Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:22]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[O:23])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:11][C:10]2=[O:21])[CH3:4].[F:30][C:31]1[CH:38]=[CH:37][C:34]([NH:35][CH3:36])=[CH:33][CH:32]=1>CN1C(=O)CCC1>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][NH:24][C:22]([C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([CH:3]([N:35]([C:34]3[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=3)[CH3:36])[CH3:4])[CH:6]=1)[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:11][C:10]2=[O:21])=[O:23]
Reactant: CNc1ccc(F)cc1
Reactant: CC(Br)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Solvent: CN1CCCC1=O
Product: CC(c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A solution of 8-(1-bromoethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (85 mg, 0.16 mmol) and 4-fluoro-N-methylaniline (0.077 mL, 0.64 mmol) in NMP (1 mL) was stirred at room temperature for 4 h then at 45° C. for 1 h. The reaction mixture was allowed to cool to room temperature and purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness. The residue was triturated in diethyl ether, collected by filtration and dried to afford N-(2-(dimethylamino)ethyl)-8-(1-((4-fluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (42.0 mg, 53.1%) as a white solid. Mass Spectrum: M+H+ 497. NMR Spectrum: (CDCl3) 1.66 (d, 3H), 2.33 (s, 6H), 2.33 (bs, 2H), 2.60 (bs, 2H), 2.61 (s, 3H), 3.09-3.24 (m, 4H), 3.44-3.57 (m, 4H), 3.57-3.66 (m, 2H), 5.36 (q, 1H), 5.48 (s, 1H), 6.75 (dd, 2H), 6.77 (dd, 2H), 7.14 (bs, 1H), 8.33 (s, 1H), 8.44 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][O:14][C:15]1[C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][C:18]([CH2:25][CH3:26])=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:17]=[C:18]([CH2:25][CH3:26])[CH:19]=[C:20]([C:21]([CH3:24])([CH3:22])[CH3:23])[C:15]=2[O:14][CH2:13][O:12][CH3:11])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCc1cc(B(O)O)c(OCOC)c(C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1cc(-c2ccc(O)c(C=O)c2)c(OCOC)c(C(C)(C)C)c1
Yield: 76.9 %

Procedure:
To a mixture of 91 mg (0.078 mmol, 5%) of Pd(PPh3)4 and 252 mg (1.26 mmol) of 5-bromo salicylaldehyde in 10 mL of dry toluene was added 685 mmol (2.5 mmol, 2 equivalents) of 2-methoxymethoxy-3-tert-butyl-5-ethyl phenylboronic acid diluted in 5 mL of ethanol followed by 1.3 mL of a 2N aqueous solution of Na2CO3. The mixture was stirred at reflux for 3 hours and after cooling extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The residual oil was purified over silica gel (eluent: ethyl acetate/hexane: 10/90) to give 333 mg (0.969 mmol, yield: 77%) of 2-hydroxy-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzaldehyde a pale brownb oil. 1H NMR (CDCl3), δ: 11.04 (s, 1H), 9.95 (s, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 7.06 (d, J=8.9 Hz, 1H), 6.98 (d, J=1.9 Hz, 1H), 4.52 (s, 2H), 3.29 (s, 3H), 2.64 (dd, J=15.2, 7.6 Hz, 2H), 1.47 (s, 9H), 1.26 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30](Cl)=[O:31])[CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:30]([C:27]2[CH:26]=[C:25]([CH3:24])[O:29][N:28]=2)=[O:31])[CH:17]=1
Reactant: COC(=O)Cn1c(-c2ccccc2)ccc1-c1cccc(N)c1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(-c2ccccc2)ccc1-c1cccc(NC(=O)c2cc(C)on2)c1
Temperature: 25 °C

Procedure:
To a solution of [2-(3-amino-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid methyl ester (0.1 mmol) in DCM (2 mL) is added 5-methyl-isoxazole-3-carbonyl chloride (0.1 mmol) and triethylamine (0.02 mmol). The reactions are agitated at room temperature over night. The solvent is removed under vacuum and the residues are subsequently dried under high vacuum at 50° C. for 2 h.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.1 %

Procedure:
To a stirred solution of 2-(4-amino-phenyl)-propionic acid ethyl ester (5.0 g, 25.9 mmol, Takahashi, 1. et al., Heterocycles 1996, 43, 2343-2346.) in tetrahydrofurane (200 ml) was slowly added lithiumaluminium hydride (1.96 g, 51.8 mmol), and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with 25% ammonia solution (50 ml) under ice-bath cooling. The resulting precipitate was filtered off, and the filtrate concentrated under reduced pressure to afford 3.88 g (99%) of the title compound as slight brown syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][C:17](=O)[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.N1C(C)=CC=CC=1C.Cl.[CH2:36]([O:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[CH2:36]([O:43]/[N:44]=[C:17](\[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[CH2:16][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([Br:15])=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=2)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NOCc1ccccc1
Reactant: O=C(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2C/C(COc1ccccc1)=N/OCc1ccccc1
Reaction time: 12 h
Yield: 93.4 %

