Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26](O)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[NH:35]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36]1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([N:35]3[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36]3)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Reactant: O[C@H]1CCNC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)N4CC[C@H](O)C4)c3n2)cn1

Procedure:
3-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid (50 mg) was reacted with (S)-pyrrolidin-3-ol via General Procedure F followed by Boc deprotection via General Procedure E to give 10.1 mg 110 as white solid following reverse phase purification. MS (Q1) 440.2 (M)+
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([CH3:46])=[C:34]([NH:36][C:37]([C:39]4[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=4)=[O:38])[CH:35]=3)=[N:25][N:24]2[CH:47]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:1][O:2]/[CH:3]=[CH:4]/[C:5]([NH:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([CH3:46])=[C:34]([NH:36][C:37]([C:39]4[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=4)=[O:38])[CH:35]=3)=[N:25][N:24]2[CH:47]=1)=[O:7]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: CO/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CO/C=C/C(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 28.4 %

Procedure:
In the same manner as in Example 279 and using (2E)-3-methoxyacrylic acid (99 mg, 0.97 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (63 mg, 28%) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:11][C@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12](CC3C=CC=CC=3)[C@H:6]1[CH2:7][CH2:8][C@H:9]2[O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)(=[O:3])[CH3:2].[ClH:42]>CO.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:42].[C:1]([NH:4][C@@H:5]1[CH2:11][C@:10]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:12][C@H:6]1[CH2:7][CH2:8][C@H:9]2[O:26][CH2:27][C:28]1[CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:33]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(=O)N[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
(1R*,2R*,5S*,6R*)-6-Acetamido-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 118; 66 mg, 0.11 mmol) was dissolved in methanol (5 ml) and 2N hydrochloric acid (1 ml) and 10% palladium hydroxide (20 mg) added. The reaction mixture was hydrogenated at 40 psi for 1 hour. The mixture was then filtered and concentrated in vacuo then the oil basified (saturated sodium hydrogen carbonate solution) and extracted with dichloromethane (×3), dried (MgSO4) and concentrated in vacuo to give a clear oil. The oil was purified by thin layer chromatography [10% methanol in dichloromethane] to give a white solid. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1.0M) to a solution in diethyl ether and the title compound-filtered and dried in vacuo at 60° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH3:12]>[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:11][CH3:12]
Reactant: CCc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Product: CCc1ccc(N)cc1Br

Procedure:
In a manner similar to that of Example 1(c), by reacting 34 g (148 mmol) of 1-bromo-2-ethyl-5-nitrobenzene with 33 g (591 mmol) of iron, and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10), 27 g (89%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:19][CH2:20][CH3:21])[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]2[OH:12])=[CH:4][C:3]=1[O:22][CH3:23].F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:19][CH2:20][CH3:21])[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]2[O:12][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCc1cc2cc(OC)c(F)cc2c(O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc2cc(OC)c(F)cc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Temperature: 100 °C
Yield: 68.4 %

Procedure:
7-Fluoro-6-(methyloxy)-2-phenyl-3-propyl-1-naphthalenol (137) (0.42 g, 1.34 mmol) was dissolved in DMF (5 mL). To this solution was added 4-fluorobenzaldehyde (0.34 g, 2.68 mmol) followed by Cs2CO3 (0.57 g, 1.74 mmol). The mixture was heated at 100° C. for 36 h, poured into water (50 mL) and extracted with EtOAc (2×75 mL). The combined organic extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as reddish brown oil. The crude product was purified by flash chromatography over SiO2 eluted with a gradient from hexanes to 15% EtOAc in hexanes to give 0.38 g (69%) of the title compound (138) as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J=7.4 Hz, 3H), 1.40-1.60 (m, 2H), 2.53 (t, J=7.8 Hz, 2H), 4.02 (s, 3H), 6.66 (d, J=8.8 Hz, 2H), 7.06-7.12 (m, 2H), 7.18-7.25 (m, 4H), 7.40 (d, J=12.1 Hz, 1H), 7.56-7.64 (m, 3H), 9.80 (s, 1H). LCMS (ESI): m/z 415 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>>[C:1]([O:9][CH2:10][C:11]([Cl:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COC(=O)c1ccccc1

Procedure:
A mixture of benzoyloxyacetic acid (5.4 g.) and thionyl chloride (50 ml.) was stirred at 70°-80° C. for an hour and then excess thionyl chloride was distilled off under reduced pressure to give benzoyloxyacetyl chloride. A solution of benzoyloxyacetylchloride obtained above in acetone (10 ml.) was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g.) in a mixture of water (16 ml.) and acetone (20 ml.) over 30 minutes interval with stirring under ice-cooling and maintaining carefully the pH at around 7-8, together with by adding dropwise at 5% aqueous sodium bicarbonate solution and stirring was continued for additional 30 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([NH2:19])=[CH:14][CH:13]=3)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.I.CS[C:34]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)=[NH:35].N>CO.C(OCC)C.C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([NH:19][C:34]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)=[NH:35])=[CH:14][CH:13]=3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc2c(c1)cc(-c1ccc([N+](=O)[O-])cc1)n2CCN1CCCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)cc(-c1ccc([N+](=O)[O-])cc1)n2CCN1CCCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.2 %

