Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]=[O+][O-]>CO>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=[O+][O-]
Solvent: CO
Product: O=Cc1ccc([N+](=O)[O-])cc1

Procedure:
224 g of p-nitrostyrene are dissolved in 1 liter of methanol and reacted with ozone and subsequently hydrogenated analogously to the procedure indicated in Example 1. The absorption of hydrogen is 31.4 standard liters, corresponding to 93.4% of theory.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CC=CC=1.[C:15]([NH:32][CH2:33][CH:34]([C:36]([OH:38])=[O:37])[OH:35])([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16].O>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:2]([Si:5]([CH3:7])([CH3:6])[O:35][CH:34]([CH2:33][NH:32][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C:36]([OH:38])=[O:37])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(NCC(O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 50 °C
Yield: 96.5 %

Procedure:
TBDMSCl (1.01 g, 6.72 mmol), DMAP (0.19 g, 1.52 mmol) and pyridine (0.97 g, 12.2 mmol) were added to a stirred solution of FMOC-isoserine (1.00 g, 3.05 mmol) in DMF (20 mL). The reaction mixture was heated at 50° C. for 18 hrs. Water (10 mL) was added and the reaction mixture was concentrated in vacuo. DCM and HCl (0.5 M) were added and the two phases were separated. The aqueous phase was extracted two times with DCM. The organic extracts were combined concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with a gradient consisting of 20-100% EtOAc in heptane) to give the title compound (1.3 g). 1H NMR (500 MHz, CDCl3) δ 7.76 (d, 2H), 7.59 (m, 2H), 7.40 (t, 2H), 7.30 (m, 2H), 5.14 (br s, 1H), 4.29 (m, 4H), 3.53 (m, 2H), 0.91 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[C:8](Cl)(=[O:10])[CH3:9].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[CH3:7][C:6]1[CH:5]=[C:4]([C:8]([CH3:9])=[O:10])[S:3][C:2]=1[CH3:1]
Reactant: Cc1ccsc1C
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)c1cc(C)c(C)s1
Temperature: -5 °C
Yield: 99.9 %

Procedure:
A solution of 5 (15.16 g, 135 mmole) and acetyl chloride (9.6 mL, 135 mmole) in 60 mL benzene dried over Na was cooled to −5° C. and vigorously stirred during the addition of a solution of tin (IV) chloride in 50 mL benzene over a period of 1 hour. The reaction mixture was removed from the cold bath and stirred for an additional hour at room temperature. The slow addition of 4 mL concentrated HCI in 28 mL water quenched the reaction. The organic layer was separated, washed with 2×10 mL water, dried over Na2SO4 and evaporated to give 20.8 g of crude product. Chromatography on a column of silica eluted with pet. ethenethyl acetate (10:1) and evaporation of relevant fractions gave a viscous yellow oil, 16.42 g, 79%. 1H NMR (CDCl3) δ:2.08, s, 3H, COCH3; 2.31, s, CH3; 2.41, s, 3H, CH3; 7.33, s, 1H, H-3. 13C NMR (CDCl3) δ: 13.3, 13.7, 26.1, 134.7, 135.3, 139.1, 143.4, 190.0.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: Cc1cccc(O)c1Br
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCC2CC2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
A 250 mL flask with stirbar was charged with 2-bromo-3-methylphenol (2.86 g, 15.3 mmol), (bromomethyl)cyclopropane (1.80 mL, 18.6 mmol) and cesium carbonate (7.46 g, 22.9 mmol) in dimethylformamide (50 mL). The mixture was stirred for 16 hours at ambient temperature and then heated at 50° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate (200 mL) and saturated aqueous sodium chloride (200 mL). The organics were washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (3.7 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][O:19][CH2:20][CH2:21][N:14]3[C@H:13]3[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][C@@H:12]23)[CH:17]=1.[OH-].[NH4+]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:8][C:9]2[CH:10]=[C:11]3[C:15]4=[C:16]([CH2:18][O:19][CH2:20][CH2:21][N:14]4[C@H:13]4[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]34)[CH:17]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: Brc1cccnc1
Agent: [NH4+]
Agent: [OH-]
Product: c1cncc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c1

