Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([C:12]3[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29]C)=[O:28])[CH:18]=4)[N:13]=3)[CH:10]=[CH:11][C:2]1=2.[OH-].[Na+]>CO.O>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([C:12]3[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:27]([OH:29])=[O:28])[CH:18]=4)[N:13]=3)[CH:10]=[CH:11][C:2]1=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCCCO4)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(c1)OCCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of methyl 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140.0 mg, 0.34 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (42.0 mg, 1.03 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (120.0 mg, 84%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([OH:35])=O)(=[O:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:50][NH:51][CH3:52]>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([N:51]([CH3:52])[CH3:50])=[O:35])(=[O:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CNC
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(=O)(=O)CC(=O)O)no2)cc1C#N
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(=O)(=O)CC(=O)N(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
Prepared using General Procedure 9: To a stirring solution of (R)-2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl) acetic acid 34 (15 mg, 0.05 mmol) in DMF (0.5 mL) was added N-hydroxybenzotriazole (6.1 mg, 0.05 mmol) and EDC (8.7 mg, 0.05 mmol). After 5 min, dimethylamine (40 wt % solution in THF, 50 μL, 0.09 mmol) was added and the reaction mixture was stirred 18 h at room temperature. The crude reaction was diluted with sat NaHCO3 and extracted with EA. The combined organic layers were dried over Na2SO4 and purified by preparative HPLC to give 4.41 mg (28%) of (R)-2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)-N,N-dimethylacetamide 40. LCMS-ESI (m/z) calculated for C26H29N5O5S: 523.6; found 546.2 [M+Na]+, tR=3.58 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.96 (dd, J=7.7, 1.2 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.36 (t, J=17.3 Hz, 1H), 4.88-4.73 (m, 2H), 4.27 (d, J=14.6 Hz, 1H), 4.07 (d, J=14.6 Hz, 1H), 3.24-3.09 (m, 4H), 3.09-2.97 (m, 4H), 2.23-2.08 (m, 2H), 2.10-1.84 (m, 2H), 1.47 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.75, 169.37, 163.15, 162.77, 137.79, 136.92, 134.13, 133.90, 132.50, 130.18, 126.36, 126.17, 116.79, 115.25, 113.55, 103.96, 72.74, 55.46, 53.05, 38.22, 35.98, 29.84, 28.10, 21.73, 19.10.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[Cl-:9].[CH3:10][N+:11]1[CH:15]=[CH:14][N:13]([CH:1]([O:8][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1
Reactant: Cn1ccnc1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CCOCC
Product: C[n+]1ccn(C(OC(=O)c2ccccc2)c2ccccc2)c1
Product: [Cl-]
Yield: 80.3 %

Procedure:
To an ether solution of benzoyl chloride (2.81 g; 0.02 mol) there was added dropwise 1.67 g (0.02 mol) of 1-methylimidazole with stirring. The resulting mixture was evaporated in vacuo and the residue was allowed to react with 2.12 g (0.02 mol) of benzaldehyde at 70° C overnight, using a CaCl2 drying tube to protect it from moisture. After cooling, the reaction mixture was titrated with ether and the solid separated by filtration to give 5.28 g (m.p. 163°-178° ; 80% yield) of crude 1-methyl-3-(α-benzoyloxybenzyl)-imidazolium chloride. After recrystallization from dichloromethane-dioxane, pure 1-methyl-3-(α-benzoyloxybenzyl)-imidazolim chloride was obtained. The mp of the compound was 199°-201° C. The ir and nmr spectra were identical with that of the compound obtained from Method A above.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:2]2[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=2)[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(Cc3ccccc3)C2)cn1
Temperature: 85 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg) and potassium carbonate (4.94 mg) in DMF (15 mL) was added (3R)-1-benzyl-3-piperidinamine dihydrochloride (668 mg) under nitrogen at ambient temperature and the mixture was stirred at 85° C. for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=97-3) to give ethyl (2E)-3-(5-{[(3R)-1-benzyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate (125 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH2:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Br[C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH:12][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