Procedure:
Compound 17 (250 mg, 0.686 mmol) and anhydrous ethanol (15 mL) were charged to a dry argon purged flask fitted with magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (254.3 mg, 0.891 mmol) is added to the flask and the reaction was stirred under argon at ambient temperature for 48 hours at which time, thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 (developed twice) shows incomplete consumption of 17. A condenser was added and the mixture heated to reflux for 5 hours. An additional amount of the thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.2 eq) was added and stirring continued at 65° C. for an additional 24 hours. A further portion of thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.2 eq) was added and stirring continued for an additional 18 hours at reflux. After cooling to room temperature, the solution was diluted with diethyl ether (150 ml) resulting in the formation of off-white precipitate that was collected on a sintered glass funnel and washed with ether. The solid was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 9-10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 2.5:97.5) to afford orange-yellow solid 18 (69 mg, 21.2%); 1H NMR (DMSO-d6) δ 8.35 (d, 2H, J=8.7 Hz), 7.93 (d, 2H, J=8.7 Hz), 7.73 (d, 1H, J=3.7 Hz), 7.60 (d, 1H, J=5.3 Hz), 7.51 (d, 1H, J=8.6 Hz), 7.10 (m, 1H), 7.07 (s, 1H), 6.80 (d, 1H, J=8.5 Hz), 6.66 (s, 1H), 6.32 (brs, 2H), 4.32 (t, 2H, J=6.5 Hz), 2.49 (m, 2H), 2.21 (m, 4H), 1.31 (m, 6H); ESI-MS (m/z, %): 474 (M+1, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COc1cc2c(cc1Br)CCC2=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)CCC2=O
Temperature: 110 °C

Procedure:
A solution of 5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one (11) (1 g, 4.149 mmol) and morpholine (0.36 g, 4.149 mmol) in toluene 15 mL was added cesium carbonate (2.69 g, 8.298 mmol). The reaction was degassed and purged with nitrogen for 10 min. Pd2(dba)3 (189.3 mg, 0.207 mmol) and BINAP (64.5 mg, 0.103 mmol) was added, degassed and purged and with nitrogen for another 10 min. The reaction was heated to 110° C. overnight under sealed microwave vial. After completion of the starting material, the reaction was diluted with chloroform and filtered through celite bed. The organic layer was concentrated to get the crude compound 13 and the resulting crude was purified through flash chromatography by using 100-200 mesh silica gel eluting the compound at 25% ethyl acetate in hexane as pale yellow coloured solid 6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 13. 1HNMR (400 MHz, CDCl3) δ ppm 7.70 (s, 1H), 7.20 (s, 1H), 3.93 (s, 3H), 3.06 (m, 2H), 2.72 (m, 2H); MS (ESI) m/z 247.9 (M+H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]([CH3:3])([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[C:4]#[CH:5]
Reactant: C1=COCCC1
Reactant: C#CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C#CC(C)(C)OC1CCCCO1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 2-methyl-3-butyn-2-ol (17.0 g, 202.1 mmol) in dichloromethane (200 mL) cooled to 0° C. was added 2,3-dihydropyran (22.0 mL, 258.4 mmol), followed by para-toluenesulfonic acid (10 mg, 0.05 mmol). The mixture was allowed to slowly warm to room temperature over 3 h, then washed with a saturated aqueous solution of sodium bicarbonate, followed by brine, then dried (sodium sulfate), and concentrated to provide 34.0 g (97%) of 2-(1,1-dimethyl-prop-2-ynyloxy)-tetrahydropyran as a clear oil.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:9]1([C:2]2([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:17][CH2:16][CH2:15][O:1]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(c2ccccc2)OCCO1

