Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Br:4])[CH2:2][OH:3].[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>C(N(CC)CC)C.ClCCl>[C:8]([O:3][CH2:2][CH2:1][Br:4])(=[O:9])[CH2:7][C:6]([CH3:5])=[O:10]
Reactant: OCCBr
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CC(=O)OCCBr
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To 30 g of ethylene bromohydrin in ice bath were added by turns 22 g of diketene and 1.5 g of triethylamine with stirring while the reaction temperature was controlled at 30°-40° C. The reaction was continued at room temperature for 3 hours. To the reaction solution was added dichloromethane, the mixture was washed successively with diluted hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by distillation to obtain 45.3 g of 2-bromoethyl acetoacetate.
Reaction SMILES: [Br-:1].O[CH:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH2:6][CH2:7]2)[CH2:4]1.[H-].[Na+].IC.O.[CH3:21][O:22]CCOC>>[Br-:1].[CH3:21][O:22][CH:6]1[CH2:7][CH:8]2[CH2:9][CH2:10][N+:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:3]2
Reactant: COCCOC
Reactant: CCCCC[N+]12CCC(CC1)C(O)C2
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCCCC[N+]12CCC(CC1)CC2OC
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of (±)-3-hydroxy-1-pentylquinuclidinium bromide (20 g, 72 mmol) in dry 1,2-dimethoxyethane (150 ml) at 0° C., under nitrogen, was added sodium hydride (3.48 g, 60% in mineral oil, 86.8 mmol) and then iodomethane (11.3 ml, 181 mmol). The temperature was allowed to rise to room temperature overnight. Water (200 ml) was added and the mixture was extracted with 6×100 ml dichloromethane. Drying and evaporation gave an oily residue which, after trituration with petrol ether, gave the title compound as a crystalline solid. Yield 23.9 g (That the yield was more than 100% is explained by the fact that there is a mixture of bromide and iodide as counter ions.).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[C:4]([CH3:18])[CH:3]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1Oc1ccc(N)cn1

Procedure:
2-(4-chloro-2-methyl-phenoxy)-5-nitropyridine (203 mg, 0.77 mmol) was dissolved in 95% ethanol (3 mL) and treated with 20% palladium hydroxide on carbon (50 mg). The reaction mixture was shaken in a hydrogen atmosphere (40 psi) for 1 hour. The solution was filtered through celite and concentrated in vacuo. MS (m/z): 234/236 (M+H)+ ; C12H11N2OCl requires 234.7.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4]Br.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C=O)C>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][N:17]=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A mixture of (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienyl bromide (1.5 g, 5.26 mmol) and sodium azide (0.68 g, 10.5 mmol) in DMF (20 mL) was stirred at room temperature for 0.5 hours, then poured into cold water and extracted with ether. The ethereal extract was washed with brine, dried, filtered and evaporated to yield a residue. Purification of the residue by flash chromatography on a silica gel column, using hexane as the eluant, afforded the title compound as an oil (1.2 g, 4.85 mmol, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:10].Cl[CH2:12][C:13](=[O:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:13]([C:14]1[O:10][C:3]2[C:2]([Br:1])=[CH:9][CH:8]=[CH:7][C:4]=2[CH:5]=1)(=[O:15])[CH3:12]
Reactant: CC(=O)CCl
Reactant: O=Cc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc2cccc(Br)c2o1
Temperature: 60 °C