Temperature: 100 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine (5.0 g, 18 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (7.0 g, 25 mmol) and N,N-diisopropylethylamine (9.4 mL, 54 mmol) in ethanol (100 mL) was heated at 100° C. (flushed with nitrogen) overnight. The reaction mixture was cooled, poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified on silica gel (eluting with 0-65% ethyl acetate in hexane) to afford the desired product. LCMS calculated for C20H24BrClN5O2 (M+H)+: m/z=480.1, 4821. found: 480.0, 482.1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C([O-])([O-])=O.[K+].[K+].[NH:21]1[CH2:25][CH2:24][N:23]=[C:22]1S(O)(=O)=O>CO>[NH:23]1[CH2:24][CH2:25][N:21]=[C:22]1[N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NCCN2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.86 of Boc-piperazine were combined with 25 ml of water, 25 ml of methanol, 2.77 g of K2CO3 and 1.5 g of imidazoline-2-sulphonic acid and stirred for 2 days at RT. After dilution with water the mixture was extracted with EE and chromatographed over silica gel. 0.8 g of 1-(imidazolin-2-yl)-4-Boc-piperazine were obtained. This substance was combined with 6.2 ml of DMF and 136 mg of NaH dispersion (60%). After one hour, 0.214 ml of methyl iodide was added dropwise and the reaction mixture was left for three days at RT. It was combined with water, extracted with EE and chromatographed over silica gel. In this way, 0.47 g of 1-(1-methylimidazolin-2-yl)-4-Boc-piperazine was obtained, which was treated with 5 ml of 4N HCl in dioxane at RT. After one hour, the mixture was concentrated by evaporation, stirred with ether and evaporated to dryness in vacuo. 0.38 g of 1-(1-methylimidazolin-2-yl)-piperazine dihydrochloride was thus obtained as a solid substance (yield 15%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:24][Si](C)(C)C)C#N)=[CH:17][CH:16]=1)[CH3:14].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=[O:33]>CCCCCC.COCCOC>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH:32]([C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[F:29])[OH:33])=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc(C(C#N)O[Si](C)(C)C)cc1
Reactant: O=Cc1ccccc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Product: CCc1ccc(C(=O)C(O)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add 217 ml (0.54 mol) of a 2.5 M n-butyllithium solution in hexane dropwise at −78° C. to a solution of 77 ml (56 g, 0.55 mol) N,N-diisopropylamine in 960 ml 1,2-dimethoxyethane in such a way that the temperature does not exceed −60° C. After stirring for 15 min at this temperature, add a solution of 116 g (0.50 mol) (4-ethylphenyl)[(trimethylsilyl)oxy]acetonitrile [D. S. Dhanoa, J. Med. Chem. 1993, 36 (23), 3738-3742] in 373 ml 1,2-dimethoxyethane dropwise in the space of 30 min. Next, after stirring for 30 min at this temperature, add a solution of 64 g (0.50 mol) 2-fluorobenzaldehyde in 373 ml 1,2-dimethoxyethane dropwise in the space of 20 min. Leave the reaction mixture to warm to room temperature in 4 h. After adding 1900 ml satd. aqueous ammonium chloride solution, extract with ethyl acetate. Wash the organic phase with satd. ammonium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation. Add 1900 ml dioxan, 1350 ml methanol and 1560 ml 1 M hydrochloric acid to the residue and stir for 16 h at room temperature. After adding 4000 ml satd. aqueous sodium chloride solution, extract with 2000 ml ethyl acetate. Wash the organic phase with 1000 ml water and 1000 ml satd. sodium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation. Purify the residue by flash chromatography on silica gel (solvent: cyclohexane/ethyl acetate 5:1). Mix the product fraction thus obtained in 80 ml diisopropyl ether and 240 ml petroleum ether, filter, wash with petroleum ether and dry under vacuum. 50 g (85% purity, 33% of theor.) of the title compound is obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[S:10][C:9]([C:11]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](=[O:32])[N:17]([CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:18]3=[O:23])=[O:12])=[CH:8][CH:7]=1.N1C=CC=CC=1>ClCCl.O>[C:1]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[NH:13][C:11]([C:9]3[S:10][C:6]([Cl:5])=[CH:7][CH:8]=3)=[O:12])[C:18]2=[O:23])[CH2:27][CH2:28]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCC(CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Reaction time: 1 h

Procedure:
At room temperature, 17 μl (0.24 mmol) of acetyl chloride are added dropwise to a solution of 50 mg (0.12 mmol) of 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide and 0.1 ml of pyridine in 1 ml of absolute dichloromethane. After 1 h at room temperature, a few drops of water are added and the mixture is diluted with dichloromethane. The mixture is washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on silica gel (dichloromethane/methanol 98:2).