Procedure:
A solution of ethyl 3-oxo-3-phenylpropanoate (23.74 g) in toluene, ethyleneglycol (23.04 g), and p-toluenesulfonic acid (200 mg) in toluene (300 mL) was stirred under reflux with a Dean-Stark trap for 15 hours. The cooled mixture was poured onto saturated aqueous sodium bicarbonate (100 mL) and the organic layer was washed with water, brine and dried over Na2SO4. Filtration and evaporation of solvent provided the title compound which was used in the next reaction without further purification.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.C([O:16][N:17]=O)CCC>CCOCC>[C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[N:17][OH:16]
Reactant: O=C1CCc2ccccc21
Reactant: CCCCON=O
Agent: Cl
Solvent: CCOCC
Product: O=C1C(=NO)Cc2ccccc21
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of 1-indanone (19.5 g, 0.15 mol) in 200 ml of ether was added 15 ml of concentrated HCl, then a solution of n-butylnitrite (18.75 ml, 0.16 mol) in 50 ml of ether at room temperature. The resulting mixture was stirred for 2 h, the precipitate was collected and dried to yield a white solid (15.4 g, 65% yield). LC-MS: 162 (MH+)
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][C:16]3[C:22]4=[C:23]([NH:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=6)=[C:30]([Cl:42])[CH:29]=5)[N:24]=[CH:25][N:26]=[C:21]4[S:20][C:17]=32)=[N:12]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:42][C:30]1[CH:29]=[C:28]([NH:27][C:23]2[C:22]3[C:16]4[CH2:15][CH2:14][C:13]5[C:18](=[CH:19][N:11]([CH2:10][CH2:9][OH:8])[N:12]=5)[C:17]=4[S:20][C:21]=3[N:26]=[CH:25][N:24]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To 80 mL THF cooled to 0° C. was added 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (2.40 g, 3.9 mmol). To the homogeneous mixture was then added TBAF in THF (1M, 4.3 mL). The dark contents were then stirred with warming to rt over a 1 h period, after which time the solvent was removed under reduced pressure. The crude residue was diluted with water (100 mL) and vigorously stirred. The precipitate formed was collected by filtration and further triturated with ethanol to afford the desired product (1.90 g, 92%) as a light-brown solid. 1H-NMR (DMSO-d6) δ 8.60 (d, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 7.94 (s, 1H), 7.88 (td, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.54 (dd, 1H), 7.38 (t, 1H), 7.24 (d, 1H), 5.29 (s, 2H), 4.94 (t, 1H), 4.12 (t, 2H), 3.74 (q, 2H), 3.39 (t, 2H), 2.93 (t, 2H); LCMS RT=2.32 min; [M+H]+=505.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[CH2:33](O)[CH2:34][CH:35]([CH3:37])[CH3:36]>S(=O)(=O)(O)O>[CH3:36][CH:35]([CH3:37])[CH2:34][CH2:33][O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:2]([NH2:1])[CH:10]=2)=[O:13]
Reactant: Nc1cc2[nH]c(C(=O)O)cc2cc1OCc1ccccc1
Reactant: CC(C)CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)CCOC(=O)c1cc2cc(OCc3ccccc3)c(N)cc2[nH]1
Temperature: 115 °C
Reaction time: 0.17 h

Procedure:
6-Amino-5-benzyloxy-1H-indole-2-carboxylic acid is suspended in isopentanol (10 mL) and concentrated sulfuric acid (10 drops) is added. The mixture is stirred at 115° C. for 10 min and then stirred at 90° C. for 3 h. Ethyl acetate is added and the mixture is neutralized with saturated sodium bicarbonate. The mixture is then washed with saturated NaCl (3×) and water (1×), dried over MgSO4, filtered, and concentrated to afford 6-amino-5-benzyloxy-1H-indole-2-carboxylic acid 3-methyl-butyl ester.
Reaction SMILES: C([O-])=O.[NH4+].Br[C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1>C(O)C.[Pd]>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]=1[CH2:13][O:12][C:9]1[N:8]=[N:7][CH:6]=[CH:11][CH:10]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Br)nn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1COc1cccnn1
Temperature: 40 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
Ammonium formate (0.20 g, 3.2 mmol) was added to a solution of 3-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine (0.54 g, 1.6 mmol) in ethanol (8 mL). The reaction flask was flushed with argon. Palladium on charcoal (10%, 0.05 g) was added and the mixture was heated to 40° C. After 16 h, additional ammonium formate (0.20 g, 3.2 mmol) and palladium on charcoal (10%, 0.05 g) was added and the mixture was heated to 40° C. for another 24 h. The mixture was filtered, concentrated and extracted (ethyl acetate/sodium bicarbonate solution). The organic layer was dried over sodium sulfate, concentrated and chromatographed (SiO2, heptane:ethyl acetate=100:0 to 60:40) to afford the title compound (160 mg, 38%) as a colorless oil. MS: m/e=268.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[CH:12][C:13]=1[C:14]#[N:15].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29].O>CN(C)C=O>[NH2:29][C:28]1[N:30]=[C:16]([C:11]2[NH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:13]([C:14]#[N:15])[CH:12]=2)[CH:17]=[CH:18][N:27]=1
Reactant: CN(C)/C=C/C(=O)c1cc(C#N)c(-c2ccc(Cl)cc2Cl)[nH]1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccnc(N)n2)[nH]c1-c1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 22 h
Yield: 83 %

