Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[C:18]([O:22][C:23](=[O:26])[CH2:24][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccccc21

Procedure:
44.1 g (0.3 mol) of isatin, 62.5 g (0.45 mol) of potassium carbonate and 66.2 g (0.34 mol) of bromoacetic acid tert-butyl ester (from Aldrich) are stirred in 100 ml of N,N′-dimethylformamide at room temperature for 24 hours. The mixture is then poured into 800 ml of water, and the precipitate formed is filtered off, washed with water and dried at 60° C. After recrystallising once from toluene-hexane (1:1), 608 g (78% of theory) of product having a melting point of 119-121° C. are obtained.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([N:17]3[CH2:25][CH2:24][CH2:23][C@@H:18]3[C:19]([O:21]C)=[O:20])[CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[CH:26]1[C:39]2[C:38](=[O:40])[CH2:37][C:36]([CH3:42])([CH3:41])[CH2:35][C:34]=2[O:33][C:32]2[CH2:31][C:30]([CH3:44])([CH3:43])[CH2:29][C:28](=[O:45])[C:27]1=2.C1COCC1.O.O>C(OCC)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([N:17]3[CH2:25][CH2:24][CH2:23][C@@H:18]3[C:19]([OH:21])=[O:20])[CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[CH:26]1[C:27]2[C:28](=[O:45])[CH2:29][C:30]([CH3:43])([CH3:44])[CH2:31][C:32]=2[O:33][C:34]2[CH2:35][C:36]([CH3:42])([CH3:41])[CH2:37][C:38](=[O:40])[C:39]1=2
Reactant: COC(=O)[C@H]1CCCN1c1cccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cccc(N3CCC[C@@H]3C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
Lithium hydroxide (16.9 mg, 403 μmol) was added to a solution of the methyl 1-{6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridin-2-yl}-D-prolinate obtained in Example 15-2 (157 mg, 269 μmol) in a mixed solvent of THF/water (2:1, v/v) (3 mL) at room temperature. The mixture thus obtained was stirred at the same temperature as above for 30 minutes, and was further stirred at 60° C. for 1 hour. Thereafter, water and diethyl ether were added to the reaction solution, and the mixed solution was then extracted with water twice. The resultant was washed with diethyl ether. Thereafter, 1 N hydrochloric acid was added to the water layer thus obtained, so that the pH was adjusted to pH 4 or lower, and the mixed solution was then extracted with ethyl acetate three times. The organic layer thus obtained was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The residue obtained was crystallized from hexane/ethyl acetate to obtain the title compound (107 mg, yield: 70%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=N)=[CH:6][CH:5]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.C[N:21](C=O)C.Cl>CC(C)=O.N1C=CC=CC=1>[ClH:1].[NH2:21][N:10]=[CH:8][C:7]1[CH:6]=[CH:5][C:4]([NH:3][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: N=C(N)c1ccc(N)cc1
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.2 g of 4-aminobenzamidine dihydrochloride, 1.1 g of succinic anhydride and 10 mL of DMF was stirred at ambient temperature for 15 min at which time 0.83 mL of pyridine was added all at once. The resulting heterogeneous mixture was warmed to 100° C. and maintained at 100° C. for 1.5 h. The disappearance of starting material was monitored by an in-process check using HPLC Method B. After cooling to 0° C., a solution of 8 wt % concentrated HCl in acetone was added slowly while maintaining the temperature at 0° C. After the addition of additional acetone, the resulting milky suspension was stirred for 30 min and the solids were collected by vacuum filtration. The solids were then washed twice each with aq 0.5M HCl followed by acetone and were dried in a vacuum oven at 30°-40° C. to afford 