Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:34])[N:16]([CH3:33])[CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[N:14]=2)[CH2:7]1)(=O)=O.[C:35]([O-:38])(=[S:37])[CH3:36].[K+]>CN(C)C=O>[C:35]([S:37][CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:34])[N:16]([CH3:33])[CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])[N:14]=2)[CH2:7]1)(=[O:38])[CH3:36]
Reactant: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(C)CCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (480.1 mg, 0.93 mmol) (obtained as described in Reference Example 58(5)) in dimethylformamide (24 ml) was added potassium thioacetate (820 mg, 5.69 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (15:1) as the eluant to afford 3-acetylthio-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (348.9 mg, yield 76%) as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]2N(C)CCN2C)=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[OH2:22]>C(OCC)C>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]=[O:22])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CN1CCN(C)C1c1ccc(C(=O)OC(C)(C)C)s1
Solvent: CCOCC
Solvent: CI
Product: CC(C)(C)OC(=O)c1ccc(C=O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.54 g (9 mmol) of 5-(1,3-dimethyl-imidazolidin-2-yl)-thiophene-2-carboxylic acid tert-butyl ester wered dissolved in 15 ml of diethyl ether, and after addition of 5 ml of methyl iodide the solution was stirred overnight at room temperature. The resulting crystalline suspension was vigorously stirred for 1 hour with 100 ml water. Then 100 ml diethyl ether were added, and after separation of the phases the organic phase was dried with anhydrous magnesium sulfate. After filtration, the solvents were removed in vacuo. 1.7 g of a light brown oil were isolated which was sufficiently pure for use in the subsequent step.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8](I)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([Sn](CCCC)(CCCC)[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC.[F-].[Cs+]>CN(C=O)C.CCOC(C)=O.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]1[C:8]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:9][CH:10]=[CH:11][C:2]=1[F:1]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: COC(=O)c1c(F)cccc1I
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)cccc1-c1ncccn1
Temperature: 115 °C

Procedure:
Methyl 2-fluoro-6-iodobenzoate (17 g, 61 mmol, 1 eq.) and 2-(tributylstannyl)pyrimidine (26.7 g, 72 mmol, 1.2 eq.) were dissolved in 120 ml of dry DMF under nitrogen atmosphere. Cesium fluoride (18.1 g, 119 mmol, 2 eq., highly hygroscopic) was added and nitrogen was bubbled into the suspension for 5 minutes. While bubbling, Copper iodide (1.1 g, 5.77 mmol 0.1 eq.) and tetrakis(triphenylphosphine)palladium(0) (6.9 g, 5.97 mmol, 0.1 eq) were added. The mixture was then heated at 115° C. for 45 minutes. After that, it was allowed to cool to room temperature, diluted with a large volume of AcOEt and filtered over celite. The resulting liquid phase was washed thoroughly with a saturated aqueous solution of ammonium chloride to remove DMF, dried with sodium sulphate, filtered and evaporated to dryness.
Reaction SMILES: C[O:2][CH2:3][C:4]([O:6][CH3:7])=O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1COCC1>CCOCC>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:3](=[O:2])[CH2:4][O:6][CH3:7])[CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCC(=O)OC
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
To a solution of methyl methoxyacetate (available from Aldrich) (0.48 mL, 4.8 mmol) in ether (20.0 mL) was added a 1.0 M solution of (3-(benzyloxy)phenyl)magnesium bromide in THF (available from Aldrich) (5.0 mL, 5.0 mmol) dropwise at −78° C. The mixture was warmed to room temperature overnight, quenched with 1 N HCl, and diluted with EtOAc. The organics were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 1-(3-(benzyloxy)phenyl)-2-methoxyethanone (0.17 g, 14%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])[CH3:5].[OH-].[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])[CH3:5]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 83 %

Procedure:
A solution of methyl 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[4-(methylsulfonyl)phenyl]oxy}benzoate (60.9 mmol) in THF (400 mL) was treated with a solution of 1M sodium hydroxide (125 mmol), and the reaction mixture stirred for 13 hours at ambient temperature. Most of the organic solvent was removed in vacuo, and the remaining solution was diluted with water (150 mL). The resulting aqueous solution was acidified to pH4 with 1M citric acid solution, and extracted with ethyl acetate (2×100 mL). The extracts were combined, washed with brine, dried (MgSO4), and evaporated to give the desired compound (83% yield).
Reaction SMILES: [CH3:1][C:2]([O:13][Si](C)(C)C)([CH3:12])[C:3]#[C:4][C:5]([C:7]1[N:8]=[CH:9][S:10][CH:11]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:13][C:2]([CH3:12])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[N:8]=[CH:9][S:10][CH:11]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1cscn1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)C#CC(=O)c1cscn1
Reaction time: 1 h
Yield: 109.8 %