Procedure:
To a suspension of 2-(2,4-dichloro-phenyl)-5-((E)-3-dimethylamino-acryloyl)-1H-pyrrole-3-carbonitrile (6.80 g, 20.35 mmol) in 82 mL of N,N-dimethylformamide was added guanidine carbonate (9.17 g, 101.75 mmol). The mixture was heated to 110° C. for 18 hours under efficient stirring. Then, a further amount of guanidine carbonate (1.83 g; 20.35 mmol) was added to the mixture and heating to 115° C. was prolonged for additional 22 hours. The resulting mixture was diluted by dropwise addition of 325 mL of water over 30 minutes. The solid was isolated by filtration, washed with 100 mL of water, dried in the air and, finally, in a vacuum oven at 60° C. affording 5.58 g of product as a light brown powder. Yield=83%.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][NH2+:9][CH2:10][S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.[Br:40][C@@H:41]([C@H:45]([OH:47])[CH3:46])[C:42](O)=[O:43]>>[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]([CH2:10][S:11][C:12]([CH3:14])([CH3:13])[CH3:15])[C:42](=[O:43])[C@@H:41]([Br:40])[C@H:45]([OH:47])[CH3:46])=[CH:6][CH:5]=1
Reactant: C[C@@H](O)[C@H](Br)C(=O)O
Reactant: COc1ccc(C[NH2+]CSC(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COc1ccc(CN(CSC(C)(C)C)C(=O)[C@@H](Br)[C@@H](C)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In succession, 2.76 g (10 mmol) of p-methoxybenzyl-tert.-butylthiomethylammonium chloride (Example 24), 2.06 g (10 mmol) of dicyclohexyl carbodiimide and, dropwise, 1.40 ml (10 mmol) of triethylamine are added at room temperature to a solution of 1.83 g (10 mmol) of 2-(S)-bromo-3-(R)-hydroxybutyric acid prepared analogously to a method of Shimohigashi Y. et al., Bull. Chem. Soc. Japan 52, 949 (1979). The resulting reaction mixture is stirred at room temperature for 2 hours. The dicyclohexylurea that has precipitated is filtered off with suction and the filtrate is diluted with methylene chloride and washed with water and phosphate buffer solution having a pH of 8. The organic phase is dried over sodium sulphate and concentrated by evaporation and the oily residue is chromatographed over silica gel using toluene/ethyl acetate. The title compound is obtained in the form of a colourless, viscous oil.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:24](OCC)[CH2:25][CH2:26][CH2:27][NH2:28])C>CCO>[CH3:17][N:13]1[C:14]2=[C:15]3[N:28]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18])[CH2:27][CH2:26][CH:25]=[CH:24]3
Reactant: CCOC(CCCN)OCC
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C=CCC3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C), (1.169 g, 3.47 mmol) in EtOH (20 mL) was treated with 4,4-diethoxybutan-1-amine (0.659 mL, 3.81 mmol) and TEA (0.966 mL, 6.93 mmol) and the mixture heated at reflux for 50 min. The reaction mixture was cooled to RT and evaporated under reduced pressure. The residue was re-dissolved in THF (20 mL), 1M hydrochloric acid (3.47 mL) was added and the mixture stirred at RT for 1.5 h. The reaction mixture was diluted with EtOAc, washed with water, brine and the organic phase was dried over sodium sulphate and evaporated under reduced pressure. The residue was triturated with DCM/hexane and the precipitate collected by filtration to give the title product as a pale pink solid.
Reaction SMILES: [C:1](O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]1[C:16]2C=CC=C[C:15]=2C=CN1>>[NH:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[CH:15][C:16]1=[O:11]
Reactant: C1=Cc2ccccc2ON1
Reactant: Nc1ccccc1C(=O)O
Product: O=c1ccc2ccccc2[nH]1

Procedure:
The required 1-H-4-quinolones for the above reactions were prepared in a similar way to that described in Example 6. The appropriate anthranilic acid was converted to the benzoxazine X which was then converted to the β-ketosulphoxide XI which then underwent ring closure to give the 1-H-quinolone XII ##STR11##
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCCO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(OCCCCO)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of 1,4-butanediol (18 ml, 0.2 mmol) in pyridine (16 ml), was added slowly at 0° C., under a nitrogen atmosphere, benzoyl chloride (1 ml), 0.1 mmol). After 4 h under stirring at 0° C., the reaction medium was concentrated and the pyridine was eliminated by co-distillation with toluene. The residue was extracted with ether (3×20 ml) and the organic phase was dried (magnesium sulfate), concentrated, and subjected to a flash column chromatography on silica gel (petroleum ether/ethyl acetate 3:2) to give the 4-hydroxybutyl benzoate (9.9 g, 55%) in the form of a colorless oil.