Procedure:
A mixture of 5.0 g (24.9 mmol) of 3-bromo-salicylaldehyde, 3.0 g (32.3 mmol, 2.6 mL) of chloroacetone and 12 g (37.2 mmol) of Cs2CO3 in 30 mL of dry DMF was heated to 60° C. overnight. After cooling at room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was directly recrystallized from hexane to afford 2-acetyl-7-bromo benzo[b]furan as a pale orange crystal.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[CH:15]=[C:16]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:18][C:13]=2[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[C:6]1=[O:34].Cl.O1CCOCC1>CO>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]2[C:12]3[C:7](=[CH:8][N:9]=[CH:10][CH:11]=3)[C:6](=[O:34])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:14]=2[CH:15]=1
Reactant: COCCn1c(=O)c2cnccc2c2ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCn1c(=O)c2cnccc2c2ccc(OC[C@@H](N)CC(C)C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-(2-methoxyethyl)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.080 g, 0.170 mmol) in anhydrous methanol (5 mL) was added a 4M solution of HCl in 1,4-dioxane (0.21 mL, 0.85 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude compound which was purified by preparative HPLC (10 mM ammonium acetate in water:acetonitrile) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6-(2-methoxyethyl)benzo[c][2,7]naphthyridin-5(6H)-one (20 mg, 0.054 mmol, 32% yield) a white solid. LC/MS (ESI) m/e 370.2 [(M+H)+, calcd for C21H28N3O3 370.2]; LC/MS retention time (method A): tR=1.34 min; HPLC retention time (method A): tR=8.36 min; HPLC retention time (method B): tR=8.78 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.45 (s, 1H), 8.76 (d, J=5.77 Hz, 1H), 8.40 (d, J=9.03 Hz, 1H,), 8.23 (d, J=6.02 Hz, 1H), 7.29 (d, J=2.26 Hz, 1H), 7.11 (d, J=8.78 Hz, 1H), 4.61 (t, J=5.65 Hz, 2H), 4.36 (s, 1H), 4.20 (s, 1H), 3.81 (t, J=5.77 Hz, 2H), 3.63-3.71 (m, 1H), 3.37 (s, 3H), 1.86 (m, 1H), 1.67 (qt, J=14.01, 7.09 Hz, 2H), 1.06 (d, J=5.77 Hz, 6H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([N+:12]([O-])=O)[C:6]([CH2:9][C:10]#N)=[N:7][CH:8]=1.C[CH2:16][OH:17].CCOC(C)=O>[Pd]>[CH3:16][O:17][C:8]1[N:7]=[C:6]2[CH:9]=[CH:10][NH:12][C:5]2=[CH:4][CH:3]=1
Reactant: CCO
Reactant: COc1cnc(CC#N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]ccc2n1
Reaction time: 6 h
Yield: 95 %

Procedure:
A suspension of (5-methoxy-3-nitro-pyridin-2-yl)-acetonitrile (Maybridge, 986 mg, 5.1 mmol) and Pd/C (10%, 986 mg) in EtOH/EtOAc (95/5, 50 mL) was shaken for 6 hours under H2 (60 PSI) in Parr apparatus. The reaction mixture was then filtered through a celite pad, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated, and the residue was dissolved in EtOAc (50 mL), washed with NaHCO3 (saturated solution, 50 mL), dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc), affording 5-Methoxy-1H-pyrrolo[3,2-b]pyridine as a white solid (720 mg, 95% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]([CH3:27])[CH2:13][C:12]=23)[N:4]=1.[CH2:28]([NH2:31])[CH2:29][CH3:30]>CN(C)C=O>[CH3:27][N:14]1[C:15](=[O:26])[C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]2[CH:10]=[N:9][C:8]([C:5]3[N:4]=[C:3]([CH2:2][NH:31][CH2:28][CH2:29][CH3:30])[O:7][N:6]=3)=[C:12]2[CH2:13]1
Reactant: CCCN
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(C(F)(F)F)c2C1=O
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2c-3cccc2C(F)(F)F)no1
Yield: 66.6 %

Procedure:
1.19 g (3 mmol) of 3-(5-chloromethyl-1,2,4-oxa-diazol-3-yl)-5-methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo [1,5-a ][1,4]benzodiazepine-6-one were stirred at room temperature overnight with 5.3 g (90 mmol) of propylamine and 10 ml of N,N-dimethylformamide. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with water. By drying the organic phase over magnesium sulfate and evaporating the solvent there was obtained 0.84 g (67%) of 5-methyl-3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 234°-237°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[N:18]([CH2:22][CH3:23])[N:19]=[CH:20][CH:21]=4)=[CH:15][N:14](COC(=O)C(C)(C)C)[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:32](=[O:36])[N:33]([CH3:35])[CH3:34].[OH-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[N:18]([CH2:22][CH3:23])[N:19]=[CH:20][CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:32]([N:33]([CH3:34])[CH3:35])=[O:36]
Reactant: CCn1nccc1-c1cn(COC(=O)C(C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1nccc1-c1c[nH]c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(2-ethyl-2H-pyrazol-3-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester was dissolved in tetrahydrofuran. 1 M sodium hydroxide in methanol was added to the mixture, and the reaction was stirred for 2 h at room temperature until complete conversion was confirmed by HPLC-MS. Saturated aqueous sodium bicarbonate solution was added and the mixture extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The crude material was purified by preparative HPLC to give 2-amino-5-[3-(2-ethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, d6-DMSO) δ 12.12 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 7.97 (d, J=2.3 Hz, 1H), 7.76 (d, J=2.3 Hz, 1H), 7.55 (s, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.53 (s, 1H), 5.29 (s, 2H), 4.20 (quart., J=7.3 Hz, 2H), 2.96 (s, 6H), 1.32 (t, J=7.1 Hz, 3H); MS: m/z 375.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]1[C:15]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH3:2].Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=1[C:14]1[C:15]2[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C(F)(F)F)ccc3OCC)ncnc12

