Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](O)=O.C1(O)C2C(=CC=CC=2)C=CC=1.[H][H]>[O-2].[Cr+3].[O-2].[O-2].[Cr+3].CO>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: [H][H]
Agent: [Cr+3]
Agent: Oc1cccc2ccccc12
Agent: [O-2]
Solvent: CO
Product: Cc1ccc2ccccc2c1O
Temperature: 400 °C
Reaction time: 3 h

Procedure:
Inoue et al (Chem. Pharm. Bull., 24 (9), 2199-2203, 1976) disclose ferric oxide and chromium oxide to be new alkylating catalyst of phenols. The activity and selectivity of these oxide catalysts were examined by liquid-phase reaction. 1-Naphthol, methanol and ferric oxide were charged in an autoclave equipped with a magnetic stirrer. After air in the autoclave was replaced by hydrogen, the temperature was raised to 400° C. over a period of 45 to 50 minutes. At such temperature, the pressure reached 100 atm. After 3 hours. 2-methyl-1-naphthol was produced in a conversion of 57.6 mol %. The remainder was starting material.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:11]=[C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][C:14]([C:22]2[N:27]=[C:26]([CH2:28]S([O-])(=O)=O)[CH:25]=[CH:24][CH:23]=2)=[N:13]1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:1]([S:8][CH2:28][C:26]1[N:27]=[C:22]([C:14]2[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:12](=[O:11])[N:13]=2)[CH:23]=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2cccc(CSCc3ccccc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.9 %

Procedure:
Benzyl mercaptan (0.41 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.18 g, 16%) as pale yellow crystals.
Reaction SMILES: OO.[Cl:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[OH2:26].C(O)(=[O:29])C>>[Cl:3][CH2:4][CH2:5][CH2:6][S:7]([C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:29])=[O:26]
Reactant: O
Reactant: CC(=O)O
Reactant: Cc1c(-c2ccccc2)oc2c(SCCCCl)cccc2c1=O
Agent: OO
Product: Cc1c(-c2ccccc2)oc2c(S(=O)(=O)CCCCl)cccc2c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
7 ml of 30% hydrogen peroxide was added at 20°-25° C. to a solution of 3.65 g of Intermediate XXXIV in 35 ml of acetic acid. After stirring for 4 hours at 60° C., the reaction mixture was cooled to 20°-25° C. 30 ml of water was added. A precipitate formed, and was collected by suction filtration, washed with water and dried, yielding 3.4 g of the title compound. After crystallization from acetone, it showed a melting point of 160°-163° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[NH:4][CH2:5][C:6]#[CH:7].N1C=CC=CC=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[N:4]([C:24]([C:20]1[O:19][CH:23]=[CH:22][CH:21]=1)=[O:25])[CH2:5][C:6]#[CH:7]
Reactant: C#CCNc1c(C)cccc1C
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C#CCN(C(=O)c1ccco1)c1c(C)cccc1C
Yield: 88.8 %

Procedure:
15.9 g (0.1 mol) of 2,6-dimethyl-N-propargylaniline and 8 g (0.1 mol) of pyridine were heated to the boil in 100 ml of tetrahydrofuran, and 13 g (0.1 mol) of furan-2-carboxylic acid chloride were added carefully. The reaction mixture was stirred under reflux for 15 minutes and then concentrated by distilling off the solvent in vacuo. The residue was taken up in methylene chloride and the methylene chloride mixture was washed with water. The organic phase was separated off, dried over sodium sulphate and concentrated. After triturating with petroleum ether, the residue crystallized. 22.5 g (89% of theory) of 2,6-dimethyl-N-(2-furoyl)-N-propargyl-aniline of melting point 109°-112° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1)C1CC1

Procedure:
Example 120 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.64–7.55 (s, 1H), 7.55–7.47 (s, 1H), 7.47–7.37 (br, 1H), 7.36–7.17 (m, 6H), 7.05–6.95 (m, 4H), 6.95–6.87 (br, 1H), 4.81 (s, 1H), 3.47–3.35 (m, 2H), 3.07–2.94 (m, 2H), 2.58–2.41 (m, 3H), 2.15–1.99 (m, 2H), 1.90–1.79 (m, 2H), 1.79–1.60 (m, 4H), 1.59–1.44 (m, 1H), 1.13–0.99 (m, 2H), 0.90–0.75 (m, 2H); ESMS m/e: 532.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32]C)=[O:31])=[CH:20][CH:19]=2)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:42])C=1>>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([OH:32])=[O:31])=[CH:20][CH:19]=2)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10]([CH3:11])=[O:42])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCCc1nc(S(C)=O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 259.4 %