2.4 g (88% molar yield) of the title compound. Acceptance testing was performed on the product using HPLC Method B to determine the presence of the title product. λmax (CH3OH) 281 nm; (0.1% H3PO4 in water) 203, 270 nm; IR (KBr): 1736 (C=O), 1674 (C--N, C=N), 1599 (C=N) cm-1 ; DSC endotherms at 167° C. and 275° C.; 1H NMR: (d6 -DMSO) δ 12.15 (s, 1H), 10.55 (s, 1H), 9.23 (s, 2H), 9.0 (s, 2H), 7.81 (s, 4H), 3.31 (s, 3H), 2.62 (m, 2H), 2.55 (m, 2H) ppm; 13C NMR: δ 173.6, 171.0, 164.8, 144.3, 129.1, 121.2, 118.3, 31.2, 28.6 ppm; Anal calcd for C11H14N3O3Cl.0.25 H2O: C, 47.83, H, 5.29; N, 15.21; Cl, 12.84; Found: C, 47.68; H, 5.02; N, 15.23; Cl, 12.92.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[Cl:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7](Cl)[N:6]=1>C1COCC1.CCOC(C)=O.O>[Cl:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([S:3][CH2:1][CH3:2])[N:6]=1
Reactant: CCS
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1cc(C(=O)OC)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of ethanethiol (0.30 g, 4.8 mmol) in THF (1 ml) was added dropwise to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (1 g, 4.8 mmol), THF (8 ml) and TEA (0.49 g, 4.8 mmol) at 0° C. under nitrogen. The mixture was stirred for 2 h and slowly warmed to room temperature. The mixture was diluted with EtOAc (50 ml) and water (10 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].Br[CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([N:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]1=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: COc1cc[nH]c(=O)c1C#N
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1ccc(OC)c(C#N)c1=O
Temperature: 110 °C
Yield: 99.9 %

Procedure:
To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (20 g, 133 mmol) in acetonitrile (800 ml) were added 1-bromobutane (15.8 ml, 146 mmol) and potassium carbonate (36.7 g, 266 mmol) and the mixture was heated at 110° C. for 24 hours. The mixture was cooled to room temperature and the solid was filtered off The filtrate was evaporated till dryness and the resulting crude residue was then triturated with diethylether to yield pure intermediate 4 (27.39 g, >99%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].C([O:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:22][C:23]1[C:24]([CH3:31])=[C:25]([CH3:30])[C:26](=[O:29])[NH:27][NH+:28]=1)=[O:17])[CH3:15])=O)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:35][C:34]1[CH:33]=[CH:32][C:21]([CH2:22][C:23]2[C:24]([CH3:31])=[C:25]([CH3:30])[C:26](=[O:29])[NH:27][NH+:28]=2)=[CH:20][C:19]=1[N:18]1[C:16](=[O:17])[CH:14]([CH3:15])[NH:13][C:11]1=[O:10]
Reactant: CCOC(=O)N[C@@H](C)C(=O)Nc1cc(Cc2[nH+][nH]c(=O)c(C)c2C)ccc1F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: Cc1c(Cc2ccc(F)c(N3C(=O)NC(C)C3=O)c2)[nH+][nH]c(=O)c1C
Temperature: 180 °C

Procedure:
To a solution of O2 in DMF (0.1 M) was added DMAP (3 eq) and the mixture was heated in a microwave oven at 180° C. for 2 h. The product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents. The desired fractions were lyophilized to afford the desired compound. 1H NMR (300 MHz, DMSO-d6) δ: 12.67 (1H, s), 8.52 (1H, s), 7.35-7.28 (2H, m), 7.25-7.18 (1H, m), 4.36-4.26 (1H, m), 3.97 (2H, s), 2.06-1.97 (6H, m), 1.38-1.31 (3H, m). MS (ES) C17H18FN4O3 requires: 344. found: 345 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3]([C:20]([OH:22])=[O:21])=[C:4]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cn1c(C(=O)O)c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ccc21

Procedure:
The title compound was prepared from ethyl 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzene sulfonyl chloride followed the procedures of Example 1 Step 2 & Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 1.25 (s, 9H, 3.94 (s, 3H, 7.00-7.10 (m, 1H, 7.10-7.27 (m, 3H, 7.27-7.45 (m, 3H, 7.45-7.62 (m, 5H, 9.86 (s, 1H), 12.97 (br s, 1H; MS (ESI) m/z 461 [M-H]−; HRMS calcd for C26H27N2O4S: 463.1689; found (ESI+): 463.1681; Anal. calcd for C26H26N2O4S.0.15H2O: C, 67.12; H, 5.70; N, 6.02. Found: C, 67.05; H, 5.42; N, 5.88.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH2:11]C)([CH2:9]C)[CH3:8])[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:15]=[C:16]([F:23])[C:17]([O:21][CH3:22])=[C:18]([OH:20])[CH:19]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:28]=O.C(=O)C1C=CC=CC=1>C(O)(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[C:15]3[C:16]([F:23])=[C:17]([O:21][CH3:22])[C:18]([OH:20])=[CH:19][C:14]=3[C:3]3[C:4]([CH3:13])=[N:5][N:6]([C:7]([CH3:9])([CH3:8])[CH3:11])[C:2]=3[N:1]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCC(C)(CC)n1nc(C)c(-c2cc(O)c(OC)c(F)c2)c1N
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Solvent: CC(=O)O
Solvent: O=Cc1ccccc1
Product: COc1c(O)cc2c(c(-c3ccc(OCc4ccccc4)c(Cl)c3)nc3c2c(C)nn3C(C)(C)C)c1F
Temperature: 90 °C
Reaction time: 7 h
Yield: 44.4 %

Procedure:
5-[5-Amino-1-(1,1-diethylethyl)-3-methyl-1H-pyrazol-4-yl]-3-fluoro-2-(methyloxy)phenol (2.2 g, 7.5 mmol.) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (2.23 g, 8.6 mmol.) were taken into acetic acid (25 mL) and the resulting mixture heated to 90° C. over 12 hours. An additional aliquot of benzaldehyde (250 mg) was then added and heating was continued an additional 7 hours. At this time air was bubbled through the solution at a steady rate while maintaining a temperature of 90° C. then the mixture was allowed to cool to room temperature. The acetic acid was removed and the residue partitioned with saturated aquyeous sodium hydrogencarbonate and ethyl acetate. The organic layer was then washed once with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give a residue containing roughly a 1:1 mixture of two cyclization products. The desired cyclization isomer was purified by silica gel flash chromatography using 2:1 hexanes ethyl acetate as eluent to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6-fluoro-1-methyl-7-(methyloxy)-3H-pyrazolo[3,4-c]isoquinolin-8-ol (1.73 g, 44% yield) as a yellow solid after concentration and drying of the pure fractions in vacuo. 1H NMR (400 MHz, CDCl3): 7.66 (dd, 1H), 7.59 (d, 1H), 7.54 (d, 1H), 7.46-7.34 (m, 5H), 7.07 (d, 1H), 6.54 (s, 1H), 5.25 (S, 2H), 4.03 (d, 3H), 2.80 (s, 3H), 1.83 (s, 9H); MS (EI) for C29H27N3O3FCl: 520 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:23](=[O:24])[CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCc1ccccc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a mixture of 3-chloroaniline (8.3 ml, 78.4 mmol), DMAP (1.0 g, 7.8 mmol), and pyridine (6.9 ml, 86.2 mmol) in anhydrous DCM (150 ml) at 0° C., was added 3-phenylpropionyl chloride (12.8 ml, 86.2 mmol). The mixture was warmed to ambient temperature and stirred under N2 overnight. Excess DCM was added to the reaction mixture. The organic layer was washed with 1N HCl (3×), saturated NaHCO3 (3×), brine, dried over MgSO4, and the solvent was removed in vacuo to yield 21.6 g of N-(3-chlorophenyl)-3-phenylpropanamide 21 as a peach colored crude solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:10]3[C:11]4[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH3:14])[C:7]=4[N:8]=[CH:9]3)=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CCn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.7 %

