Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[CH3:29].O>CS(C)=O>[F:25][C:23]([F:26])([F:24])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:31](=[O:32])[O:30][CH2:28][CH3:29])=[S:35])=[N:7][CH:6]=1)=[O:27]
Reactant: Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (600 mg, 1.61 mmol) in dimethyl sulfoxide (30 mL) was added ethoxycarbonyl isothiocyanate (230 μL, 1.95 mmol), and the mixture was stirred at room temperature for 12 hr. Water (150 mL) was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl ({[5-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (485 mg, 59%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:16][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(C)c2cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2ncnc(CBr)c2cc1OC
Temperature: 25 °C

Procedure:
4-Methyl-6,7-dimethoxyquinazoline (D-1) (3.43 g, 14.7 mMol), N-bromosuccinimide (NBS) (2.64 g, 14.7 mMol) and benzoyl peroxide (BPO) (500 mg) were heated under reflux in 200 mL of carbon tetrachloride with irradiation by a 200 W sun lamp for 5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and extracted twice with water. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel, eluting with hexanes/ethyl acetate gave 4-bromomethyl-6,7-dimethoxyquinazoline (E-1) as a pinkish solid, 1.39 g; 1H NMR (CDCl3, 300 MHz) 9.07 (s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 4.85 (s, 2H), 4.06 (s, 6H) ppm; 13C NMR (CDCl3, 75 MHz) 161.22, 156.32, 153.45, 150.72, 149.22, 118.85, 107.47, 101.78, 56.84, 56.70, 30.13; MS (ES) 283/285 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1)=[O:6]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2c(OC)cccc2OC)cc1
Yield: 37 %

Procedure:
A mixture of 2 g (10 mmol) of 2,6-dimethoxybenzoyl chloride, 1.65 g (10 mmol) of ethyl 4-aminobenzoate, 1.11 g of triethylamine and 61 mg of 4-dimethylaminopyridine in 10 ml of dichloromethane is refluxed for 20 hours. The mixture is diluted with water and the organic layer separate. The organic layer is washed with water, 1N HCl, 1N Na2CO3, brine and dried (Na2SO4). The solvent is removed to give a solid which is crystallized from ethyl acetate to give 1.22 g of ethyl 4-[(2,6-dimethoxybenzoyl)amino]benzoate as crystals, m.p. 183°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[S:11])[NH:9][CH:10]=2)[CH:7]=1.[CH3:12][O-].[Na+].CI>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[CH:7]=1
Reactant: Fc1ccc2c[nH]c(=S)n2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1ncc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.5 %