Procedure:
To a solution of the product of Step 1 (17.7 mg, 0.0374 mmol, 1.0 equiv) in THF (400 μL) were added 2,6-lutidine (4.4 μL, 0.0374 mmol, 1.0 equiv), O-benzylhydroxylamine hydrochloride (14.3 mg, 0.0898 mmol, 2.4 equiv) and 4A molecular sieves (15.8 mg). The mixture was stirred for 12 h until TLC indicated complete consumption of starting material. The reaction mixture was quenched with saturated NaHCO3 and extracted 3 times with dichloromethane. The combined organic extracts were dried with MgSO4 and concentrated to give crude product. It was further purified by silica gel chromatography (5-10% EtOAc/Hex) to afford 20.2 mg white solid as product, yield 93.4%. 1H NMR (CDCl3, 400 MHz) δ=4.68 (s, 2H) 5.00 (s, 2H) 5.14 (s, 2H) 6.72 (d, J=8.2 Hz, 2H) 6.94 (t, J=7.3 Hz, 1H) 7.47-7.16 (m, 11H) 8.06 (s, 2H)
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][O:7][CH2:6][C@H:5]1[NH:10][C:11]1[N:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]3[C:26]([Cl:27])=[C:25]([O:28][CH3:29])[CH:24]=[C:23]([O:30][CH3:31])[C:22]=3[Cl:32])[CH:17]=2)[N:12]=1)=[N+]=[N-]>CO.CCOC(C)=O.[Pd]>[Cl:27][C:26]1[C:25]([O:28][CH3:29])=[CH:24][C:23]([O:30][CH3:31])=[C:22]([Cl:32])[C:21]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:5]1[C@@H:4]([NH2:1])[CH2:9][CH2:8][O:7][CH2:6]1)[N:20]=[CH:19]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COCC[C@@H]4N=[N+]=[N-])ncc3c2)c1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COCC[C@@H]4N)ncc3c2)c1Cl
Reaction time: 1 h
Yield: 100.8 %

Procedure:
N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-amine (0.063 g, 0.133 mmol) was taken up in Methanol (7 ml) and EtOAc (7.00 ml), Pd—C (0.014 g, 0.133 mmol) was added and stirred under a H2 balloon for 1 hour. After the reaction was completed, it was filtered through celite and the solvent removed. (3S,4S)—N3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)tetrahydro-2H-pyran-3,4-diamine (0.060 g, 0.134 mmol, 101% yield) was recovered as a yellow solid, which was carried on without further purification. MS (ES+) C21H22Cl2N4O3 requires: 448, found: 449 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[CH:26]=2)=[CH:4][C:5]([F:23])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[O:10])[CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:42]1[CH:41]=[C:40]([C:27]2[CH:26]=[C:25]([O:24][C:3]3[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:9]([N:11]4[CH2:15][CH2:14][N:13]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[C:12]4=[O:22])=[O:10])=[C:5]([F:23])[CH:4]=3)[CH:30]=[CH:29][N:28]=2)[CH:44]=[N:43]1
Reactant: O=C(Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F)N1CCN(C2CCOCC2)C1=O
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cc(Cl)c(Oc2ccnc(-c3cn[nH]c3)c2)cc1F)N1CCN(C2CCOCC2)C1=O
Temperature: 80 °C
Yield: 75 %

Procedure:
A mixture of Example C8 (0.200 g, 0.426 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.124 g, 0.639 mmol) and K2CO3 (0.177 g, 1.279 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.025 g, 0.021 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(4-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (160 mg, 75%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 10.91 (d, J=2.7 Hz, 1 H), 8.40 (1H, d, J=8.1 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.33 (s, 1 H), 8.04 (s, 1 H), 7.57 (d, J=11.2 Hz, 1 H), 7.30 (d, J=2.5 Hz, 1 H), 6.61 (dd, J=5.7, 2.5 Hz, 1 H), 3.94-3.77 (m, 5 H), 3.47 (t, J=8.2 Hz, 2 H), 3.37 (t, J=11.8 Hz, 2 H), 1.75-1.64 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: 501.1 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[C:4]1=[O:14])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.COC(C)(C)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:13][C:5]1[C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:12]2[C:7]([N:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CCn1c(=O)c(C)nc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: COC(C)(C)C
Product: CCn1c(=O)c(CBr)nc2ccccc21
Yield: 40.3 %