Procedure:
To a stirred solution of 4-methyl-1-(thiazol-4-yl)-4-(trimethylsilyloxy) pent-2-yn-1-one (0.15 g, 0.56 mmol) in DCM (3 mL) was added PTSA (0.16 g, 0.84 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-1-(thiazol-4-yl) pent-2-yn-1-one (0.12 g, crude) as an oil.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:7]
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)c1ccc(Cl)cc1
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(Cl)cc1
Yield: 97 %

Procedure:
Ethyl(4-chlorophenyl)[(4-hydroxyphenyl)sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromo(4-chlorophenyl)acetate (16.5 g, 59.6 mmol) and 4-mercaptophenol (7.5 g, 59.6 mmol); 18.8 g white solid. mp: 63° C.; Yield 97%; MS: 321.3 (M−H)−
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.C1(COC2N=C(C(O)=O)C=CC=2C2CCCO2)CC1.[CH3:39][C:40]([CH3:48])([C:42]1[N:46]=[C:45]([CH3:47])[O:44][N:43]=1)[NH2:41]>>[CH3:39][C:40]([NH:41][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:42]1[N:46]=[C:45]([CH3:47])[O:44][N:43]=1)[CH3:48]
Reactant: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Agent: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCOC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d), and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:4].[O:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[O:13]=[C:11]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:9][C:8]#[C:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)CCC#CCCC(=O)O
Reactant: c1ccoc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCC#CCCC(=O)c1ccco1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
To a mixture of 6-methoxycarbonyl-1-carboxy-3-hexyne [VI-1] (27.6 g, 0.15 mole), furan (30.7 g, 0.45 mole) and dichloromethane (150 ml) is added trifluoroacetic anhydride (37.8 g, 0.18 mole) at room temperature, and the mixture is reacted at 30°-35° C. for 24 hours. After completion of the reaction, the reaction solution is poured into ice-water, and neutralized with 20% aqueous sodium hydroxide solution. The organic layer is separated and washed successively with 5% aqueous sodium hydrogen carbonate solution and water, and concentrated under reduced pressure to give 1-oxo-1-furyl-7-methoxycarbonyl-4-heptyne [VII-1] (32.3 g, yield; 92%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([C:29]([NH:31][CH3:32])=[O:30])=[C:27]3[C:22]([CH:23]=[C:24]([N:36]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:37][CH2:38][CH2:39][CH:40]4[CH2:42][O:41]4)[C:25]([CH:33]4[CH2:35][CH2:34]4)=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1>C(O)(C)(C)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([C:29]([NH:31][CH3:32])=[O:30])=[C:27]3[C:22]([CH:23]=[C:24]([N:36]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:37][CH2:38][CH2:39][CH:40]4[CH2:42][CH2:1][O:41]4)[C:25]([CH:33]4[CH2:34][CH2:35]4)=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCC3CO3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCC3CCO3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 15.8 %