Procedure:
In a round-bottomed flask, 6-fluoro-2H-imidazo[1,5-a]pyridine-3-thione (158 mg, 0.94 mmol) was suspended in methanol (1 ml) and sodium methoxide (0.5 M in MeOH, 2.0 ml, 1.0 mmol) was added dropwise. The reaction was stirred at room temperature for 10 min then methyl iodide (0.07 ml, 1.12 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane then the organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 179 mg of 6-fluoro-3-methylsulfanyl-imidazo[1,5-a]pyridine as a brown oil which was used without further purification. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.98-8.05 (m, 1H), 7.58 (s, 1H), 7.45 (dd, J=9.3, 4.8 Hz, 1H), 6.73 (ddd, J=9.6, 7.6, 2.0 Hz, 1H), 2.56 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([CH3:8])=[CH:6][N:7]=1.[H-].[Na+].Br.Br[CH2:13][CH2:14][NH2:15].CN(C=O)C>C(Cl)Cl.CCO.O>[CH3:1][N:2]([C:3]1[S:4][C:5]([CH3:8])=[CH:6][N:7]=1)[CH2:13][CH2:14][NH2:15]
Reactant: NCCBr
Reactant: CNc1ncc(C)s1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cc1cnc(N(C)CCN)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A mixture of 512 mg (4.0 mmol) of N,5-dimethylthiazol-2-amine, 352 mg (8.8 mmol, 60% strength in mineral oil) of sodium hydride and 2-bromoethylamine hydrobromide with DMF (10 ml) was stirred for 2 h at RT. The mixture was then poured into water and extracted with DCM. The organic phase was dried over MgSO4, filtered and evaporated under a vacuum. 232 mg (1.4 mmol, 34%) of N1-methyl-N1-(5-methylthiazol-2-yl)ethane-1,2-diamine were obtained by CC (DCM/EtOH/conc. aq. NH4—OH soln. 5:1:0.06) with the residue.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:35])[CH2:6][O:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:10][C:9]=1[CH3:34])[CH3:3].[H-].[Na+].[Br:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O>C1COCC1>[Br:38][C:39]1[CH:40]=[C:41]([CH:42]=[CH:12][C:11]2[CH:32]=[CH:33][C:8]([O:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:35])=[C:9]([CH3:34])[CH:10]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: CCOC(=O)COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Reactant: O=Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C=Cc2cccc(Br)c2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
A suspension of [4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphonium chloride (500 mg, 0.99 mmol) in dry THF (10 mL) was cooled to 0° C. (ice/water bath) and treated with NaH (44 mg of a 60% dispersion in mineral oil, 1.10 mmol) portion-wise over 5 minutes. The resulting yellow suspension was stirred for 15 minutes and was then treated with 3-bromobenzaldehyde (184 mg, 0.99 mmol) in dry THF (5 mL). The resulting white suspension was allowed to warm to rt over 3.5 hours and was then heated at reflux for 1 hour. The reaction mixture was then allowed to cool to rt, stirred overnight and was then reduced under vacuum. The residue was then partitioned between CHCl3 (20 mL) and water (20 mL) and the layers separated. The cloudy organic layer was dried through a hydrophobic frit and then concentrated to a cream coloured gum (700 mg). Purification by SPE (silica) eluting with cyclohexane:EtOAc (9:1) afforded the title compound (mixture of E:Z isomers) (258 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: COCCN
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Product: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
The compound from Example 34c (1.0 g, 3.2 mmol) in CH2Cl, was added to a mixture of 2-methoxyethanamine (722 mg, 9.61 mmol) in CH2Cl2. Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc/hexane giving the title compound as a yellow oil (1.1 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:19][CH2:20][CH2:21][CH2:22]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:26])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:33]1[CH:37]2[CH2:38][NH:39][CH2:40][CH:36]2[CH2:35][N:34]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:19][CH2:20][CH2:21][CH2:22][N:39]4[CH2:38][CH:37]5[CH2:33][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH:36]5[CH2:40]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:26])[CH:3]=1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCCl
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCN1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a mixture of N-(4-bromo-2-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (1.25 g), K2CO3 (0.78 g) and a catalytic amount of KI in DMF (20 mL) was added tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.78 g) at room temperature. The reaction mixture was heated to 80° C. and stirred for 8 h, then diluted with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a white solid (1.16 g, 66.50%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:13]([O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1cccc(I)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: Ic1cccc(CCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Into a 50-mL 3-necked round-bottom flask under N2 was placed a solution of 2-(3-iodophenyl)ethanol (470 mg, 1.90 mmol) in tetrahydrofuran (10 mL). Sodium hydride (91 mg, 3.8 mmol, 2 equiv.) was added at 0° C. The resulting mixture was warmed to room temperature and stirred at room temperature for 2 h. Benzyl bromide (272 μL, 3.9 mmol, 2.05 equiv.) and tetra-n-butylammonium bromide (61 mg, 0.19 mmol, 0.10 equiv.) were added at room temperature. The resulting solution was stirred for 20 h at room temperature. The reaction progress was monitored by TLC (EtOAc/petroleum ether 1:30). The reaction was then quenched by the addition of aqueous NH4Cl (10 mL). The resulting solution was extracted with EtOAc (3×60 mL), and the organic layers were combined and washed with brine (50 mL). The residue was chromatographed on silica gel with EtOAc/petroleum ether 1:20 to give 0.48 g (75%) of 1-[2-(benzyloxy)ethyl]-3-iodobenzene as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.62 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.42-7.25 (m, 5H), 7.22 (d, 1H, J=7.8 Hz), 7.05 (t, 1H, J=7.8 Hz), 4.55 (s, 2H), 3.69 (t, 2H, J=6.9 Hz), 2.89 (t, 2H, J=6.9 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:24]2[CH2:25][CH2:26][N:21]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:22][CH2:23]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(N2CCN(Cc3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 6 h

