Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37]C1C=CC=C2C=1OC(C1C=CC=CC=1)=C(I)C2=O>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([Br:37])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(Br)cccc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Yield: 67 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-bromo-3-iodo-2-phenyl-chromen-4-one was reacted to give the title compound (73 mg, 67%). 1H NMR (400 MHz, CDCl3): δ 8.24 (dd, J=7.9 and 1.6 Hz, 1H), 7.94 (dd, J=7.7 and 1.5 Hz, 1H), 7.50 (d, J=7.0 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.36-7.19 (m, 6H), 5.06 (s, 1H), 2.60-2.47 (m, 4H), 2.14-2.01 (m, 1H), 1.91-1.77 (m, 1H), 1.37 (bs, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:21]=1[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:20]=2[O:19][CH3:18])[N:7]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(CC2CCCCO2)n1
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)cc1C(=O)Nc1cc(C(C)(C)C)nn1CC1CCCCO1
Temperature: 60 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
To a solution of Example 63C (0.73 g, 3.1 mmol) in tetrahydrofuran (20 mL) were added 2-methoxy-5-(trifluoromethyl)benzoic acid (0.68 g, 3.1 mmol, JRD Fluorochemicals), 1-hydroxybenzotriazole (0.47 g, 3.1 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (0.59 g, 3.1 mmol) and triethylamine (1.3 mL, 9.2 mmol). After stirring at 60° C. for 16 hours, the reaction mixture was cooled and quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to provide 0.2 g of the title compound. MS (ESI+) m/z 440 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:30][C:31](=[O:43])[C:32]([NH:35]C(=O)OC(C)(C)C)([CH3:34])[CH3:33])[C:11]([N:13]1[CH2:17][CH2:16][C:15]2([CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][N:19]([CH3:28])[C:18]2=[O:29])[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:35][C:32]([CH3:34])([CH3:33])[C:31]([NH:30][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([N:13]1[CH2:17][CH2:16][C:15]2([CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][N:19]([CH3:28])[C:18]2=[O:29])[CH2:14]1)=[O:12])=[O:43]
Reactant: CN1CC(c2ccccc2)C2(CCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CC(c2ccccc2)C2(CCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of tert-butyl 1-((2R)-3-(benzyloxy)-1-(7-methyl-6-oxo-9-phenyl-2,7-diazaspiro[4.4]nonan-2-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (step 3) (206.5 mg) in DCM (4 mL) was treated with TFA (537 uL, 6.97 mmol). The reaction mixture was stirred at room temperature for 2 days. A further portion of TFA (2 ml) was added and stirring continued for 20 minutes. The mixture was concentrated in vacuo to afford a colourless oil. The oil was dissolved in MeOH and applied to a 10 g pre-wetted (MeOH) SCX-2 cartridge. The column was washed with MeOH (70 mL) and the product was eluted with 2M NH3 in MeOH (70 mL). The clean fractions were concentrated in vacuo to afford a colourless oil. The oil was further purified by mass-directed LC-MS to afford the title compound;
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:24]=[N:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: BrCc1cccnc1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1sc(Br)cc1NCc1cccnc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (100 mg, 1.51 mmol), 3-(bromomethyl)pyridine hydrobromide (457 mg, 1.81 mmol), cesium carbonate (1.72 g, 5.29 mmol) and DMA (15 mL) was stirred at 80° C. for 2 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (5 mL). To the solution were added potassium carbonate (500 mg) and water (2.5 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 50:50 hexane/EtOAc) to give the title compound (260 mg, 53%) as a yellow solid:
Reaction SMILES: [C:1]1([CH2:7][C:8]([C@@H:10]2[CH2:14][CH2:13][CH2:12][O:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32]>C(O)C.Cl>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][O:11]3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)[C@@H]1CCCO1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC([C@@H]3CCCO3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 8.8 %