Procedure:
In DMF (10 ml) was dissolved 1-ethyl-3-methylxanthine (385 mg), a production process for which is described in Journal of American Chemical Society 75, 114, 1953. To this solution were added potassium carbonate (415 mg) and 4-(4-chlorobenzoyl)benzyl bromide (619 mg) and the mixture was stirred at room temperature for 14 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:4) and recrystallized (ethyl acetate-ether-hexane) to provide the title compound as white powder (207 mg, 25%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][O:75][CH2:76][CH2:77][NH2:78]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:78][CH2:77][CH2:76][O:75][CH3:74])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: COCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (100 mg, 0.24 mmol), PyBOP® (125 mg, 0.24 mmol), DIEA (125 μL, 0.72 mmol) in CH2Cl2:DMF (4 mL:0.5 mL) stirred at RT for 10-15 minutes. To this solution of activated acid was added 2-methoxyethanamine (21 μL, 0.24 mmol) and the reaction mixture was stirred at RT for 3 h. Concentrated in vacuo and the crude product was purified using prep HPLC (method 10-35—90 mins) and was further washed with ethyl ether and drops of CH2Cl2 to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methoxyethyl)acetamide. (25 mg, 0.053 mmol, 22%)
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH2:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Br[CH:23](Br)[CH3:24]>C1(C)C=CC=CC=1.C1COCC1>[CH3:4][C:3]1[CH:21]([CH2:23][CH2:24][CH:15]2[C:14]3[C:9](=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:11]=[CH:12][CH:13]=3)[CH:8]=[C:7]2[CH3:6])[C:20]2[C:1]([CH:2]=1)=[C:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)[CH:17]=[CH:18][CH:19]=2
Reactant: CC1=Cc2cccc(-c3ccccc3)c2C1
Reactant: CC(Br)Br
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccccc3)cccc2C1CCC1C(C)=Cc2c(-c3ccccc3)cccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
90 cm3 (0.24 mol) of a 20 % strength solution of butyl-lithium in toluene were added at room temperature under argon to a solution of 50 g (0.24 mol) of 3 in 500 ml of THF. The mixture was stirred at 60° C. for 2 hours, and cooled to -78° C., 22.5 g (0.12 mol) of dibromoethane were added, and the mixture was warmed to room temperature over the course of 18 hours. The reaction mixture was washed with 50 cm3 of H2O, the solvent was removed in vacuo, and the residue was chromatographed on 500 g of silica gel (hexane/methylene chloride 9:1), giving 2.5 g (5%) of 32 as a yellow oil which solidified slowly at -20° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([C:12]2[C:11]([CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[CH2:8][CH3:9])=[CH:16][C:15]([CH3:17])=[CH:14][N:13]=2)[CH:26]=1)[CH3:21]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(C)cnc1Cl)C(=O)OC(C)(C)C
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 6, using the following starting materials: (2-chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-carbamic acid tert-butyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].O>CN(C=O)C>[N+:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:23])=[O:22]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To phenol (6.5 g) in 20 ml DMF at room temperature was added K2CO3 (20 g) and this mixture stirred for 15 minutes at room temperature. Then 4-chloro-3-nitropyridine (10.0 g) in 60 ml DMF was added dropwise and the mixture stirred for two hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH2:21]1[CH:25]2[CH2:26][NH:27][CH2:28][CH:24]2[CH2:23][N:22]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C(O)(C)C>[C:15]([O:14][C:12]([NH:10][C@H:9]([CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=1)[CH2:11][N:27]1[CH2:26][CH:25]2[CH2:21][N:22]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:23][CH:24]2[CH2:28]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: O=C(OCc1ccccc1)N1CC2CNCC2C1