Procedure:
The mixture of 20 g of 2-nitro-5-chlorobenzoic acid and 50 mL of N-benzylpiperazine is stirred at 120° C. for 6 hours. To the reaction mixture 250 mL of ethyl acetate is added. The precipitated yellow crystalline material is filtered off, dissolved in 200 mL of water. The pH of the mixture is adjusted to 6 with acetic acid. The precipitated material is filtered off, washed with water and dried, to obtain 30 g of the title compound. M.p.: 172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=CC=C[CH:23]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:27]2[CH:22]=[CH:23][N:14]=[C:10]([S:11][CH3:12])[N:9]=2)[CH:13]=[CH:12][S:11]3)=[CH:6][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(-c2cn3ccsc3n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3sccn23)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a mixture of 6-(4-fluorophenyl)-imidazo[2,1-b]thiazole (J) (6.0 g, 27.6 mmol), 4-iodo-2-thiomethylpyrimidine (10.4 g, 41.3 mmol), cesium carbonate (13.4 g, 41.3 mmol), triphenylphosphine (2.88 g, 11 mmol), and palladium acetate (1.22 g, 5.5 mmol) is added anhydrous dimethylformamide (60 mL). The reaction mixture is sealed and shaken at 80° C. for 12 hours. The reaction was quenched by addition of water (200 mL). The aqueous layer is extracted with ethyl acetate (3×100 mL). The organic phase is washed sequentially with water (100 mL) and a saturated aqueous, sodium chloride solution (100 mL). The organic phase is dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The crude product is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate/hexane (20-30%). After evaporation of the solvent, 6-(4-fluorophenyl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[2,1-b]thiazole (K) (Compound CXXXIX, Table 2) is obtained as a white solid (3.5 g, 37%) m.p. 151-152° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH2:7][CH2:6]2.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([OH:13])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=O)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(O)O2
Temperature: -70 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A solution of 6-methoxy-chroman-2-one (3.66 g, 20.53 mmol) in 300 ml of dichloromethane was cooled to −70° C., and a solution of diisobutylaluminium hydride (40 ml of a 1M solution in toluene, 40 mmol) was added dropwise. The solution was stirred at −70° C. for 2 h, and then ethyl acetate (10 ml) was added. After stirring for 15 min, 200 ml of a saturated solution of Rochelle salt was added dropwise, and the mixture was warmed to room temperature. 200 ml of ethyl acetate were added, and the mixture was stirred vigorously for 2 h and then decanted. The organic layer was washed with water and brine and dried with sodium sulfate, and the solvent removed under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl acetate in cyclohexane) to afford 2.90 g of white crystals (78%).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[F:34][C:35]1[CH:36]=[N:37][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:39][CH:40]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[N:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=3)[CH2:42][CH2:43]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: NC1(c2ncc(F)cn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC.
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1.CS(C)=[O:33]>>[CH2:29]1[O:33][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)=[CH:23][C:24]=2[O:28]1
Reactant: COc1ccc(N2C[C@H](CN3CCC(Oc4cccc(OC)c4)CC3)OC2=O)cc1
Reactant: CS(C)=O
Product: c1cc2c(cc1OC1CCNCC1)OCO2

Procedure:
3-p-methoxyphenyl-5(S)-[(4-m-methoxyphenoxypiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 208°-209°; [α]D =-29.1° (DMSO);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]([C:11]([OH:13])=O)=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]2[C:11](=[O:13])[O:16][C:14](=[O:15])[C:4]=2[CH:3]=1)(=[O:19])[CH3:18]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc2c(cc1C(=O)O)C(=O)OC2=O
Temperature: 25 °C
Yield: 38 %