Procedure:
Using 3-bromopyridine and following the procedures described in EXAMPLE 56, Part C, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into (7bR,11aS)-N-(3-pyridinyl)-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine, bis-trifluoroacetic acid salt. This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 115. LRMS (ES)+: 323.4 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:12])[C:4]([CH:7]1[O:11][CH2:10][CH2:9][O:8]1)([CH3:6])[CH3:5].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(#N)C>[N:13]1([CH2:2][C:3](=[O:12])[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)([CH3:6])[CH3:5])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CC(C)(C(=O)CCl)C1OCCO1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)(C(=O)Cn1ccnc1)C1OCCO1
Yield: 58.1 %

Procedure:
106.8 g (0.55 mol) of 1-chloro-3-(dioxolan-2-yl)-3-methyl-butan-2-one and 74.8 g (1.1 mols) of imidazole in 500 ml of acetonitrile are stirred for 15 hours at 65° C. The solvent is distilled off, the residue is taken up in 800 ml of methylene chloride and the solution is extracted with twice 1 liter of water. The methylene chloride phase is dried over sodium sulphate, and the solvent is distilled off. 71.7 g (57.7% of theory) of 1-(imidazol-1-yl)-3-(dioxolan-2-yl)-3-methyl-butan-2-one are obtained (purity according to gas chromatography 95.4%).
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([N+:35]([O-])=O)[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]>[Pd].C1COCC1.CN(C=O)C>[C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([NH2:35])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)O)CC(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(N(CC(=O)O)CC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 0.6 g of N-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine and 0.2 g of 10% palladium on carbon in 170 ml of THF and 10 ml of DMF was stirred in ahydrogen atmosphere at room temperature until uptake ceased after 4 hours. The reaction mixture was heated to dissolve the precipitated product and the catalyst was removed by filtration. The filtrate was concentrated at reduced pressure and the solid residue was dissolved in THF and the solution was passed through a SEP-PAK silica cartridge (Waters Associates). The eluent was concentrated at reduced pressure to a solid which was triturated with ethyl acetate and filtered to give 0.25 g (44% yield, mp 185°-195°) of N-(carboxymethyl)-N-[3-amino-5-(octadecyloxy)phenyl]glycine. The structurewas confirmed by nmr and mass spectra.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)c(OC)cc21
Yield: 32 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (51 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine were combined to prepare the title compound (32 mgs, 32%) as a white foam. 1H-NMR (CDCl3): δ 10.24 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.85 (d, J=14.4 Hz, 2H), 7.56 (s, 1H), 7.43-7.37 (m, 2H), 7.23 (t, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.53 (s, 1H), 3.91 (s, 3H), 2.68-2.54 (m, 1H), 2.28 (broad s, 2H), 2.17-2.09 (m, 1H), 1.27 (brad s, 2H), 1.18 (t, J=7.1 Hz, 3H). LC/MS: found (M+H)+=504.24; MP: 82-85° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][C:24]#[N:25].[NH2:26][OH:27]>CS(C)=O>[OH:27][N:26]=[C:24]([NH2:25])[CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: NO
Reactant: N#CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: CS(C)=O
Product: NC(CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
To a stirred solution of 3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanenitrile (2.00 g, 6.0 mmol) in dimethyl sulfoxide (15.0 mL) was added hydroxylamine (50% wt solution in water, 1.6 mL, 24 mmol). The reaction was stirred at ambient temperature for 16 h, then the product was precipitated upon addition of water/ethanol (3:1, 100 mL). The solvent was decanted and the remaining solid was triturated in distilled water (75 mL). The solid was filtered and air-dried to afford N′-hydroxy-3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanimidamide as a colorless solid (2.00 g, 91%): MS (ES+) m/z 368.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([O:21]C)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].C([O-])(O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: COc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: O=C(Nc1c[nH]nc1-c1nc2cc(O)ccc2[nH]1)c1c(F)cccc1F
Temperature: 80 °C
Yield: 2.7 %

