Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][C:12]([N:14]([CH3:27])[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[C:17](=[O:26])[N:18]([CH3:25])[C:19]3=[O:24])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][C:12]([N:14]([CH3:27])[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[C:17](=[O:26])[N:18]([CH3:25])[C:19]3=[O:24])=[O:13])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CN1C(=O)c2cccc(N(C)C(=O)NNc3ccc([N+](=O)[O-])cc3)c2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1C(=O)c2cccc(N(C)C(=O)NNc3ccc(N)cc3)c2C1=O
Yield: 87 %

Procedure:
1-p-Nitrophenyl-4-methyl-4-(2-methyl-1,3-dioxoisoindolin-4-yl)semicarbazide (2.6 g) was dissolved in 300 ml tetrahydrofuran and a catalytic amount (about 200 mg) of 10% palladium on carbon was added. The mixture was hydrogenated on a Parr hydrogenation apparatus overnight at 40 psi hydrogen pressure. The mixture was filtered and the solvent was evaporated to give 2.0 g (87% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=O)=[CH:4][CH:3]=1.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:13][C:14]([OH:15])=[N:16][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=CC(=O)c1ccc(F)cc1
Reactant: NCC(N)=O
Product: Oc1cnc(-c2ccc(F)cc2)cn1
Yield: 42 %

Procedure:
The title compound was prepared according to the method described for Preparation 25 using (4-fluoro-phenyl)-oxo-acetaldehyde and 2-amino-acetamide to afford the title compound as a pale yellow oil (2.33 g, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16](O)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2.S(Cl)(C)(=O)=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:40][CH2:39]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:26][O:25][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:9]([C:14](=[O:19])[C:15]=1[C:16]([NH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:41]1[CH2:42][CH2:43][N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:39][CH2:40]1)=[O:17])=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: NCCCCN1CCN(c2ccccn2)CC1
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)NCCCCN2CCN(c3ccccn3)CC2)cc(OC)c1OC

Procedure:
Under the conditions described in Example 1 (a) 3.6 g 3',4',5'-trimethoxyflavone-3-carboxylic acid were converted with 2.1 g 4-dimethylaminopyridine and 0.72 ml mesyl chloride in 100 ml absolute dichloromethane into the mixed anhydride, and this was then reacted under the conditions described in Example 4 (d) with 2.2 g of 4-[4-(2-pyridyl)-piperazin-1-yl]-butylamine. The reaction mixture was then worked up analogously to Example 4 (d). 3.4 g of 3',4',5'-trimethoxy-3-{4-[4-(2-pyridyl)-piperazin-1-yl]-butylaminocarbonyl}-flavone were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][C:6]([C:13](O)=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22]C1(C)OC(=O)CC(=O)O1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:13]([C:6]1[O:7][C:8](=[O:9])[C:10]2[C:4]([C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:12][CH:11]=2)(=[O:14])[CH3:22]
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
[Step 1] To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid (10.3 g), 2,2-dimethyl-[1,3]dioxane-4,6-dione (4.76 g), dimethylpyridin-4-yl-amine (5.50 g) and triethylamine (6.3 ml) in dichloromethane (100 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (8.6 g) at room temperature and the mixture was stirred at room temperature for 15 hrs. The mixture was diluted with dichloromethane, washed with 1N hydrochloric acid and saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue dissolved in water (200 ml) and acetic acid (100 ml) and the mixture was heated under reflux for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was crystallized from diisopropyl ether to give 3-acetyl-6-bromo-4-phenyl-isochromen-1-one (8.29 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1cnc(-c2ccc(Cl)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a suspension of 1-[2-(4-chloro-phenyl)-thiazol-5-yl]ethanone (5 g, 21 mmol) in methanol (100 ml) is added sodium borohydride (832 mg, 22 mmol) at room temperature. The reaction mixture is stirred at room temperature for 0.5 hour. The reaction mixture is quenched with 100 ml of an aqueous saturated solution of ammonium chloride, extracted with dichloromethane (2×150 ml). The combined organic extracts are dried over magnesium sulphate, filtered and evaporated to dryness to give 1-[2-(4-chloro-phenyl)-thiazol-5-yl]ethanol (4.88 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][CH2:4][OH:5].C[O:18][C:19](=O)[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:29]Br.C(N(CC)CC)C>CN(C=O)C>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]([C@H:2]([N:1]2[CH2:29][C:21]3[C:20](=[C:25]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:23][CH:22]=3)[C:19]2=[O:18])[CH2:3][CH2:4][OH:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]
Reactant: CCOc1cc([C@H](N)CCO)ccc1OC
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CCO)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC

Procedure:
(1R)-2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-7-nitro-2,3-dihydro-isoindol-1-one was prepared by the procedure of Example 1 from (3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propan-1-ol (3.0 g, 13 mmol), 2-bromomethyl-6-nitro-benzoic acid methyl ester (3.6 g, 13 mmol) and triethylamine (2 mL, 14 mmol) in DMF (40 mL) to give a yellow solid (4.1 g, 81% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.13-2.31 (m, 2H, CH2), 3.54-3.59 (m, 1H, CHH), 3.71-3.77 (m, 1H, NCHH), 3.87 (s, 3H, CH3), 3.94 (d, J=16 Hz, 1H, NCHH), 4.06 (q, J=7 Hz, 2H, CH2), 4.26 (d, J=16 Hz, 1H, NCHH), 5.70 (dd, J=4, 11 Hz, 1H, NCH), 6.85-6.99 (m, 3H, Ar), 7.55-7.77 (m, 3H, Ar); 3C N (CDCl3) δ 14.76, 33.92, 45.80, 51.30, 55.98, 58.65, 64.63, 65.84, 111.39, 113.22, 119.75, 122.91, 124.13, 126.74, 130.66, 132.11, 143.84, 146.66, 148.68, 149.33, 164.22.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCCl>[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:20]2[CH:21]=[CH:22][C:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:12](=[O:13])[C:11]4[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=4)=[CH:33][CH:34]=3)=[CH:18][CH:19]=2)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: c1ccc(CCCCCCc2ccccc2)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccc(CCCCCCc2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 33.3 g of aluminum chloride and 200 milliliters of 1,2-dichloroethane were mixed and then 40.8 g of paranitrobenzoyl chloride was introduced with ice cooling to be dissolved. Then, a solution of 23.6 g of 1,6-diphenylhexane in 50 milliliters of 1,2-dichloroethane was added dropwise for 30 minutes. After the end of the dropwise adding, the solution was stirred for 3 hours with warming back to the room temperature. After the end of reaction was confirmed by a liquid chromatography, the reaction solution was poured in 500 milliliters of ice water, and then extracted with 1.8 liters of chloroform. The solution was washed with an aqueous solution of sodium hydrogencarbonate and water, and then dried with magnesium sulfate. Chloroform was removed off by a rotary evaporator, and then 56.0 g of 1,6-bis(4-(4-nitrobenzoyl)phenyl)hexane was obtained as crystals by recrystallizing from a mixed solvent of chloroform and ethyl acetate.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][C@H:6]([NH2:10])[CH2:5][C:4]=2[CH:3]=[N:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:15]=[C:16]([Cl:26])[C:17]=1[CH2:18][C@@H:19]1[CH2:23][CH:22](O)[O:21][C:20]1=[O:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH:15]=[C:16]([Cl:26])[C:17]=1[CH2:18][C@H:19]([CH2:23][CH2:22][NH:10][C@H:6]1[CH2:7][CH2:8][C:9]2[NH:1][N:2]=[CH:3][C:4]=2[CH2:5]1)[C:20]([OH:25])=[O:21]
Reactant: N[C@H]1CCc2[nH]ncc2C1
Reactant: O=C1OC(O)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)[C@@H](CCN[C@H]1CCc2[nH]ncc2C1)Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 66.6 %

Procedure:
To a solution of 0.30 g (2.2 mmoles) of (S)-(4,5,6,7-tetrahydro-1H-indazol-5-yl)amine in 15 mL of ACN at 43° C., add 0.732 g (2.05 mmoles) of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-hydroxy-dihydro-furan-2-one. Heat the mixture at 50° C. for 0.5 h and allow to cool to room temperature. Add 0.70 g (3.3 mmoles) of sodium triacetoxyborohydride. After 2.5 h, add an additional charge of sodium triacetoxyborohydride (100 mg). After 1 h, heat to 50° C. and add 15 mL of water slowly. Allow to cool to room temperature and stir the slurry overnight. Collect the solids by filtration and rinse with water (2×5 mL). Stir the wet cake with 15 mL of acetonitrile and filter. Rinse the cake with acetonitrile (2×5 mL) and dry in a vacuum oven to afford 0.65 g (62%) of the title compound as a solid. MS (m/z): 476 (M+1, 35Cl), 478 (M+1, 37Cl).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][NH:7][C:6]1=[O:13].[N:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][N:7]([CH2:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[C:6]1=[O:13]
Reactant: Cc1c[nH]c(=O)n(CCCCl)c1=O
Reactant: ClCc1ccncc1
Product: Cc1cn(Cc2ccncc2)c(=O)n(CCCCl)c1=O