Procedure:
The operation is carried out as in Example 15 starting with 1.55 g of the product obtained in Example 21 using 213 mg of metachloroperbenzoic acid. 1.8 g of crude product is obtained which is chromatographed on silica (eluant: methylene chloride--acetone (7-3)). 1.5 g of desired product is obtained.
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.[CH2:26](O)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:26]([O: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[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 18.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.697 g, 2.00 mmol), ethanol (0.140 mL, 2.40 mmol) and triphenylphosphine (0.787 g, 3.00 mmol) in toluene (8 mL) was added with a 40% solution of diethyl azodicarboxylate in toluene (1.31 g, 3.00 mmol), and the mixture was stirred at 110° C. for 5 hours in a sealed tube. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.138 g, 18%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]5[CH:28]=[CH:27][C:26](OC)=[CH:25][CH:24]=5)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[Cl:32]C1C=CC=CC=1C[Zn+].O1C2C=CC(C3(C(NC4C=CC=C(Br)N=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:32])[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Clc1ccccc1C[Zn+]
Reactant: COc1ccc(Cc2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)n2)cc1
Agent: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: O=C(Nc1cccc(Cc2ccccc2Cl)n1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-chlorobenzyl)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(4-methoxybenzyl)pyridin-2-yl)cyclopropanecarboxamide by reacting (2-chlorobenzyl)zinc(II) chloride with 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1B(O)O.C(O)(=[O:16])C.OO>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[OH:16]
Reactant: CC(=O)O
Reactant: COc1ccc(F)c(B(O)O)c1F
Agent: OO
Solvent: C1CCOC1
Product: COc1ccc(F)c(O)c1F
Reaction time: 120 h
Yield: 88 %

Procedure:
To a solution of 2,6-difluoro-3-methoxy-phenylboronic acid (10.0 g, 0.053 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 120 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2,6-difluoro-3-methoxy-phenol (7.50 g, 88%) as a pale brown solid.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].[CH3:10][C@H:11]1[CH:15]=[CH:14][C@H:13]([CH3:16])[N:12]1[CH2:17][C:18](OC)=[O:19].Cl>C(O)C.C(OCC)(=O)C>[NH2:4][C:3]([NH2:5])=[N:2][C:18](=[O:19])[CH2:17][N:12]1[C@@H:13]([CH3:16])[CH:14]=[CH:15][C@@H:11]1[CH3:10]
Reactant: COC(=O)CN1[C@@H](C)C=C[C@@H]1C
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H]1C=C[C@H](C)N1CC(=O)N=C(N)N
Reaction time: 18 h

Procedure:
A solution of guanidine hydrochloride (2.3 g., 0.024 mol) and sodium ethoxide (from 0.55 g, 0.024 mol of sodium) in absolute ethanol (24 cm3) was stirred at room temperature for 1 h. The precipitated sodium chloride was removed by filtration and washed with ethanol (4 cm3). Methyl (trans-2,5-dihydro-2,5-dimethyl-1H-pyrrol-1-yl)acetate (3.4 g., 0.02 mol) was added to the combined filtrate and washings obtained above and the solution stoppered and stirred for 18 h. The reaction mixture was then evaporated and the residue crystallised from ethanol to give the product (1.25 g.). The base was suspended in ethanol and acidified with ethanolic hydrogen chloride, the clear solution thus obtained was diluted with ethyl acetate and concentrated by evaporation to precipitate the title compound as the dihydrochloride (1.6 g.) m.p. 210°-11° C.(d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+].CCOC(C)=O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1[nH]c2ncc(Br)cc2c1C
Yield: 71.1 %

Procedure:
To a suspension of 5-bromo-2,3-dimethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (B-6-3) (0.9 g, 2.5 mmol) in THF (30 mL) and MeOH (30 mL) was added aq. NaOH (20%, 19 mL) at room temperature. The mixture was heated to reflux overnight. TLC (Petroleum ether: EtOAc=5:1) showed the reaction was complete. After the solvent was removed under reduced pressure, water (20 mL) and CH2Cl2 (20 mL) were added into the mixture. The organic layer was separated, dried over anhydrous Na2SO4. The mixture was concentrated to give crude mixture which was purified via prep. HPLC to afford 5-bromo-2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (B-6-4) (0.4 g, 72.4%) as a white solid.
Reaction SMILES: C(ON=O)(C)(C)C.[O:8]1[CH2:12][CH2:11][C:10]([C:13]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=2N)=[N:9]1.[CH3:21][S:22]SC>[Cu]>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:14]([S:22][CH3:21])[C:13]=1[C:10]1[CH2:11][CH2:12][O:8][N:9]=1
Reactant: Cc1cccc(N)c1C1=NOCC1
Reactant: CSSC
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1cccc(C)c1C1=NOCC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
19.5 g (170 mmol) of tert-butylnitrite and 20 g of copper powder are initially charged in 30 ml of dimethyl disulfide, and a solution of 20 g (114 mmol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline in 100 ml of dimethyl disulfide is added dropwise at from 50 to 55° C. The mixture is subsequently stirred at 60° C. for 1.5 hours. For work-up, the solid is filtered off with suction, and the filtrate is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO3 solution and dried over sodium sulfate, the drying agent is filtered off and the filtrate is concentrated. Excess dimethyl disulfide is removed under oil pump vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(Br)c2)c1-c1ccccc1