Procedure:
To a mixture of (S)-2-phenyl-1-(tetrahydrofuran-2-yl)ethanone (Intermediate 93) (150 mg, 0.8 mmol), 3-ethoxy-4-hydroxy-5-nitro-benzaldehyde (200 mg, 0.9 mmol), and urea (142 mg, 2.4 mmol) in absolute ethanol (3 mL) was added conc. HCl (one drop). The mixture was refluxed under N2 for 3 hrs. The reaction mixture was concentrated in vacuo, and was purified by silica gel column chromatography (PE:EtOAc=10:1 to PE:EtOAc=1:2) and prep-HPLC (0.1% TFA as additive) to give Compound 175 (30 mg, yield 9%). 1H NMR (DMSO 400 MHz): δ 10.28-10.16 (m, 1H), 7.65-7.45 (m, 0.5H), 7.40-7.17 (m, 4.5H), 7.10-7.03 (m, 1.5H), 6.98-6.95 (m, 0.5H), 5.38-5.36 (s, 0.5H), 5.16-5.08 (m, 0.5H), 4.30-4.20 (m, 0.5H), 4.10-3.85 (m, 3H), 3.62-3.53 (m, 0.5H), 2.21-1.65 (m, 3.5H), 1.31-1.19 (m, 3H); MS (ESI): m/z 426.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C1(C)C=CC=CC=1.[SH-].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [SH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
1-Bromo-3,5-dinitrobenzene (14.77 g, 59.8 mmol) was dissolved in methanol (150 mL) and toluene (374 mL) and a solution of sodium hydrosulfide (10.06 g, 179 mmol) in water (10 mL) and methanol (150 mL) was added dropwise over a period of 60 minutes. The reaction was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and then extracted 3 times with ethyl acetate. The organic layers were combined, washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The crude material required no further purification to yield 12.93 g (59.6 mmol, 100%) of 3-bromo-5-nitroaniline.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(F)c1Br
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1cccc(F)c1Br
Yield: 96 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (6.5 g, 34.17 mmol) and pyridine (2.7 g, 34.17 mmol) in 20 ml of CH2Cl2, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH2Cl2 are added dropwise and mixture was refluxed for 30 min. The reaction mixture is diluted with CH2Cl2, the organic layer washed with diluted HCl, saturated Na2CO3 solution, water, and dried (Na2SO4). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide. To a solution of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide (10.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130° C. AlCl3 (21.9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76%). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1H-quinolin-2-one are refluxed in 30 mL of POCl3 during 2 h, then poured on ice, extracted with benzene, the benzene extract dried (Na2SO4) to yield 6.1 g 8-bromo-2-chloro-7-fluoroquinoline after solvent removal. To a mixture of 10 ml 10%-oleum and 1.4 g (22.2 mmol) of fuming HNO3 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is added portionwise. The mixture is heated at 100° C. for 2 h. Additional HNO3 (0.17 g) is added and stirred for additional 1 h. The reaction mixture is poured in ice-water, extracted with EtOAc, filtered through silica gel, and crystallized from heptane-toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100° C. for 5 h in a solution containing 16 ml of CH3COOH, 3.2 ml of H2O and 5 ml of conc. HCl. The mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one. To a suspension 1.7 g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one and 2.3 g (35.5 mmol) of HCOONH4 in 10 ml of ethanol 0.1 g 10% Pd—C are added, and stirred for 2 h at 60° C. A solid disappeared and then formed again. The precipitate is filtered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to the eluate, the precipitate is filtered off and dried to yield 0.5 g (47%) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-d6); δ=6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:22])[C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(Cl)(=O)C(Cl)=O.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][NH2:43])=[CH:37][CH:36]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:22])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:43][CH2:42][CH2:41][C:38]3[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)NCCc3ccc(Cl)cc3)cc1)c2Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
4-(6,8-Dichloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (22.96 g, 55.832 mmol) was dissolved in dichloromethane (200 ml) and DMF (0.2 ml). Oxalyl chloride (8.6 ml, 98.585 mmol) was added slowly over a period of 30 minutes at ambient temperature. The crude mixture was concentrated under reduced pressure. Dry dichloromethane (200 ml) was added and the mixture was cooled in an ice bath. 2-(4-Chlorophenyl)ethylamine (8.5413 ml, 61.415 mmol) and diisopropylethylamine (11.701 ml, 66.999 mmol) were added sequentially to the mixture. The mixture was stirred in an ice bath for 10 minutes and warmed to ambient temperature. The crude mixture was washed with 1N HCl (100 ml), water (2×50 ml), and brine (50 ml), dried over MgSO4, filtered through GF paper, and concentrated to provide 30.1 g of a light brown solid after drying under high vacuum for 2 hours. The crude solid was recrystallized from hot EtOAc-hexanes to provide 26.8 g of the title compound as a light brown solid (87%).
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2(OCC[O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([OH:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].O1CCCC1.Cl>O>[OH:37][C:25]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:24]=[CH:23][CH:6]1[CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:13][C:8](=[O:9])[CH:7]1[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC(=O)C1CC=CCCCC(=O)O)c1ccccc1

