Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[CH2:25]([N:32]1[CH2:36][CH2:35][O:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH2:33][N:32]([CH2:36][CH2:35][OH:34])[CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Reactant: c1ccc(CN2CCOC2)cc1
Solvent: CCO
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1cc(CN(CCO)Cc3ccccc3)c(O)c(OC)c1)O2
Yield: 57.3 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofurane and 20.0 g of 3-benyl-1,3-oxazolidine are held in 200 ml of absolute ethanol for 48 hours at 70° C. and subsequently solvent and excess 3-benzyl-1,3-oxazolidine are removed, finally in vacuum. After purification by means of a chromatographic column there is obtained 17.2 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxy-phenylmethyl)-N-(2-hydroxyethyl)-N-benzylamine, a colourless oil, which solidifies in the manner of glass at oil pump vacuum.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][Cl:14]
Reactant: COc1cccc(F)c1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cccc(F)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.57 g (3.64 mmol) of 2-fluoro-6-methoxybenzyl alcohol was dissolved in 10 ml of benzene, and the resultant solution was added with 0.56 g (4.73 mmol) of thionyl chloride under a room temperature. The obtained solution was stirred for 1 hour at a room temperature to complete a reaction. The reacted solution was then condensed under reduced pressure to obtain a crude product of 2-fluoro-6-methoxybenzyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl.[N:33]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[C:26]1([S:23]([C:22]2[C:3]3[C:2](=[CH:21][CH:20]=[C:5]([O:6][CH2:7][CH2:8][O:9][S:10]([C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=4)(=[O:11])=[O:12])[CH:4]=3)[NH:1][N:33]=2)(=[O:24])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3ccccc3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a mixture of toluene-4-sulfonic acid 2-(4-amino-3-benzenesulfonylmethyl-phenoxy)-ethyl ester (11.7 g, 25.3 mmol) of in ethanol (350 mL) and 1.0 N hydrochloric acid (425 mL) was dropwise added sodium nitrite (2.67 g, 38.7 mmol) in water (50 mL). After stirring at ambient temperature for 1.5 hours, solid sodium carbonate was added to basic pH. The reaction mixture was stirred for an additional 2 hours. It was then solvent evaporated and extracted with warm ethyl acetate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 2% methanol in chloroform to yield toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester as an orange solid (9.54 g, 79.5%): MP: 174-7° C.; Mass Spectrum (−EI, [M−H]−) m/z 471. 1HNMR (500 MHz, DMSO-d6): δ14.11 (s, 1H), 7.96-7.98 (m, 2H), 7.74-7.77 (m, 2H), 7.62-7.66 (m, 1H), 7.53-7.59 (m, 3H), 7.39 (d, 2H, J=8.05 Hz), 7.24 (d, 1H, J=2.32 Hz), 6.97-7.00 (m, 1H), 4.35-4.37 (m, 2H), 4.21-4.23 (m, 2H), 2.33 ppm (s, 3H).
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][C:33]1[C:38]([C:39]([C:41]2[N:45]([CH3:46])[N:44]=[N:43][CH:42]=2)=[O:40])=[CH:37][CH:36]=[C:35]([CH3:47])[N:34]=1.O>O1CCCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:38]3[C:33]([CH3:32])=[N:34][C:35]([CH3:47])=[CH:36][CH:37]=3)([C:41]3[N:45]([CH3:46])[N:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 0.73 mL, 1.2 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (500 mg, 1.2 mmol, Intermediate 10) in tetrahydrofuran (10 mL) at −78° C. After 5 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (250 mg, 1.2 mmol, Intermediate 19: step b) in tetrahydrofuran (1.6 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 30 minutes, water (5 mL) was added and the mixture was allowed to warm to 23° C. The biphasic mixture was partitioned between half-saturated aqueous sodium chloride solution (100 mL) and ethyl acetate (100 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. The filtrate was concentrated and the residue was purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (600 MHz, CDCl3) δ ppm 8.08 (d, J=2.2 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.59-7.54 (m, 2H), 7.40-7.34 (m, 3H), 6.98-6.91 (m, 3H), 6.45-6.41 (m, 1H), 4.32 (s, 2H), 4.10 (s, 3H), 3.93 (s, 3H), 3.61 (s, 1H), 2.55 (s, 3H), 2.38 (s, 3H); MS (ESI): mass calcd. for C31H28ClN7O2, 565.2. m/z found, 566.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][C:16](=[N:19][OH:20])[CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH:24]1[CH2:29][CH2:28][O:27][C:25]1=[O:26]>C1COCC1>[O:26]=[C:25]1[CH:24]([O:20][N:19]=[C:16]2[CH2:17][CH2:18][C:12]3([O:11][N:10]=[C:9]([C:8]#[C:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:13]3)[CH2:14][CH2:15]2)[CH2:29][CH2:28][O:27]1
Reactant: ON=C1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Reactant: O=C1OCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCCC1ON=C1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of the compound of Example 46 (50 mg, 0.186 mmol) in THF (5 mL) was added sodium hydride (60% oil dispersion, 7.81 mg, 0.195 mmol) and the mixture was stirred at r.t. for 1 h. Afterwards, 2-bromo-gamma-butyrolactone (17.2 μL, 0.186 mmol) was added and the reaction was stirred overnight, quenched with water, extracted with EtOAc. The combined organic layers were washed with brine, evaporated to dryness in vacuo to afford a crude, which was purified by automated RP chromatography (Isolera®TM-Biotage; gradient buffer NH4HCO3-MeCN from 40-60 a 30-70. Yield: 32%
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN.O>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCCc1ccccc1