Procedure:
A mixture of 2,6-difluoro-N-[3-(5-methoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 27) (850 mg) and aluminium (III) chloride (220 mg) in toluene (4 ml) was heated at 80° C. for 3 hours, cooled to ambient temperature and saturated aqueous NaHCO3 (4 ml) followed by 5% aqueous citric acid (4 ml) added. The mixture was extracted with EtOAc and organic extract washed with brine, dried (MgSO4) and reduced in vacuo. Residue submitted for preparative LC/MS to give 2,6-difluoro-N-[3-(5-hydroxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (22 mg) as a beige solid. (LC/MS: Rt 2.01, [M+H]+ 356.09).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][CH:7]=[C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=3)[N:9]=2)[CH2:3][CH2:2]1.CI.[C:21](=O)([O-])[O-].[K+].[K+].[Li+].[OH-].Cl>CN(C=O)C.CO.C1COCC1>[CH:1]1([N:4]([CH3:21])[C:5]2[S:6][CH:7]=[C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=3)[N:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2csc(NC3CC3)n2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: CN(c1nc(-c2ccc(C(=O)O)cc2)cs1)C1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(2-Cyclopropylamino-thiazol-4-yl)benzoic acid (1.98 mmol), methyliodide (4.36 mmol) and potassium carbonate were mixed in DMF (20 mL) and stirred for 72 hours at room temperature. The mixture was concentrated to dryness and partitioned between dichloromethane and water. The organic layer was dried (MgSO4) and concentrated to dryness. This solid was mixed with THF (4 mL), methanol (2 mL) and 1N LiOH (3 mmol) and heated to 50° C. for 1 hour. The mixture was then cooled to room temperature and 1N HCl was added until pH 4. The mixture was concentrated in vacuo, then the obtained residue was redissolved in dichloromethane-methanol and concentrated onto silica. Flash chromatography of the residue (silica gel, dichloromethane-methanol) gave the title compound as an off-white solid (0.1 g), m/z=275.0 in MS ES+, which was characterised by hplc and MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(C#N)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[Mg]I.CC[O:20][CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21](=[O:20])[CH3:22])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: CCOCC
Agent: C[Mg]I
Product: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (163.6 g) in ether (130 ml) was added dropwise over 0.5 hours at ambient temperature under nitrogen to stirred methylmagnesium iodide (3M solution in ether; 300 ml), then the mixture was heated under reflux for 1 hour, diluted with ether (100 ml), heated under reflux for a further 2.5 hours, then stirred at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed well with ether, and added in portions at <20° C. to a stirred mixture of concentrated hydrochloric acid (410 ml) and water (650 ml). The mixture was heated at 95° C. for 0.5 hours with occasional stirring then cooled to ambient temperature. The product was extracted into dichloromethane (3×200 ml), the combined extracts were dried over magnesium sulphate, and the solvent removed in vacuo to leave 1-[1-(3,4-dichlorophenyl)-cyclobutyl]ethanone as a dark red oil (172.7 g) which was used without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[CH:11]=[O:12].[CH3:14][Mg]Br.C(OCC)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[CH:11]([OH:12])[CH3:14]
Reactant: CN(C)c1cnn(C)c(=O)c1C=O
Reactant: C[Mg]Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1c(N(C)C)cnn(C)c1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In THF (10 ml) was dissolved 5-dimethylamino-4-formyl-2-methyl-3(2H)-pyridazinone (362 mg) followed by dropwise addition of 3.0M methylmagnesium bromide/diethyl ether (1.0 ml) with ice-cooling, and the mixture was stirred at 50° C. for 30 minutes. To this reaction mixtrue was added 1N-hydrochloric acid (3 ml) with ice-cooling. Then, saturated aqueous NaHCO3 solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. Yellow oil, 371 mg. 1H-NMR (CDCl3) δ: 1.64(3H,d,J=6.6Hz), 2.94(6H,s), 3.72(3H,s), 4.93(1H,dq,J=6.6&11.4Hz), 5.31(1H,d,J=11.4Hz), 7.66(1H,s).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]1[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]2[CH:2]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) and 2-aminopyridine (47 mg, 0.5 mmol) in ethanol (3.1 mL) was heated under reflux under argon for 3.5 h. Then another portion of 2-aminopyridine (24 mg, 0.25 mmol) was added and heating under reflux continued for another 1 h. The resulting mixture was then cooled to room temperature and then sodium hydrogen carbonate (63 mg, 0.75 mmol) added and the resulting mixture heated under reflux for 2 h. After cooling to room temperature, the mixture was poured onto water and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (76 mg, 55%) which was obtained as a light yellow gum. MS: m/e=276.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:26].[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:24]=[CH:25][C:2]([NH:1][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:32]=2)=[O:39])=[C:3]([F:26])[CH:4]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1C#N
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(S(C)(=O)=O)c4)c(F)c3)c2cc1C#N
Yield: 7.9 %