Procedure:
A solution of 0.3 g. of 7-[8-nitromethyl-7-(3-hydroxy-3-phenyl-1-octenyl)-1,4-dioxaspiro[4.4]-non-6-yl]-5-heptenoic acid in 6 ml. of dry tetrahydrofuran was treated at 0° C. with 0.6 ml. of concentrated hydrochloric acid and stirred at 0° C. for 1.5 hours. The reaction mixture was added to water and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 33% ethyl acetate in hexane gave 0.08 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.40, 5.75, 6.40, 7.20, 10.20, 13.20, 14.18 μ. NMR: δ 4.45 (m, 2, --CH2NO2), 5.40 (m, 2, 5 and 6-H), 5.85 (m, 2, 13 and 14-H), 5.90 (s, 2, OH), 7.40 (s, 5, aromatic -H) ppm. Mass spectrum: M+ at m/e 471 (theory 471), M+ -H2O at m/e 453 (theory 453).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](CN)[N:3]=1.[K+].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH-:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[CH3:26][N:27]1CCCC1=O>>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:27][CH3:26])[N:3]=2)(=[O:23])=[O:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: NCc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Reactant: CN1CCCC1=O
Agent: [K+]
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Yield: 73 %

Procedure:
0.39 g (0.0022 mol) of (4,6-dichloro-pyrimidin-2-yl)methylamine and 1.1 g (0.0044 mol) of 4-tert-butyl-benzenesulfonamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was saturated with sodium chloride, de-gassed in a vacuum and made acid with 4N HCl, with a precipitate separating. The mixture was suction filtered, the extract and the solid were combined and chromatographed over silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. The product was recrystallized from ethyl acetate/n-hexane. There was obtained 0.57 g (73%) of 4-tert-butyl-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 118-137° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2=[CH:12][N:13]([CH2:14][C:15]([O:17]CC)=[O:16])[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[OH-].[Li+:21].Cl>C(O)C.O>[O:1]=[C:2]1[CH2:11][C:10]2=[CH:12][N:13]([CH2:14][C:15]([O-:17])=[O:16])[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[Li+:21]
Reactant: CCOC(=O)Cn1cc2c3c(cccc31)NC(=O)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])Cn1cc2c3c(cccc31)NC(=O)C2
Reaction time: 0.08 h

Procedure:
To a solution of ethyl (4-oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3H)-yl)acetate from Step G (79 mg, 0.306 mmol) in ethanol (3 mL) and water (0.5 mL) was added dropwise 1.0 N aqueous lithium hydroxide (0.34 mL, 0.34 mmol). After 5 min, 1 N aqueous HCl was added to adjust the mixture to pH 7 and the solution was concentrated in vacuo to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.[C:17]([CH:19]=[C:20]([O-])[CH3:21])#[N:18].[Na+].[NH2:24][C:25]([CH3:34])=[CH:26][C:27](=[O:33])[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1.C(O)(=O)C>CC(O)C>[CH:29]1([CH2:28][C:27]([C:26]2[CH:13]([C:9]3[CH:10]=[C:11]([F:12])[C:2]([F:1])=[C:3]4[C:8]=3[O:7][C:6]([CH3:15])=[CH:5][C:4]4=[O:16])[C:19]([C:17]#[N:18])=[C:20]([CH3:21])[NH:24][C:25]=2[CH3:34])=[O:33])[CH2:32][CH2:31][CH2:30]1
Reactant: CC([O-])=CC#N
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Reactant: CC(N)=CC(=O)CC1CCC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cc(F)c(F)c3c(=O)cc(C)oc23)C(C(=O)CC2CCC2)=C(C)N1