Procedure:
An oven-dried flask was charged with a mixture of potassium tert-butoxide (426 mg, 3.8 mmol) and trimethylsulfoxonium iodide (860 mg, 3.9 mmol) in anhydrous tert-butanol (7.5 mL) under argon. The reaction mixture was stirred vigorously at 50° C. for 5 h under argon then added to a stirred solution of crude (ii) (191 mg) in anhydrous tert-butanol (2.5 mL) in a single portion. The reaction was stirred at 50° C. overnight under argon, cooled to RT and concentrated in vacuo. The residue was then partitioned between water (50 mL) and EtOAc (50 mL) and the organics separated. The aqueous layer was extracted aq with EtOAc (2×50 mL) and the combined organic layers dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DMSO (2.5 mL) and the mixture centrifuged. The supernatant solution was collected and subjected to preparative HPLC (0.1% formic acid in acetonitrile: 0.1% formic acid in water, gradient elution 0% to 45% to 60% to 100%) to give Compound (4) (31 mg, 16% over 2 steps). 1H NMR (400 MHz, CD3CN) δ 7.80 (s, 1H), 7.60-7.50 (m, 4H), 7.35 (s, 1H), 6.98 (br s, 1H), 4.75-4.64 (m, 1H), 4.55-4.46 (m, 1H), 4.39-4.31 (m, 1H), 3.78-3.69 (m, 2H), 3.07 (s, 3H), 2.89 (d, J=4.8 Hz, 3H), 2.64-2.53 (m, 1H), 2.42-2.32 (m, 1H), 2.31-2.19 (m, 1H), 1.81-1.49 (m, 3H), 1.09-0.97 (m, 3H), 0.67-0.58 (m, 1H). ESI-MS m/z calculated for [M+H]+: 517.2. found: 517.0; m/z calculated for [M+Na]+: 539.2. found: 539.1.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]([CH3:13])[C:6]([CH2:8][O:9]C(=O)C)=[O:7].C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:7])[CH2:8][OH:9]
Reactant: CC(=O)OCC(=O)N(C)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(Cc1ccccc1Br)C(=O)CO
Reaction time: 1.5 h

Procedure:
To a solution of acetic acid [(2-bromo-benzyl)-methyl-carbamoyl]-methyl ester (11.0 g, 36.8 mmol) in methanol (250 mL) is added a solution of potassium carbonate (7.63 g, 55.2 mmol) in water (45 mL). After stirring for 90 minutes the reaction is concentrated to near dryness and then dissolved in dichloromethane. The resulting solution is washed with brine, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 1:99 to 3:47) to furnish N-(2-bromo-benzyl)-2-hydroxy-N-methyl-acetamide; MS: (ESI) m/z 258.1, 260.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:12][CH2:13][C@@H:14]1[C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][N:15]1[C:21]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[N:34]=[CH:33][CH:32]=[N:31]1)=[O:22])=[N:7]2.C([O-])=O.[NH4+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][C@@H:19]1[CH2:18][CH2:17][CH2:16][N:15]([C:21]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[N:30]2[N:31]=[CH:32][CH:33]=[N:34]2)=[O:22])[C@@H:14]1[CH2:13][NH:12][C:6]1[N:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=2)[N:7]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3c(Br)cccc3n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3ccccc3n2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(((5-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.057 g, 0.111 mmol), HCOONH4 (0.14 g, 0.222 mmol) and Pd(PPh3)4 (0.026 g, 0.022 mmol) in dioxane and water (4:1, 2 mL) was heated for 2 h at 100° C. The mixture was cooled to rt and filtered through diatomaceous earth. The solvent was removed and the crude residue was purified via silica gel chromatography to obtain the title compound. ESI-MS (m/z): 442 [M+1]+.
Reaction SMILES: N[C@H](C(O)=O)CCSC.C[O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:24]3[CH:19]([CH2:20][C:21](=[O:31])[N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[N:23]=3)[CH2:18][CH2:17][C:16]=2[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CS(O)(=O)=O>[OH:11][C:12]1[CH:13]=[CH:14][C:15]2[C:24]3[CH:19]([CH2:20][C:21](=[O:31])[N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[N:23]=3)[CH2:18][CH2:17][C:16]=2[CH:32]=1
Reactant: COc1ccc2c(c1)CCC1CC(=O)N(c3ccccn3)N=C21
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Product: O=C1CC2CCc3cc(O)ccc3C2=NN1c1ccccn1
Temperature: 55 °C
Reaction time: 26 h
Yield: 28.3 %

Procedure:
A mixture of 1.0 g of methionine, 70 ml of methanesulfonic acid and 10 g of 8-methoxy-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one is stirred at 55° C. for 26 hours. The reaction mixture is poured into ice-water, and the mixture is neutralized with potassium carbonate and extracted with chloroform. The extract is washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is purified by silica gel chromatography (chloroform:methanol =10:1) and recrystallized from chloroform methanol to give 2.7 g of 8-hydroxy-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one as white crystals, m.p. 193°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([C:16]([N+:21]([O-:23])=[O:22])=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:15][C:14]2[C:16]([N+:21]([O-:23])=[O:22])=[CH:17][C:18]([O:19][CH3:20])=[C:12]([Br:11])[CH:13]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1cc([N+](=O)[O-])c(N)cc1Br
Product: COc1cc([N+](=O)[O-])c(NC(=O)c2ccc(Cl)nc2)cc1Br