Procedure:
4-Hydroxy-benzene-1,2,5-tricarboxylic acid (4.1 g, 18.1 mmol), prepared according to J. Am. Chem. Soc. (1949) 71, 11, was treated with acetic anhydride (50 mL) and heated at reflux for 5 hours. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The orange-pink residue was washed with diethyl ether (3×30 mL) and dried under reduced pressure at room temperature overnight to provide the title compound (1.71 g, 38%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[C:9]([CH3:27])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd]>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[C:9]([CH3:27])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C2=CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Agent: [Pd]
Product: Cc1cc(C2CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Yield: 55.5 %

Procedure:
To N-(4-bromo-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (50 mg, 0.14 mmol), cyclohexen-1-ylboronic acid (35 mg, 0.28), and Pd(dppf)Cl2-DCM (11 mg, 0.01 mmol) was added Na2CO3 (980 μL, of 2 M, 1.96 mmol) and acetonitrile (2 mL). The reaction mixture was heated under microwave irradiation for 10 min at 150° C. under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel column chromatography (30-100% ethyl acetate/hexane) to obtain N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white solid (35 mg, 70%). N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (35 mg, 0.10 mmol) was stirred vigorously with 10% Pd/C (wet) (30 mg, 0.01 mmol) under an atmosphere of H2 for 30 min at 50° C. The reaction mixture was filtered, concentrated in vacuo, and purified by HPLC (30-95% CH3CN/5 mM HCl) to yield N-(4-cyclohexyl-2-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (20 mg, 57% yield). LC/MS m/z 361.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 12.94 (d, J=6.0 Hz, 1H), 12.24 (s, 1H), 8.89 (d, J=6.5 Hz, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 2.45 (m, 1H), 2.38 (s, 3H), 1.80-1.69 (m, 5H), 1.42-1.21 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][NH:20][C@H:21]4[CH2:26][CH2:25][CH2:24][NH:23][C:22]4=[O:27])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](O)(=O)C.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>C=O>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][N:20]([CH3:31])[C@H:21]4[CH2:26][CH2:25][CH2:24][NH:23][C:22]4=[O:27])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN[C@H]1CCCNC1=O
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)[C@H]1CCCNC1=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
(3S)-3-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidin-2-one (165 mg, 0.38 mmol, Example 85) was dissolved in 37% aqueous formaldehyde (2 ml) and acetic acid (0.22 ml, 3.84 mmol) and sodium acetate (315 mg, 3.84 mmol) added. The mixture was cooled to −10° C. and sodium cyanoborohydride (24 mg, 0.38 mmol) added. The mixture was stirred for 15 minutes and then purified by reverse phase HPLC to give the title product (114 mg, 67%) as a white solid; 1H NMR Spectrum: (DMSO d6) 1.77 (m, 3H); 2.02 (m, 1H); 2.40 (s, 3H); 3.09 (m, 2H); 3.29 (dd, 1H); 3.95 (s, 5H); 7.18 (s, 1H); 7.28 (t, 1H); 7.40 (brs, 1H); 7.48 (t, 1H); 7.55 (m, 1H); 8.35 (s, 1H); 8.42 (s, 1H); 9.76 (s, 1H). Mass Spectrum: (M+H)+ 444.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([O:11]C)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>ClCCCl>[Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc2c(Cl)cccc2s1
Agent: Cl
Solvent: ClCCCl
Product: O=c1[nH]c2c(Cl)cccc2s1
Yield: 26 %

Procedure:
Prepared analogous to Example 5 from 4-chloro-2-methoxy-benzothiazole and concentrated hydrochloric acid with a yield of 26% of theory. M.p.: 205°-206° C. (from 1,2-dichloro-ethane)
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[N:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C.O>[N:10]([CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[N:7]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1csc(CBr)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1csc(CN=[N+]=[N-])n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
2-Bromomethyl-thiazole-4-carbonitrile (1.6 g, 7.8 mmol) was dissolved in 20 mL DMF and sodium azide (0.768 g, 11.8 mmol) was added. The reaction was allowed to stir for 16 h at room temperature and then diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were washed again with 75 ml of brine, dried with anhydrous sodium sulfate and concentrated in vacuo to yield 1.20 g (92%) of the title compound as a gummy material which was used in next step with out further purification.