Procedure:
m-Bromoaniline (5 mmol, 0.9 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate and brine. The organic layer was dried over MgSO4, then the solids were separated and the solvents evaporated under vacuum. The crude product was recrystallized from ethanol to yield the named product (m.p. 117.5° C.-119.2° C.).
Reaction SMILES: CC(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[C:20]3[CH:21]=[CH:22][C:23]4[NH:27][C:26](=[O:28])[CH2:25][C:24]=4[C:19]=3[O:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+].C(Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CN(C=O)C>[C:43]1([CH2:6][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]3[C:20]4[CH:21]=[CH:22][C:23]5[NH:27][C:26](=[O:28])[CH2:25][C:24]=5[C:19]=4[O:18][N:17]=3)[CH2:10][CH2:9]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2noc3c4c(ccc23)NC(=O)C4)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1Cc2c(ccc3c(CCC4CCN(Cc5ccccc5)CC4)noc23)N1
Yield: 44 %

Procedure:
The procedure described in Example 12f was followed with the piperidine obtained in step e (0.042 g, 0.109 mmol) and TFA (1.5 mL) in CH2Cl2 (6 mL), Na2CO3 (0.058 g, 0.545 mmol) and benzyl bromide (0.016 mL, 0,131 mmol) in DMF (6 mL). After purification by chromatography (1-10% MeOH-CH2Cl2), the title compound (0.018 g, 44%) was obtained as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-:23].[Na+].OO>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1)(=[O:23])[NH2:2]
Reactant: N#Cc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 25 °C

Procedure:
One gram of 2-(p-cyanophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, 3.50 ml of 1 N aqueous sodium hydroxide and 10 ml of ethanol are mixed and stirred at room temperature until the solid has dissolved. The solution is then treated with 1.4 ml of 30% hydrogen peroxide, giving an immediate precipitate. After stirring for 2 hours at room temperature, the mixture is filtered, and the solid is crystallized from dimethylformamide, to yield the 2-(p-carbamoylphenyl)-pyrazolo [4,3-c]quinolin-3(5H)-one, showing peaks in the IR-spectrum at 885, 853, 830, 785, 775, 752 and 732 cm-1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].Cl.[CH3:8][C:9](=[CH2:27])[CH2:10][NH:11][CH2:12][C@H:13]1[O:23][C@H:17]([O:18]CCCC)[C@H:16]([OH:24])[C@@H:15]([OH:25])[C@@H:14]1[OH:26].[OH2:28]>C(#N)C.C(=O)([O-])[O-].[Ag+2]>[CH3:8][C:9](=[CH2:27])[CH2:10][N:11]([CH:12]([OH:28])[C@H:13]1[O:23][C@:17]([CH2:12][CH2:13][CH2:14][CH3:15])([OH:18])[C@H:16]([OH:24])[C@@H:15]([OH:25])[C@@H:14]1[OH:26])[C:5](=[O:6])[NH:4][CH2:3][CH2:2][Cl:1]
Reactant: C=C(C)CNC[C@H]1O[C@H](OCCCC)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C=NCCCl
Reactant: O
Agent: [Ag+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: C=C(C)CN(C(=O)NCCCl)C(O)[C@H]1O[C@@](O)(CCCC)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 65.2 %

Procedure:
2-Chloroethyl isocyanate (1.35 g) and silver carbonate (2.14 g) were added to a solution of n-butyl 6-(2-methyl-2-propenylamino)-6-deoxy-α-D-glucopyranoside hydrochloride (3.47 g, 10.6 mmol) in a mixture of water (25 ml) and acetonitrile (40 ml) at 0° to 5° C., and the mixture was heated under reflux on a water bath for 1 hour. Then, the reaction mixture was filtered while hot to remove the insoluble silver salt. The filtrate was vacuum-concentrated and crystallized from ethanol and water, giving 2.73 g of 3-(2-methyl-2-propenyl)-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea; yield 65.2%, m.p. 110°-112° C., [α]D20 +59.2° (C 1.0, methanol).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][C:9]1([CH2:13][CH2:14][CH3:15])[CH2:12][O:11][CH2:10]1.C(N(CC)CC)C.O>ClCCl>[CH:8]([C:9]1([CH2:13][CH2:14][CH3:15])[CH2:12][O:11][CH2:10]1)=[O:7]
Reactant: CCCC1(CO)COC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC1(C=O)COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.7 %