Procedure:
4,2 g (22,3 mM) of 1-ethyl-3-methyl-quinoxalin-2(1H)-one, 3.97 g (22,3 mM) of N-bromosuccinimide and 53,3 mg of benzoylperoxide in 220 ml of carbon tetrachloride were refluxed for 4 h. The reaction mixture was filtered and the solvent was removed under vacuum. The residue was further purified by silica gel column chromatography, using dichloromethane/cyclohexane (70/30) as eluant to give a solid, which was taken up in methylterbutyloxide. After filtration, 2,4 g of 3-(bromomethyl)-1-ethyl-quinoxalin-2(1H)-one were obtained as a tan solid. Yield: 40,3%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH2:7][C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ncsc1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2scnc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
To a solution of 4-methyl-5-thiazoleethanol (2 mL, 16.7 mmol) in CH2Cl2 (10 mL) and pyridine (10 mL) was added p-toluenesulfonyl chloride (3.5 g, 18.4 mmol) portionwise over 15 min. This mixture was stirred at ambient temperature for 18 h then was quenched with 5% aqueous HCl (15 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 50% hexanes/ethyl acetate) to give 2-(4-methylthiazol-5-yl)ethyl 4-methylbenzenesulfonate (3.24 g, 10.9 mmol, 65% yield). MS (DCI/NH3) m/z 298 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:21]=1>C(O)(CC)C>[N:1]1([C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=3)[CH:21]=2)[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: FC(F)(F)Oc1ccc(Nc2cc(-n3ccc4cccnc43)ncn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution of compound 7-azaindole (18 mg, 0.15 mmol) in sec-BuOH (5 mL) was added DIEA (0.20 mL) and the reaction mixture was stirred for 15 min at RT. 6-Chloro-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine (29 mg, 0.1 mmol) was then added and the temperature was raised to 90° C. and continued stirring for another 16 h. The solvent was removed and the title compound was purified by prep. HPLC (15 mg, 40% Yield). MS m/z 372.10 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:11])=[CH2:10])=[CH:5][C:4]=1[CH3:12]>>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([Cl:1])([CH3:11])[CH3:10])=[CH:5][C:4]=1[CH3:12]
Reactant: C=C(C)c1ccc(C)c(C)c1
Reactant: Cl
Product: Cc1ccc(C(C)(C)Cl)cc1C
Reaction time: 0.08 h
Yield: 98.2 %

Procedure:
A 0.25 l flask with a stirrer following the wall and a gas inlet tube was filled with hydrogen chloride gas. 73 g of 1,2-dimethyl-4-isopropenylbenzene were then added drop-wise at -5° to -10° C. with vigorous stirring in the course of 30 minutes, hydrogen chloride being re-added. The absorption of gas was complete 5 minutes after the end of the dropwise addition. Hydrogen chloride was stripped off from the reaction product under reduced pressure (35° C./0.8 mbar) and 89.6 g (98.2% of theory) of 1,2-dimethyl-4-(α-chloroisopropyl)benzene were obtained, m.p.: -20° to -19° C., decomposition at >50° C./1 mbar with elimination of HCl.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC(F)(F)c1coc(Cn2ncc(N)n2)n1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)co3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-difluoro-ethyl)-oxazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyloxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([OH:5])=[O:4].N([C:18](C)([CH2:22][C:23]1C=CC(O)=C(OC)C=1)[C:19](O)=O)N>>[NH2:1][C:2]([CH3:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([O:5][CH2:19][CH2:18][CH2:22][CH3:23])=[O:4]
Reactant: CC(N)(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: COc1cc(CC(C)(NN)C(=O)O)ccc1O
Product: CCCCOC(=O)C(C)(N)Cc1ccc(O)c(O)c1
Yield: 82 %

Procedure:
The procedure of Example 1 was repeated employing 2-amino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid rather than 2-hydrazino-2 -methyl-3-(4-hydroxy-3-methoxyphenyl)propionic acid. The butyl (±)-2-amino-2-methyl-3-(3,4-dihydroxyphenyl)propionate was obtained in a yield of 82%. The product was recrystallized from acetonitrile (77% yield) to give pure ester: mp 121.5 ° C. to 122.0° C.; HPLC analysis (C-18 column, 280 nm, tR =14.5 min) showed >99% purity.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[CH3:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]1[CH2:31]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:31][C:21]1[N:20]([CH3:19])[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: Cn1c(CCl)nc2ccccc2c1=O
Reactant: Cc1cccc(COc2cccc(O)c2)c1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(COc2cccc(OCc3nc4ccccc4c(=O)n3C)c2)c1CO
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(2-hydroxymethyl-3-methyl-benzyloxy)-phenol (87 mg, 0.38 mmol, example 100) and (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl chloride (94 mg, 0.45 mmol, example 99) in DMF (1 mL) is added powdered K2CO3 (78 mg, 0.5 mmol). The resulting mixture is warmed to 60° C. and stirred at this temperature for 5 h. This mixture is cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 40% ethyl acetate/30% dichloromethane in hexanes) to give the title compound as a foam. MS (ESI) 417 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(Cl)c2cc(Cl)ccc2n(C)c1=O
Solvent: O
Product: CCOC(=O)c1c(N2CCOCC2)c2cc(Cl)ccc2n(C)c1=O