Procedure:
Batch size: 11.0 g (34.2 mmol) 2-(7-phenyl-heptyl)-isoindol-1,3-dione and 3.4 g (68.4 mmol) hydrazine.hydrate in 100 ml ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]([C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43]>C(#N)C>[C:42]([C:46]1[CH:51]=[CH:50][C:49]([S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:54])=[O:53])=[CH:48][CH:47]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(C(C)(C)C)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 43 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0294 g, 0.0637 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0530 mL, 0.382 mmol) and 4-tert-butylbenzenesulfonyl chloride (0.0440 g, 0.191 mmol) to obtain 4-(4-tert-butylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0180 g, yield 43%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])SCCCS1.O.C(=O)(O)[O-:17].[Na+]>CC(C)=O>[O:17]=[C:2]([CH3:1])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)C1(C)SCCCS1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
tert-Butyl 2-methyl-1,3-dithiane-2-carboxylate (2 g, 8.547 mmol) was dissolved in acetone (85.5 mL), and water (0.5 mL) was added. The flask was then cooled in a cold bath at −20° C. Small aliquots of N-bromosuceinimide (15.4 g, 85.47 mmol) were added over 20 minutes. The reaction mixture was stirred at the same temperature for further 30 minutes, and then quenched by adding an aqueous solution of sodium bicarbonate (7.18 g, 85.47 mmol in 90 mL of water). Insoluble material was removed by filtration. The filtrate was diluted in water (200 mL) and extracted with tert-butyl methyl ether (150 mL). The separated organic layer was washed with water and a saturated brine in order, then dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the target compound as pale yellow oil at a yield of 40%.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][OH:10])[CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[OH:10][CH2:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:3](=[O:2])[CH2:4]1
Reactant: COC1(OC)CCC(CCO)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: O=C1CCC(CCO)C1
Reaction time: 16 h
Yield: 95.1 %

Procedure:
A solution of 2-(3,3-dimethoxycyclopentyl)ethanol (203.3 g, 1167 mmol), in Et2O (1000 mL) was treated with p-toluene sulfonic acid (6.66 g, 35.0 mmol) and stirred for 16 hrs. The solution was extracted with water (4×100 mL) and the combined extracts were concentrated under reduced pressure to give the title compound (142.33 g, 1110 mmol, 95% yield), as a dark brown oil. 1H NMR (500 MHz, CDCl3) δ ppm 3.64-3.76 (2 H, m), 2.41 (1 H, dd, J=17.85, 7.17 Hz), 2.24-2.35 (2 H, m), 2.13-2.23 (2 H, m), 1.82 (1 H, dd, J=18.01, 10.38 Hz), 1.64-1.77 (2 H, m), 1.49-1.60 (1 H, m). 13C NMR (126 MHz, CDCl3) δ ppm 219.75, 61.30, 45.21, 38.54, 38.41, 34.01, 29.67.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:22](=[O:23])[C:13]3=[CH:14][NH:15][C:16]4[C:21]([N:12]3[C:11]2=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:6][CH:5]=1)[CH3:2].[CH3:25]OC(OC)N(C)C>CN(C=O)C>[CH3:25][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[C:11](=[O:24])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=3)[C:22](=[O:23])[C:13]2=[CH:14]1
Reactant: COC(OC)N(C)C
Reactant: CCOc1ccc(-n2c(=O)c3c[nH]c4ccccc4n-3c2=O)cc1
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c(=O)c3cn(C)c4ccccc4n-3c2=O)cc1
Temperature: 100 °C