Procedure:
A solution on dimethyl sulphoxide (12 ml) in dry dichloromethane (4.0 ml.) was added to a solution of oxalyl chloride (7.4 ml) in dichloromethane (25 ml) stirred at -70° under nitrogen. After the addition was complete the resulting mixture was stirred for a further 5 minutes at -70° before a solution of 3-hydroxymethyl-3-n-propyloxetane (10.0 g) in dichloromethane (25 ml) was added, dropwise, over 10 minutes. The resulting mixture was allowed to stir for a further 30 minutes when neat triethylamine (54 ml) was added over approximately 30 minutes. The reaction mixture was allowed to warm to room temperature over 3 hours when it was poured into water. The organic phase was separated and the aqueous layer further extracted with fresh dichloromethane. The combined organic extracts were washed with dilute hydrochloric acid, saturated sodium bicarbonate and brine. The resulting organic phase was dried over anhydrous magnesium sulphate and evaporated in vacuo to give 3-formyl-3-n-propyloxetane (10.5 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:16][CH2:15][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CCOCC1
Reactant: Fc1cccc(Br)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Brc1cccc(NCC2CCOCC2)n1
Temperature: 110 °C

Procedure:
To a solution of 2-bromo-6-fluoropyridine (3 g, 17.05 mmol) in DMSO (8 mL) was added (tetrahydro-2H-pyran-4-yl)methanamine (3.10 g, 20.46 mmol) and triethylamine (5.68 mL, 40.9 mmol). The mixture was heated at 110° C. for 18 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution (1×), water (1×), brine (1×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel providing 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 4.24 g. LCMS (m/z): 270.9/273.0 [M+H]+; Retention time=0.78 min.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:13]([O:20][N:21]1[C:30](=[O:31])[C:29]2[CH:32]=[C:33]([C:36]#[N:37])[C:34](Cl)=[C:27]3[C:28]=2[C:23](=[CH:24][CH:25]=[CH:26]3)[C:22]1=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:20][N:21]1[C:30](=[O:31])[C:29]2[CH:32]=[C:33]([C:36]#[N:37])[C:34]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:27]3[C:28]=2[C:23](=[CH:24][CH:25]=[CH:26]3)[C:22]1=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CCNC1
Reactant: N#Cc1cc2c3c(cccc3c1Cl)C(=O)N(OCc1ccccc1)C2=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(OCc1ccccc1)C2=O
Temperature: 0 °C
Yield: 68.6 %

Procedure:
To a solution of pyrrolidine (0.070 g, 0.98 mmol) and triethyl amine (0.11 g, 1.1 mmol) in acetonitrile (5 mL) at reflux was added 2-benzyloxy-6-chloro-5-cyano-benzo[de]isoquinoline-1,3-dione (0.20 g, 0.55 mmol, from Example A2). The reaction was heated at reflux for 20 minutes, then cooled to 0° C. The resulting precipitate was removed by filtration, washed with cold acetonitrile, and dried to give 0.15 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(-c2ccncc2)cc1=O
Yield: 160.5 %

Procedure:
A solution of 2S-(4-bromophenyl)-4-benzyloxycarbonyl-piperazine (788 mg, 2.10 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (444 mg, 2.00 mmol) and diisopropylethylamine (0.70 mL, 4.00 mmol) in dimethylformamide (20 mL) was stirred at 80° C. for 3 h. The reaction mixture was poured into water and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. Chromatographic purification of the residue provided 2-(2S-(4-bromophenyl)-4-benzyloxycarbonyl-piperazin-1-yl)}-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (601 mg, 54%). 1H NMR (300 MHz, CDCl3), δ 3.05(1H, m), 3.30-3.48(3H, m), 3.64(3H, s), 4.08-4.22(2H, m), 4.68(1H, m), 5.15(1H, d, J=12.3 Hz), 5.21(1H, d, J=12.6 Hz), 6.63(1H, s), 7.21(2H, d, J=8.4 Hz), 7.28-7.39(7H, m), 7.59(2H, d, J=6.3 Hz), 8.68(2H, d, J=6.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[C:17]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([OH:19])=[O:18]>>[OH2:12].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:23]2[CH2:24][CH2:25][CH:20]([C:17]([OH:19])=[O:18])[CH2:21][CH2:22]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(O)C1CCNCC1
Product: COc1cc2nc(N3CCC(C(=O)O)CC3)nc(N)c2cc1OC
Product: O

Procedure:
The above was prepared similarly to Example 1, starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and 4-carboxypiperidine and had an m.p. of 295°.