Reaction SMILES: C(Cl)CCl.[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:47]([OH:49])=O)=[CH:16][C:17]=3[N:18]3[CH2:24][C:23]([C:25]4[N:29]([CH:30]5[CH2:32][CH2:31]5)[N:28]=[C:27]([CH:33]([CH3:35])[CH3:34])[C:26]=4[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:22][C:21]4[CH:41]=[C:42]([O:45][CH3:46])[CH:43]=[CH:44][C:20]=4[C:19]=23)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:50][CH:51]([S:53]([NH2:56])(=[O:55])=[O:54])[CH3:52]>CN(C1C=CN=CC=1)C.ClC(Cl)C.CCOC(C)=O>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:47](=[O:49])[NH:56][S:53]([CH:51]([CH3:52])[CH3:50])(=[O:55])=[O:54])=[CH:16][C:17]=3[N:18]3[CH2:24][C:23]([C:25]4[N:29]([CH:30]5[CH2:31][CH2:32]5)[N:28]=[C:27]([CH:33]([CH3:35])[CH3:34])[C:26]=4[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:22][C:21]4[CH:41]=[C:42]([O:45][CH3:46])[CH:43]=[CH:44][C:20]=4[C:19]=23)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1c(C(C)C)nn(C2CC2)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reactant: CC(C)S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)c1c(C(C)C)nn(C2CC2)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C(C)C)cc3n2C1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
EDC (151 mg, 0.790 mmol) was added to a stirring solution of 13-cyclohexyl-6-(1-cyclopropyl-4-(ethoxycarbonyl)-3-isopropyl-1H-pyrazol-5-yl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (320 mg, 0.527 mmol), propane-2-sulfonamide (227 mg, 1.843 mmol), DMAP (193 mg, 1.58 mmol) in dichloroethane (5 mL) at room temperature. The reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, sat NaHCO3 and Brine. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product (375 mg, 0.526 mmol, quant) as a light brown residue consistent by LCMS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:23]>C(Cl)Cl>[C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:6]([Cl:17])=[CH:5][N+:4]([O-:23])=[CH:3][C:2]=2[Cl:1])[CH2:9][CH2:10]1)(=[O:15])[NH2:16]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: OO
Solvent: ClCCl
Product: NC(=O)C1CCN(c2c(Cl)c[n+]([O-])cc2Cl)CC1
Yield: 19.1 %

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (100 mg, 0.36 mmol) and hydrogen peroxide.urea complex (72 mg, 0.77 mmol) in CH2Cl2 (2 mL) cooled to 0° C. was added trifluoroacetic anhydride (0.10 mL, 0.73 mmol). After 30 min the solution was warmed to r.t., after a further 16 hours a saturated solution of Na2S2O5 (10 mL) was added. The mixture was extracted with CH2Cl2 (2×20 mL), the combined organic extracts were washed with a saturated solution of NaHCO3 (20 mL), brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 98:2) to furnish the title compound as a white solid (20 mg, 19%), m.p. 130-133° C.; umax (CHCl3)/cm−1 3026. 2855, 1724, 1452, 1273, 1107.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:22]=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:22]=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)=[CH:31][C:32]#[N:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C(c1ccc2c(c1)OCCO2)c1ccc2c(c1)OCCO2
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC=C(c1ccc2c(c1)OCCO2)c1ccc2c(c1)OCCO2
Yield: 74.7 %

Procedure:
Bis-(2,3-dihydrobenzo[1,4]dioxin-6-yl)methanone (1.12 g, 3.75 mmol), cyanomethylphosphonic acid diethyl ester (1.18 ml, 7.51 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 7.51 ml, 7.51 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give a foam, which was lyophilized to give 3,3-bis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acrylonitrile as an light yellow solid (0.90 g, 75%): mp, 138-140° C.; 1HNMR (DMSO-d6) δ 6.98 (d, J=8 Hz, 1H, Ar), 6.91-6.77 (m, 5H, Ar), 6.08 (s, 1H, double bond proton), 4.33-4.24 (m, 4H, 2CH2CH2); 13C NMR (DMSO-d6) δ 160.4, 145.6, 144.7, 143.2, 143.1, 131.2, 130.0, 122.5, 121.9, 118.6, 117.9, 117.2, 117.1, 116.9, 93.3, 64.3, 64.2, 64.0, 64.0. Anal. Calcd. For C19H15NO4: C, 70.62; H, 4.74; N, 4.33. Found: C, 70.45; H, 4.67; N, 4.20.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][NH:14][CH3:15].C(=O)(O)[O-].[Na+].CO>C(O)(=O)C>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:14]([CH3:15])[CH3:13])=[CH:5]1
Reactant: CNC