Procedure:
Starting from ethyl 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a9) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:32][C@@H:33]1[CH2:37][NH:36][C@H:35]([CH2:38][O:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)[CH2:34]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:36]3[CH2:37][C@@H:33]([O:32][C:23]4[CH:24]=[CH:25][C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:22]=4)[CH2:34][C@H:35]3[CH2:38][O:39][C:40]3[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)cc1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In DMF (10 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (141 mg, 0.50 mmol), methyl 4-((2S,4S)-4-(2-naphthyloxy)-2-pyrrolidinylmethoxy)benzoate (189 mg, 0.50 mmol), EDC•HCl (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol) and triethylamine was stirred at room temperature for 16 hours. The reaction mixture was poured in ice water (30 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was separated and purified by chromatography on a thin-layer silica gel column with (chloroform/acetone (5/1)), whereby the title compound (312 mg, 97%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[C:17]([O:19][C:20]1[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]>>[CH2:1]([NH:9][C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]([O:19][C:17](=[O:18])[C:16]2[CH:15]=[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])[C:35]([OH:36])=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=2)=[CH:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)(C)c1cc(C(=O)Cl)ccc1OC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)c1ccc(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1

Procedure:
Following the procedure of Example 8, n-octylamine is reacted with 4-(3,5-di-t-butyl-4-hydroxybenzoyloxy)-5-t-butylbenzoyl chloride to yield N-n-octyl-4-(3,5-di-t-butyl-4-hydroxybenzoyloxy)-5-t-butylbenzamide.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:18][CH2:17][N:16]2[CH:11]([CH2:12][S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=32)[CH2:10]1)=O)(C)(C)C>C(O)(=O)C>[ClH:1].[CH2:17]1[N:16]2[CH:11]([CH2:12][S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=32)[CH2:10][NH:9][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3SCC2C1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc2c(c1)SCC1CNCCN21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 ml portion of 5 N hydrochloric acid was added to acetic acid solution (10 ml) containing 0.52 g (1.70 mmol) of 3-t-butoxycarbonyl-1,2,3,4,4a,5-hexahydropyrazino[2,1-c]-1,4-benzthiazine, and the mixture was stirred overnight at room temperature and then at 60° C. for 2 hours. The solvent was removed by evaporation under a reduced pressure and the resulting residue was recrystallized from ethanol to obtain 0.36 g (88% in yield) of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.O[CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:27][C:26](=[O:34])[CH:25]=1>C(O)(=O)C.CN(C)C=O>[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:27][C:26](=[O:34])[C:25]=1[CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(c2c(O)c3ccccc3oc2=O)N1c1ccccc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 85.8 %

Procedure:
Sulphuric acid (210 cc) is added dropwise to a suspension of 3-hydroxy-2-phenylisoindolin-1-one (67.5 g) and 4-hydroxycoumarin (97.3 g) in acetic acid (675 cc) whilst maintaining the temperature between 15° and 18° C, and the mixture is stirred for 15 hours at a temperature of about 20° C. The reaction mixture is then run into icewater (3000 cc) and the precipitate is filtered off and washed with water (2500 cc). The filter cake is dried in a stream of air at a temperature of about 20° C. The product obtained is dissolved in dimethylformamide (800 cc) at 90° C. The solution is filtered and acetonitrile (900 cc) is then added. After cooling in an ice-bath for 2 hours, the solid is filtered off and washed with acetonitrile (1000 cc). It is dried under reduced pressure (0.1 mm Hg) for 15 hours at 20° C and then for 4 hours at 55° C and 2 hours at 80° C. 3-(4-Hydroxycoumarin-3-yl)-2-phenylisoindolin-1-one (95 g), melting at 335°-337° C, is thus obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[O:13][C:14]([CH3:16])=[CH:15][C:11]=3[C:10]([CH:17]=[O:18])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH:1]1([O:6][C:7]2[C:12]3[O:13][C:14]([CH3:16])=[CH:15][C:11]=3[C:10]([C:17]([OH:21])=[O:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc2c(C=O)ccc(OC3CCCC3)c2o1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc2c(C(=O)O)ccc(OC3CCCC3)c2o1
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 68.3 %