Procedure:
A solution of 200 mg. of 4,6-dichloro-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester, (prepared in Example 4) in 1 ml. of morpholine was heated in a test tube for a few minutes and then was poured into 40 ml. of water. The resulting precipitate was collected and washed with water. Recrystallization from ethanol gave the title compound with m.p. 167°-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][CH:18]1[NH:23][CH:22]([CH3:24])[CH2:21][N:20]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=2)[CH2:19]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([N:20]3[CH2:19][CH:18]([CH3:17])[NH:23][CH:22]([CH3:24])[CH2:21]3)=[CH:26][CH:27]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:20]3[CH2:19][CH:18]([CH3:17])[NH:23][CH:22]([CH3:24])[CH2:21]3)=[CH:33][CH:32]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: CC1CN(c2ccc(C(=O)[O-])cc2)CC(C)N1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: CC1CN(c2ccc(C(=O)Nc3ccc(C(=O)c4ccc(NC(=O)c5ccc(N6CC(C)NC(C)C6)cc5)cc4)cc3)cc2)CC(C)N1

Procedure:
Compound 319 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(3,5-dimethylpiperazino)benzoate. [M+H]+ calcd for C39H44N6O3: 645.35; found: 645.16.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:28])[N:3]1[CH2:29][CH2:30][CH3:31]>C1COCC1.CO.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:28])[N:3]1[CH2:29][CH2:30][CH3:31]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C=CC(=O)O)(CCC3)C4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CCC(=O)O)(CCC3)C4)nc2n(CCC)c1=O

Procedure:
3-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]non-1-yl]-acrylic acid (150 mg) was hydrogenated in the presence of 10% Pd/C in THF:MeOH (2:1, 5 ml) @ 60 psi overnight. Catalyst was filtered through celite and the solvent was concentrated. Solid was purified by crystallizing from ether Yield 105 mg. Mass (ES+ 431)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[NH:15].[F:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=1>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]2[CH:29]=[CH:30][C:20]([F:19])=[CH:21][CH:22]=2)[C:7]1=[NH:15]
Reactant: Fc1ccc(OCC2CO2)cc1
Reactant: N=c1[nH]c2ccccc2n1Cc1cccc(Br)c1
Solvent: CCO
Product: N=c1n(Cc2cccc(Br)c2)c2ccccc2n1CC(O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.2 %

Procedure:
To a solution of 1-(3-bromo-benzyl)-1,3-dihydro-benzoimidazol-2-ylideneamine (0.50 g, 1.66 mmol) in EtOH (30 ml) at rt was added 2-(4-fluoro-phenoxymethyl)-oxirane (278 mg, 1.66 mmol). The reaction was heated to reflux where it was maintained for 24 h. After this time, additional 2-(4-fluoro-phenoxymethyl)-oxirane (278 mg, 1.66 mmol) was introduced and the reaction was heated to reflux where it was left for a further 6 h. The mixture was cooled to rt and concentrated under reduced pressure. Purification by column chromatography on silica eluting with MeOH/dichloromethane (2-5% gradient) provided 1-[3-(3-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-3-(4-fluoro-phenoxy)-propan-2-ol (361 mg, 46%). HPLC-MS 470, 472 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:23](=[O:24])[O:25][CH2:26][CH3:27]
Reactant: COc1ccc(CCN)c(Cl)c1OC
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1ccc(OC)c(OC)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To the solution of 2-(2-chloro-3,4-dimethoxyphenyl)ethanamine (2.8 g, 12.98 mmol) in dichloromethane (DCM) (40 mL) at 0° C. was added triethylamine (1.990 mL, 14.28 mmol) and ethyl chloroformate (1.371 mL, 14.28 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was washed with water, brine, dried over magnesium sulfate and chromatographed to give ethyl 2-chloro-3,4-dimethoxyphenethylcarbamate (1.7 g, 5.91 mmol, 97% yield). LCMS (M+H)+: 288.1