Reactant: BrCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 250 mg of 3-(2-bromoethyl)indole in a round-bottomed flask, a 10 M excess of dimethylamine (6 mL of 2M in MeOH) was added and the solution was stirred at r.t. overnight. After adding 5 mL sodium bicarbonate (2%), the reaction mixture was extracted with chloroform (3×5 ml) and back extracted with H2O (1×5 mL). The combined extracts were dried over MgSO4 and evaporation of the solvent gave the product in crystalline form. Yield: 0.21 g, 84%, yellowish crystals. m.p.: 45-47° C.; TLC (EtAc:MeOH:acetic acid, 8:2:0.5 v/v/v): RF=0.33. 1H NMR, δ: 10.43 (s, 1H), 7.42-7.06 (m, 5H), 2.68 (m, 4H), 2.26 (S, 6H). 13C NMR (CDCl3): δ 136.5, 124.3, 123.2, 121.2, 119.7, 117.6, 113.4, 111.1, 61.7, 41.2, 22.4. Anal. calcd for C12H16N2: C, 76.55; H, 8.57; N, 14.88%. Found; C, 76.60; H, 8.70; N, 14.70%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)([O-])[O-].C1(C)C=CC(S([CH2:37][C@H:38]2[NH:42][C:41](=[O:43])[CH2:40][CH2:39]2)(=O)=O)=CC=1>CN(C=O)C>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:37][C@H:38]5[NH:42][C:41](=[O:43])[CH2:40][CH2:39]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CCC(=O)N1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
To a solution of 7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (600 mg, 1.95 mmol), (prepared as described for the starting material in Example 107), in DMF (20 ml) was added powdered potassuim carbonate (540 mg, 3.9 mmol) and (5S)-5-(p-toluene-sulphonylmethyl)-2-pyrrolidinone (580 mg, 2.16 mmol). The reaction was then heated at 100° C. for 4 hours. The inorganic material was filtered off and the DMF removed by evaporation. The residue was then purified by chromatography eluting from methylene chloride to 12% methanol/88% methylene chloride (+1% ammonium hydroxide). The product was evaporated, triturated with ether, and filtered to give (5S)-4-(1H-indol-5-yloxy)-6-methoxy-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (240 mg, 31%) as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[I:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][C:22]1[CH:26]=[CH:25][S:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[I:12][C:13]1[CH:14]=[N+:15]([O-:9])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][C:22]1[CH:26]=[CH:25][S:24][CH:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Ic1cnccc1OCCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc(OCCc2ccsc2)c(I)c1
Reaction time: 18 h
Yield: 96.3 %

Procedure:
m-Chloroperbenzoic acid (1.55 g, 6.29 mmol) was added portionwise to a solution of 1.0 g (3.02 mmol) of 3-iodo-4-(2-(thiophen-3-yl)ethoxy)pyridine in 150 ml of methylene chloride. The mixture was stirred for 18 hours then mixed with 100 ml of 1 M aqueous sodium carbonate. The organic layer was separated and the aqueous one was extracted 2 times with 10 ml of methylene chloride. Combined organic extracts were washed with brine and dried over sodium sulfate. The solution was concentrated in vacuum to give 3-iodo-4-(2-(thiophen-3-yl)ethoxy)pyridine 1-oxide (1.01 g, 92%). MS: (ESI+) 348.0
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=O)[CH3:25])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1ccc(Cl)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(4-chloro-phenyl)-butan-2-one.
Reaction SMILES: CO.O1CCOCC1.[OH:9][C:10]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH2:43][CH2:44][CH2:45][O:46]C(=O)C)[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:12][CH2:11]1.[OH-].[Na+]>O>[OH:9][C:10]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH2:43][CH2:44][CH2:45][OH:46])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:12][CH2:11]1
Reactant: CC(=O)OCCCOc1ccccc1C1(O)CCN(CCC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CN(C)C(=O)C(CCN1CCC(O)(c2ccccc2OCCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
In a liquid mixture of 5 mL of methanol and 5 mL of dioxane was dissolved 180 mg (0.32 mmol) of 4-(4-hydroxy-4-(2-(3-acetoxypropoxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide. To the resulting solution, 5 mL of a 1N aqueous solution of sodium hydroxide was added. The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform, washing with water and drying. The residue obtained by distilling off the solvent was purified by chromatography on a silica gel column, whereby 150 mg (yield: 89.8%) of 4-(4-hydroxy-4-(2-(3-hydroxypropoxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide (Compound No. 25) was obtained.