, yielding 8 parts (80%) of 2,3-dihydro-7-nitroimidazol[2,1-b]benzothiazole; mp. 238.9° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Mg].[CH:15]1[C:27]2[C:26](=[O:28])[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[N:18]=[CH:17][CH:16]=1>CCOCC.C1COCC1>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]1([OH:28])[C:27]2[C:19](=[N:18][CH:17]=[CH:16][CH:15]=2)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]12
Reactant: Ic1ccccc1-c1ccccc1
Reactant: O=C1c2cccnc2-c2ncccc21
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2-c2ccccc2)c2cccnc2-c2ncccc21
Temperature: 25 °C
Yield: 93.6 %

Procedure:
Referring to scheme 6, under reflux, a flask containing with arylmagnesium iodide that was firstly prepared in advance from 2-iodo-biphenyl (11.2 g, 40 mmol) and magnesium (0.97 g, 40 mmol) in ether was added into 4,5-diazafluoren-9-one (3.64 g, 20 mmol) in THF. The mixture was refluxed for another 12 hours, then quenched with water after cooling to ambient temperature and extracted with CHCl3. The combined organic extracts were dried (MgSO4) and concentrated by rotary evaporation. The resulting crude solid was washed with n-hexane to give 5-biphenyl-2-yl-5H-cyclopenta[2,1-b;3,4-b′]dipyridin-5-ol (6.3 g, 93% yield) as a light brown solid, which was used for cyclization without further purification. 5-biphenyl-2-yl-5H-cyclopenta[2,1-b;3,4-b′]dipyridin-5-ol was heated to dissolve in 500 ml acetic acid. The solution was added 6 ml sulfuric acid as catalyst and refluxed for 24 hours. The reaction was quenched with cold water after cooling to room temperature and neutralized with NaOH(aq) to basic, then extracted with CHCl3 and dried with MgSO4. The combined organic solution was concentrated by rotary evaporation and washed with n-hexane to give 4,5-diaza-9,9′-spirobifluorene (4.3 g, 75%) as a light brown solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:20]([O:22]C)=[O:21])[CH:13]=[CH:12]1.CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:31]>C1COCC1>[OH:31][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:3][C:2](=[O:1])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:20]([OH:22])=[O:21])[CH:13]=[CH:12]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COC(=O)c1cccc2ccn(Cc3nc4ccccc4o3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cn1ccc2cccc(C(=O)O)c21)Nc1ccccc1O
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To methyl 1-(1,3-benzoxazol-2-ylmethyl)-1H-indole-7-carboxylate (0.22 g), methanol (2.0 mL), and THF (2.0 mL) was added a 1 M aqueous sodium hydroxide solution (1.0 mL), followed by stirring at 70° C. for 14 hours. The reaction mixture was ice-cooled, a 10% aqueous citric acid solution (5.0 mL) was added thereto, and the precipitated solid was collected by filtration, and washed with water and diethyl ether/hexane (1/1) to obtain 1-{2-[(2-hydroxyphenyl)amino]-2-oxo ethyl}-1H-indole-7-carboxylic acid (0.18 g).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=O)[CH2:8][S:9][C:4]=2[C:3]=1[F:13].[Li]>C1COCC1>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][CH2:7][CH2:8][S:9][C:4]=2[C:3]=1[F:13]
Reactant: O=C1CSc2c(ccc(F)c2F)N1
Agent: [Li]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1F)SCCN2
Yield: 104 %

Procedure:
A solution of 7,8-difluoro-4H-benzo[1,4]thiazin-3-one (Example L-3, 2.27 g, 11.3 mmol) in THF (100 mL) was reacted with lithium aluminumhydride (1.07 g, 28.2 mmol) under an N2 atmosphere and heated to reflux overnight. The mixture was cooled and quenched with 1.0N HCl and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated to provide 2.2 g of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[CH3:13].[CH3:14][NH2:15].CO>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:15][CH3:14])=[C:3]1[CH3:13]
Reactant: CN
Reactant: Cc1c(C=O)c2ccccc2n1C
Solvent: CO
Product: CNCc1c(C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1,2-dimethylindole-3-carboxaldehyde (11.50 g, 66.4 mmole) was added a solution of 2 M methylamine in methanol (100 mL, 200 mmole). The reaction was stirred for 4 h at RT then was concentrated to dryness to afford the crude title compound: 1H NMR (400 Hz, CDCl3) δ 8.55 (d, J=1.4 Hz, 1 H), 8.16 (d, J=7.5 Hz, 1 H), 7.42 (d, J=7.8 Hz, 1 H), 7.15 (t, 1 H), 7.07 (t, 1 H), 3.68 (s, 3 H), 3.41 (s, 3 H), 2.55 (s, 3 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][C:10]=1CO)O.[Cl:19]([O-:23])(=[O:22])(=[O:21])=[O:20].[Na+]>O=P(Cl)(Cl)Cl>[Cl:19]([O-:23])(=[O:22])(=[O:21])=[O:20].[CH2:7]([C:15]1[N+:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:7]=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=12)[CH2:2][CH2:3][CH3:4]
Reactant: OCc1cccc(CO)c1C(O)c1ccccn1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1c2ccccc2cc2cccc[n+]12
Reaction time: 4 h

Procedure:
A mixture of 0.6 g (2.5 mmol) of 1-(2-pyridyl)-1-[2,6-di(hydroxymethyl)-phenyl]methanol and 10 ml of POCl3 was refluxed with stirring for 4 hours. The mixture was cooled, poured onto ice, stirred and treated with a 20% sodium perchlorate solution. The resulting mixture was filtered, the resulting solid was washed with water, and dried to afford 0.58 g of 10-chloromethylrbenzo[b]quinolizinium perchlorate (Formula II: R1 =R2 =H; R7 =10--CH2Cl; X- =ClO4-).