Procedure:
A solution of 100 mg (0.45 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 46.9 mg (0.45 mmol) of sodium 1-cyanoprop-1-en-2-olate, 85.44 mg (0.45 mmol) of 4-amino-1-cyclobutylpent-3-en-2-one (example 13, stage a) and 0.04 ml (0.67 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). 70.9 mg (37.44% of theory) of the title compound are obtained as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH:7]([NH2:9])=O.ClC1[C:20]2[N:21]=[CH:22][NH:23][C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>CC(N(C)C)=O>[CH2:1]([N:23]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:7]([NH2:9])[C:20]=2[N:21]=[CH:22]1)[CH:2]([CH3:5])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: Clc1nc2ccccc2c2[nH]cnc12
Reactant: NC=O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
Potassium tert-butoxide (4.32 g, 0.038 mole), 4.5 mL of dimethylacetamide and 1.53 mL (0.038 mole) of formamide were added in a 50-mL round-bottomed flask, under inert atmosphere followed by stirring for 30 minutes. After addition of 4-chloro-1H-imidazo[4,5-c]quinoline (1 g, 3.8 mmoles), the mixture was heated at 120° C., followed by stirring for 1 hour and then cooled to room temperature. The reaction mixture was filtered followed by washing with abundant water and dried to give 0.4 g of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine. Yield 39%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1.[OH:20][C@H:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:1].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:23]3[CH2:24][CH2:25][C@H:21]([OH:20])[CH2:22]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: O[C@H]1CCNC1
Product: COc1ccc(-c2cc(N3CC[C@H](O)C3)c3ccccc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 270-271° C., MS: m/e=321.3 (M+H+), was prepared 4-chloro-2-(4-methoxy-phenyl)-quinoline and (S)-3-hydroxypyrrolidine.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1ncc2scc(Br)c2n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Clc1ncc2scc(-c3ccccc3)c2n1
Temperature: 25 °C
Yield: 141.9 %

Procedure:
A mixture of 7-bromo-2-chlorothieno[3,2-d]pyrimidine (1.0 g, 4.0 mmol), phenyl boronic acid (0.6 g, 4.9 mmol), Pd[PPh3]4 (0.47 g, 0.4 mmol) and aqueous sodium carbonate (2M, 4.5 mL, 9.0 mmol) in toluene (25 mL)/isopropanol (8 mL) was heated under reflux overnight. The mixture was allowed to cool to room temperature, was diluted with ethyl acetate then washed with 10% aqueous sodium bicarbonate, dried (Na2SO4) filtered and concentrated. The resultant solid was sonicated in diethyl ether (2×70 mL) and the combined ether washes were evaporated to afford the crude product (1.4 g), still containing starting material and OPPh3.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:5][C:4]=1[C:13]([N:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:21]=2)[CH2:16]1)=[O:14].[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>N1C=CC=CC=1>[CH3:31][N:32]([CH3:36])[C:33]([O:2][C:3]1[C:4]([C:13]([N:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH:21]=3)[CH2:16]2)=[O:14])=[CH:5][C:6]([CH:10]([CH3:11])[CH3:12])=[C:7]([O:9][C:13](=[O:14])[N:15]([CH3:23])[CH3:16])[CH:8]=1)=[O:34]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(N4CCN(C)CC4)cc3C2)c(O)cc1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1cc(C(=O)N2Cc3ccc(N4CCN(C)CC4)cc3C2)c(OC(=O)N(C)C)cc1OC(=O)N(C)C
Temperature: 140 °C

Procedure:
A mixture of (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-yl)-1,3-dihydro-isoindol-2-yl]-methanone hydrochloride salt (100 mg) and dimethylcarbamyl chloride (420 μl; 20 equivalents) in pyridine (1 ml) was heated at 140° C. for 20 minutes in a CEM discover microwave synthesiser then evaporated and re-evaporated with toluene (×3). The crude material was purified by preparative LC/MS and 55 mg of the title compound were isolated as a brown solid (formate salt). 1H NMR (400 MHz, DMSO-d6): 8.15 (1H, s), 7.42 (1H, d), 7.25-7.10 (1H, m), 7.05-6.85 (3H, m), 4.70 (2H, d), 4.54 (2H, d), 3.20-3.10 (4H, m), 3.09 (3H, s), 3.08-3.00 (1H, m), 2.95 (3H, s), 2.88 (3H, s), 2.79 (3H, s) 2.65-2.47 (4H, m), 2.35 (3H, d), 1.20 (6H, d). MS: [M+H]+ 538.