Reactant: CC(C)(C)OC(=O)N1C[C@H]1COc1ccc(C#N)cc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 56 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
tert-Butyl (2S)-2-[(4-cyanophenoxy)methyl]aziridine-1-carboxylate (2.5 g, 9.1 mmol; see step (f) above) and benzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.24 g, 9.1 mmol; see step (h) above) was dissolved in isopropanol (30 mL) and was stirred at 56° C. for 24 h. The solvent was then evaporated. The product was purified by chromatography on silica (ethyl acetate, 0–5% MeOH eluant), giving 3.8 g (80%) of the sub-title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:13]=[N:12][C:11]2[N:10]3[CH2:14][CH2:15][CH2:16][CH:9]3[CH2:8][C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[N:18]1([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CS(C)=O>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:21]3[CH2:20][CH2:19][N:18]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[CH2:23][CH2:22]3)[CH:13]=[N:12][C:11]=2[N:10]2[CH2:14][CH2:15][CH2:16][CH:9]2[CH2:8]1
Reactant: O=C1CC2CCCN2c2ncc(CO)cc2N1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCC#N
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)CC3CCCN43)CC2)cc1
Temperature: 90 °C
Yield: 72 %

Procedure:
3-(hydroxymethyl)-7a,8,9,10-tetrahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one (100 mg, 0.429 mmol), 4-(piperazin-1-yl)benzonitrile (96 mg, 0.514 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.685 mmol) and N,N-diisopropylethylamine (0.374 mL, 2.141 mmol) were suspended in propiononitrile (Volume: 2 mL) and heated in a closed vial at 90° C. for 5 h. The reaction mixture was cooled, diluted with DMSO (2 mL) and purified using preparative HPLC (basic phase, 25-95% ACN). The fractions containing product were concentrated in vacuo and crystallized from water (5 mL). The precipitate was filtered and dried in vacuum to afford 4-(4-((6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-3-yl)methyl)piperazin-1-yl)benzonitrile (124.2 mg, 0.309 mmol, 72.1% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.65 (m, 1H) 1.72-1.86 (m, 1H) 1.87-1.97 (m, 1H) 2.14 (qd, J=5.81, 4.04 Hz, 1H) 2.40-2.48 (m, 4H) 2.52-2.59 (m, 1H) 2.66 (dd, 1H) 3.30 (br. s., 4H) 3.33-3.40 (m, 2H) 3.45-3.54 (m, 1H) 3.66 (td, J=10.61, 6.82 Hz, 1H) 3.88 (td, J=9.47, 6.06 Hz, 1H) 7.00 (d, J=9.35 Hz, 2H) 7.14 (d, J=2.02 Hz, 1H) 7.57 (d, J=9.09 Hz, 2H) 7.75 (d, J=2.02 Hz, 1H) 9.56 (d, 1H). [M+H] calc'd for C23H26N6O, 402; found, 402.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1([CH3:27])[CH2:26][C:24](=O)[CH2:23][C:21](=[O:22])[CH2:20]1.[NH2:28][C:29]1[NH:33][N:32]=[C:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:30]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:23]4[C:21](=[O:22])[CH2:20][C:19]([CH3:18])([CH3:27])[CH2:26][C:24]=4[NH:28][C:29]4[NH:33][N:32]=[C:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:30]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(C)(C)OC(=O)c1cc(N)[nH]n1
Reactant: O=C/C=C/c1ccc(-c2cccc(F)c2)cn1
Product: CC1(C)CC(=O)C2=C(C1)Nc1[nH]nc(C(=O)OC(C)(C)C)c1C2/C=C/c1ccc(-c2cccc(F)c2)cn1

Procedure:
The title compound is prepared according to procedure A from 620 mg of (E)-3-[5-(3-fluorophenyl)pyridin-2-yl]propenal, 383 mg of dimedone and 500 mg of tert-butyl 5-amino-1H-pyrazole-3-carboxylate.