Procedure:
2-(4-Ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (100 mg) was added to a solution of dimethylformamide dimethylacetal (10 ml,) and DMF (5 mL), and the reaction mixture was heated to 100° C. for 4 h. The solution was cooled to room temperature and poured onto water (200 mL). The resulting precipitate was collected and dried to yield 5-N-Methyl-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 42). m.p. 263-266° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(N(Cc2cccnc2)c2ccc(OC)c(OC3CCCC3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(N(Cc2cccnc2)c2cccc(C(=O)O)c2)cc1OC1CCCC1
Reaction time: 6 h
Yield: 78.8 %

Procedure:
A solution of 6.5 g of ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate in 50 mL of EtOH was treated with 10 mL of 6N NaOH. The mixture was allowed to stand for 6 hours, concentrated, and diluted with 50 mL of H2O. The aqueous mixture was extracted with 2×50 mL of ether, acidified with AcOH to pH 3, and extracted with 2×50 mL of EtOAc. The combined EtOAc fractions were washed with 25 mL of H2O and 25 mL of brine, dried (MgSO4), and concentrated. The residue was purified by chromatography over SiO2 (35 g RediSep® column) using a linear gradient of EtOAc and hexanes as eluant (50% EtOAc to 70% EtOAc over 20 minutes) to provide 4.8 g of a yellow solid product after drying in vacuo for 12 h at 60° C. 1H NMR (CDCl3) δ 11.15 (bs, 1H), 8.708.55 (m, 2H), 7.77-6.71 (m, 9H), 4.99 (s, 2H), 4.65 (p, J=3.8 Hz, 1H), 3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:18]([N:20](CC)CC)C.COC(Cl)=O.CN>O.O1CCCC1>[OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:20][CH3:18])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc(Oc2ccc(O)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of 4-(4-Hydroxy-phenoxy)-benzoic acid (0.25 g, 1.09 mmol), triethylamine (0.15 mL, 1.07 mmol) and tetrahydrofuran (THF) (5.0 mL) at 0° C. was added methylchloroformate (0.084 mL, 0.10 g, 1.1 mmol). After stirring for 15 minutes, excess methylamine was added via a sparge tube, and stirring was continued for 10 minutes. The mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo, affording 1 4-(4-Hydroxy-phenoxy)-N-methyl-benzamide as a colorless syrup.
Reaction SMILES: [C:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)(=O)[CH2:2][CH2:3][CH3:4].[CH:18]([NH2:20])=[O:19]>C(O)=O>[CH:18]([NH:20][CH:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4])=[O:19]
Reactant: CCCC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: NC=O
Solvent: O=CO
Product: CCCC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 5 h

Procedure:
The ketone produced as described above (37.0 g) and 98% formic acid (9 ml) were added to formamide (23.5 ml) at 170° C. and the temperature kept at 175°-180° C. for five hours. A further portion of formic acid (4.5 ml) was added and the mixture was maintained at 175°-180° C. for a further fifteen hours. The mixture was extracted with ether which on evaporation gave a thick oil which was crystallised from petroleum ether (b.p. 60°-80°) to give N-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine having a melting point of 103°-105° C. (Formula I R1 =propyl; R2 =H; R3 =H; R4 =CHO; R5 =4-Cl and R6 =3-Cl).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=O.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:25][C:23]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:22]=1[CH2:21][C:20]([O:27][CH3:28])=[O:26]
Reactant: Nc1sc2c(c1C(=O)c1ccccc1Cl)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1Cl)CCCC3
Yield: 78.3 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-chlorophenyl)methanone (0.291 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.302 g (78%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[C:4]([F:14])[CH:3]=1.Cl.Cl.[NH2:17][C@@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@@H:18]([NH:17][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][C:4]([F:14])=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:19]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc(F)cc(Br)c2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(Br)c2o1
Reaction time: 0.33 h