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 3-bromo-4-methoxy-6-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (DMSO-d6): 10.84 (s, 1H), 8.93 (d, J=2.4, 1H), 8.34-8.30 (m, 1H), 7.98 (s, 1H), 7.76 (d, J=8.4, 1H), 7.70 (s, 1H), 3.97 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41].[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55]O)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55][O:20][C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])[CH:27]=[N:28]3)=[CH:23][C:22]=2[O:40][CH3:41])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9213.9 %

Procedure:
Triphenylphosphine (1.7 g, 6.5 mmol) was added under nitrogen to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.53 g, 5 mmol) in methylene chloride (20 ml), followed by the addition of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine (1.29 g, 6 mmol), (prepared as described for the starting material in Example 1), and by a solution of diethyl azodicarboxylate (1.13 g, 6.5 mmol) in methylene chloride (5 ml). After stirring for 30 minutes at ambient temperature, the reaction mixture was poured onto a column of silica and was eluted with ethyl acetate/petroleum ether (1/1 followed by 6/5, 6/4 and 7/3). Evaporation of the fractions containing the expected product led to an oil that crystallised following trituration with pentane. The solid was collected by filtration and dried under vacuum to give 7-(1(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (232 g, 92%).
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])[N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:16][N:17]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: C1CCNC1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCCC1

Procedure:
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(pyrrolidin-1-yl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and pyrrolidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13].[As+3]=O.[CH:16]([CH:18]=[CH2:19])=O.N>S(=O)(=O)(O)O.O>[N:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:19]=[CH:18][CH:16]=1
Reactant: Nc1ccccc1N1CCCC1=O
Reactant: C=CC=O
Agent: N
Agent: O=S(=O)(O)O
Agent: O=[As+3]
Solvent: O
Product: O=C1CCCN1c1cccc2cccnc12
Yield: 21 %

Procedure:
A mixture of 1-(2-aminophenyl)-2-pyrrolidinone (J. Chem. Soc. C, 1969 (10), 1444-8) (3.2 g, 0.018 mole) and arsenic (V) oxide (2.5 g, 0.011 mole) in aqueous sulphuric acid (concentrated sulphuric acid (4.0 ml) in water (1.3 ml)) was heated to 70° and stirred vigorously. Acrolein (2.5 ml, 0.037 mole) was added dropwise at a rate such that the reaction temperature did not exceed 95°. The reaction temperature was maintained at 95° to 115° by heating and stirring in a nitrogen atmosphere for 1 hour after addition of acrolein was complete. The product was poured into water and the pH was adjusted to pH 6 with concentrated ammonia. Extraction of the aqueous solution with methylene chloride, after removal of the solvent, afforded an oil. Separation was achieved by column chromatography (200 g SILICA GEL 60 (Trade Name)). The oil was eluted first with acetone/ethyl acetate (30:70) then acetone/ethyl acetate (50:50) and finally acetone. The solvet was removed from the acetone/ethyl acetate (50:50) and the acetone fractions to afford a homogeneous solid as shown by tlc analysis. Crystallization from acetone afforded 1-(8-quinolyl)-2-pyrrolidinone (m.p. 121° -122°), yield 21%. Analysis of the sample by tlc and NMR as well as elemental analysis verified the identity of this material with that obtained in Example 1.
Reaction SMILES: Cl[Si:2]1(Cl)[CH2:5][CH:4]([CH3:6])[CH2:3]1.C[Si]([CH2:12][C:13]([O-:15])=[O:14])(C)C>>[C:13]([O:15][Si:2]1([O:15][C:13](=[O:14])[CH3:12])[CH2:5][CH:4]([CH3:6])[CH2:3]1)(=[O:14])[CH3:12]
Reactant: C[Si](C)(C)CC(=O)[O-]
Reactant: CC1C[Si](Cl)(Cl)C1
Product: CC(=O)O[Si]1(OC(C)=O)CC(C)C1

Procedure:
In accordance with the general procedure of Example 1, when 1,1-dichloro-3methylsilacyclobutane and trimethylsilylacetate are reacted it is predicted that the title compound is obtained.