Procedure:
4-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (106 mg) and phenyl N-(3-(methylsulfonyl)phenyl)carbamate (96 mg) were added to 5 ml of toluene, and then 0.06 ml of diisopropylethylamine was added and the mixture was heated to reflux for 3 hours. After cooling, ethyl acetate was added and the precipitated insoluble portion was filtered out. The filtrate was concentrated, the resulting residue was dissolved in tetrahydrofuran, toluene was added, and the precipitated solid was filtered out to obtain 13 mg of the title compound as light brown crystals (8% yield).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27]C)[CH:25]=4)[C:20](=[O:29])[NH:19][C:18]3=[O:30])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:31]>C(O)(=O)C>[BrH:31].[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=4)[C:20](=[O:29])[NH:19][C:18]3=[O:30])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(=O)[nH]c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: Br
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n(CCCCN2CC=C(c3ccccc3)CC2)c2cc(O)ccc12

Procedure:
A mixture of 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-methoxy-2,4(1H,3H)-quinazolinedione (300 mg) and 47% hydrobromic acid (3.8 ml) in acetic acid (6 ml) was refluxed for 24 hours. After dilution with water, precipitates were collected. A crude crystalline material was recrystallized from ethanol to give 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-hydroxy-2,4(1H,3H)-quinazolinedione hydrobromide (140 mg).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Ni]>[O:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:1])[C:12]=2[O:11][CH2:10]1
Reactant: O=[N+]([O-])c1cccc2c1OCO2
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc2c1OCO2
Reaction time: 4 h
Yield: 63.2 %

Procedure:
To a solution of 4-nitrobenzo[d][1,3]dioxole (2.0 g, 12 mmol) in ethanol (80 mL) was added Raney Ni (ca. 0.5 g). The mixture was stirred under an atmosphere of hydrogen for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography (dichloromethane) to afford the product benzo[d][1,3]dioxol-4-amine (1.04 g, yield 63%). 1H NMR (400 MHz, CDCl3) δ ppm 6.64-6.68 (t, 1H, J=8.0 Hz), 6.29-6.35 (dt, 2H, J=0.8 Hz, 6.4 Hz), 5.90 (s, 2H), 3.52 (br, 2H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21]1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH2:5][CH:6]([CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21]1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CC(=O)SCC(CC1CN(Cc2ccccc2)CCO1)C(=O)Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(NC(=O)C(CS)CC2CN(Cc3ccccc3)CCO2)c1
Reaction time: 1 h
Yield: 33 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-benzyl-2-morpholinyl)-propionyl]amino]benzoic acid (compound of Example 47) (1.0 g) is dissolved in 50% aqueous methanol (20 ml), and the mixture is adjusted to pH 12.0 with 10% aqueous sodium hydroxide solution under nitrogen. After reacting at room temperature for one hour, the reaction mixture is adjusted to pH 4.5 with 10% hydrochloric acid, and methanol is distilled off under reduced pressure. The residue is extracted with ethyl acetate, and the extract is washed with water and ethyl acetate is distilled off. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure and the residue is lyophilized to give the title compound (0.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccccn2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Nc2ccccn2)cc1

Procedure:
The N-(4-nitrophenyl)pyrid-2-amine (5) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.