Procedure:
To a well stirred solution of 7-cyclopentyloxy-2-methylbenzo[b]furan-4-carboxaldehyde (55.0 g, 0.225 moles), sulphamic acid (76.0 g, 0.787 moles) in acetone (600 mL) was added a solution of sodium chlorite (51.0 g, 0.562 moles) in water (150 mL) at 0-5° C. and stirred for 5-6 hrs. Ice cold water (1.0 L) was added to reaction mixture; solid separated was filtered and purified by acid-base technique to get 40.0 g of pure product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:14]([OH:15])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
A solution of phenol (Kappe, T.; Witoszynskyj, T. Arch. Pharm., 1975, 308 (5), 339-346) (1.14 g, 5.00 mmol) in THF (15 mL) was cooled in a dry ice/acetone bath and treated dropwise with phenyllithium (7.5 mL, 13.5 mmol, 1.8M in cyclohexane/ethyl ether 70/30). The reaction mixture was allowed to warm gradually to ambient temperature. After 18 h, the reaction was quenched with aqueous saturated NH4Cl solution (1 mL) and partitioned between EtOAc (50 mL) and 1N HCl (20 mL). The organic layer was washed with brine (75 mL), dried (Na2SO4), and concentrated to a brown oil (2.3 g). The crude product was purified by flash chromatography using hexanes:ethyl acetate (3:1 to 2:1) to give a pale yellow oil (1.42 g, 93%): 1H NMR (400 MHz, CDCl3) δ 2.79 (s, 1H), 4.92 (s, 2H), 5.95, (s, 1H), 6.51 (s, 1H), 6.81 (d, 3H, J=1.5 Hz), 7.28-7.38 (s, 10H); MS (ES) m/e 305 [M−1].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[CH2:10][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:8][CH2:7][C:6]=2[NH:5][C:4]1=O.C(O)(=O)C.Cl>C1COCC1>[OH:1][CH2:2][CH:3]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10]2)[NH:5][CH2:4]1
Reactant: COc1ccc(CC2CCC3=C(C2)CC(CO)C(=O)N3)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CC2CCC3NCC(CO)CC3C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
3,4,5,6,7,8-Hexahydro-3-hydroxymethyl-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one (24.7 g) (prepared according to step c) in THF (200 ml) was treated with borane-dimethylsulphide complex (25 ml) and stirred at room temperature under argon for 18 hours. The reaction mixture was then treated with aqueous acetic acid (20%) until pH 5 and then stirred for an hour. HCl was added until the mixture was strongly acidic and then the solvent removed in vacuo. The residue was dissolved in methanol, concentrated to remove borate esters then converted to the hydrochloride salt (28 g). This salt was recrystallised from ethyl acetate-methanol (200 ml-15 ml) to yield a fraction (15.7 g) containing 34% of the title compound. This fraction was triturated with ethyl acetate, converted to the free base and fractionally crystallised from t-butylmethyl ether, yielding a fraction containing 84% of the title compound. Further recrystallisation was carried out from t-butylmethyl ether diethylether (1:1) and the product converted to the hydrochloride salt (1.8 g), mp 288°-289.5° C.
Reaction SMILES: [H-].[Na+].[CH:3]12[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8]2.[O:14]1[CH2:34][CH:15]1[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=3[O:26][N:25]=2)[CH2:20][CH2:19]1>CN(C)C=O>[F:33][C:31]1[CH:30]=[CH:29][C:28]2[C:24]([CH:21]3[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH:15]([OH:14])[CH2:34][N:10]4[C:9](=[O:13])[CH:4]5[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]5[C:11]4=[O:12])[CH2:19][CH2:20]3)=[N:25][O:26][C:27]=2[CH:32]=1
Reactant: O=C1NC(=O)C2CCCCC12
Reactant: Fc1ccc2c(C3CCN(CCC4CO4)CC3)noc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C2CCCCC2C(=O)N1CC(O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 49.1 %

Procedure:
To a mixture of 60% sodium hydride (0.12 g) and dimethylformamide (5 ml), cyclohexane-1,2-dicarboximide (0.5 g) was portionwise added. A solution of 1-(3,4-epoxybutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.8 g) in dimethylformamide (10 ml) was dropwise added thereto at room temperature, and the resultant mixture was kept at an inner temperature of 90 to 100° C. for 16.5 hours. Insoluble materials were removed by filtration, and the residue was combined with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude crystals were recrystallized from a mixture of isopropyl ether and isopropanol to give the objective compound (0.6 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: Clc1ccccc1I
Reactant: C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cncc(C#Cc2ccccc2Cl)c1
Temperature: 70 °C

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (63.2 mg, 0.090 mmol), copper (I) iodide (34.3 mg, 0.180 mmol), and 5-ethynylnicotinonitrile (242 mg, 1.89 mmol), (prepared essentially as described in PREPARATION 4), to a solution of 1-chloro-2-iodobenzene (0.22 mL, 1.77 mmol) in triethylamine (3.60 mL, 25.8 mmol) and heat to 70° C. in a sealed tube for 1.5 h. Cool to room temperature and dilute with ethyl acetate. Wash with a saturated aqueous solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient from 95:5 to 80:20 (90:10 hexanes:ethyl acetate):dichloromethane, to give the title compound as a yellow solid. Further purify the title compound by recrystallizing from cyclohexane (20 mL) to give a white solid (95 mg, 22%).