Procedure:
143 mg (0.55 mmol) of 5-fluoro-7-bromo-1-benzofuran-2-carboxylic acid (Example 4A), 100 mg (0.50 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 229.14 mg (0.6 mmol) of HATU, 234 mg (1.81 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted by general method C. DMF is removed under reduced pressure, and the crude product is dissolved in 1N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution. The combined organic phases are dried over magnesium sulphate, and the solvent is removed in a rotary evaporator under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with water, again with methanol, with dichloromethane and finally again with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. 181 mg (98% of theory) of the title compound are isolated.
Reaction SMILES: [N:1]1([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:14])[CH2:9][CH2:8]3)[CH2:4][CH2:3][CH2:2]1.CS(O)(=O)=O.[N-:20]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl>[N:1]1([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:14])[NH:20][CH2:9][CH2:8]3)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCc2cc(N3CCC3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(N3CCC3)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-azetidin-1-yl-indan-1-one (1.9 g, 10.14 mmol) and methane sulfonic acid (10.8 ml) were added to CH2Cl2 (100 ml). The reaction mixture was cooled to 0° C. and sodium azide (1.32 g, 20.29 mmol) was carefully portion wise added over 30 min then reaction mixture was stirred at 0° C. for 2 hours. After the reaction was done, it was slowly added 20% NaOH aq. at 0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Cl-].[Li+].[CH2:14](C([Sn])=C(CCCC)CCCC)[CH2:15]CC>C1(C)C=CC=CC=1>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2)=[CH2:15]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Brc1ccc2nccnc2c1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc2nccnc2c1
Temperature: 100 °C
Yield: 86.7 %

Procedure:
A mixture of 6-Bromo-quinoxaline (1.05 g, 5.02 mmol), palladium tetrakistriphenylphosphine (0.232 g, 0.2 mmol), and lithium chloride (0.639 g, 15.1 mmol) in dry toluene (50 mL) under nitrogen was treated with tributylvinyl tin (4.4 mL, 15.1 mmol) and heated to 100° C. for three hours. After cooling to room temperature the mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was discarded and the organics washed with brine (2×100 mL), dried with magnesium sulfate, filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 10% ethyl acetate in dichloromethane as eluant yielded 680 mg (87% yield) of 6-Vinyl-quinoxaline as a light orange solid. 1H NMR (DMSO-d6): 8.92 (dd,2H,J=14.1,1.9 Hz), 8.10 (m,3H), 7.03 (dd,1H,J=17.7,10.9 Hz), 6.15 (dd,1H,J=17.7,0.4 Hz), 5.52 (d,1H,J=11.1 Hz). LC/MS (Method A): r.t.=1.14 min., purity=99%, calculated mass=156, [M+H]+=157.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].I[CH:13]([CH3:15])[CH3:14]>>[CH:13]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\OC(C)C)C(C)=O

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (3.2 g, 20 mmol) was converted into the title compound by reaction with 2-iodopropane in an analogous reaction to that described in Example 4a Method 1, except that reaction was complete in 3 h. After purification the title compound was obtained as an oil (3.01 g; 74%); νmax (CH2Cl2) 1740, 1685, 1600, 1370, 1315, 1225 and 1070 cm-1 ; δH (CDCl3) 1.31 (3H, t, J 6.5 Hz), 1.33 (6H, d, J 6.5 Hz), 2.37 (3H, s), 4.38 (2H, q, J 6.5 Hz), ca 4.6 (1H, m) [Mass spectrum (+ve ion, 3NNOBA) MH+ (202)].
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)[N:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1CCN(c2cccc(Cc3ccccc3)n2)CC1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ccc(I)c(Cc3ccccc3)n2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Under stirring in an ice bathe, 1.25 g of N-iodosuccinimide was added little by little to a mixture of 1.2 g of 2-benzyl-6-(4-ethoxycarbonylpiperidino)pyridine and 10 ml of N,N-dimethylformamide, followed by stirring as it was overnight. Sodium sulfite was added thereto, and the mixture was extracted with ethyl acetate-water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 1-5% ethyl acetate/hexane, to give 1.42 g of the target compound.