Procedure:
substituting 3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione and pyrid-4-ylmethyl chloride gave 3-(3-chloropropyl)-5-methyl-1-pyrid-4-ylmethyl-2,4(1H,3H)-pyrimidinedione;
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[N:16]=3)[C:12]([Cl:32])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[F:33][C:34]([F:39])([F:38])[C@H:35]1[O:37][CH2:36]1>CC(O)C>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:32])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:36][C@H:35]([OH:37])[C:34]([F:39])([F:38])[F:33])[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][C:26]([CH3:30])([CH3:31])[CH2:25]2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)CCO1
Solvent: CC(C)O
Product: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(N[C@H]4CC[C@H](NC[C@H](O)C(F)(F)F)CC4)ncc3Cl)n2)CCO1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (19 mg, 0.040 mmol) in 2-propanol (0.3 mL) was added (S)-(−)-3,3,3-trifluoro-1,2-epoxypropane (3.4 uL, 0.040 mmol). The mixture was stirred at 70° C. for 2 hr. The reaction mixture was concentrated. The resulting residue was purified by reverse phase HPLC and lyophilized to give 9.1 mg of (2S)-3-(trans-4-(3,5′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol as its TFA salt. LCMS (m/z): 590.5 (MH+), retention time=0.71 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81-1.32 (m, 12H) 1.33-1.66 (m, 4H) 1.82-1.99 (m, 1H) 1.99-2.21 (m, 4H) 2.89-3.04 (m, 2H) 3.04-3.19 (m, 2H) 3.27 (d, J=2.35 Hz, 2H) 4.40 (br. s., 1H) 6.38 (s, 1H) 6.55 (d, J=9.00 Hz, 1H) 6.77 (br. s., 1H) 6.91 (br. s., 1H) 7.21 (br. s., 1H) 7.48 (d, J=9.00 Hz, 1H) 8.03 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5](OC)=[O:6].[CH3:13][NH2:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([NH:14][CH3:13])=[O:6]
Reactant: CN
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1
Product: CNC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 3,5-dichlorobenzoate (2-D) (1.07 g, 5.0 mmol) was suspended in a vigorously stirring solution of methylamine (40%/H2O, 5.0 mL). After heating gently for 10 min, the mixture was stirred at room temperature for 18 h. The mixture was extracted with methylene chloride and the extract dried (MgSO4) to provide 3,5-dichloro-N-methylbenzamide (2-E).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)=[CH:35][CH:34]=1>>[N:39]1([C:36]2[CH:37]=[CH:38][C:33]([C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15]([CH:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]5)=[N:14][C:13]=4[CH:30]=3)=[CH:34][CH:35]=2)[CH:43]=[N:42][N:41]=[N:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: Brc1ccc(-n2cnnn2)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4)ccc3o2)CC1
Yield: 40.7 %

Procedure:
Following the General Procedure-1, the titled compound (80 mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and 1-(4-bromophenyl)-1H-tetrazole (100 mg, 0.44 mmol) as a brown solid. M.P.: 207-211° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.02 (s, 1H), 7.91 (d, J 1.2, 1H), 7.82-7.79 (m, 4H), 7.62-7.55 (m, 2H), 4.16 (d, J 10.6, 2H), 3.21-3.12 (m, 1H), 3.00 (t, J 12.3, 2H), 2.20-2.14 (m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Br:10]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)CCO2
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a chilled (10° C.) solution of 10 g (83 mmol) of 2,3-dihydrobenzofuran in 50 mL of acetic acid, 4 mL (78 mmol) of bromine in 6 mL of acetic acid was added dropwise over a 10 minute period. After 1 hour, the mixture was made basic by cautiously pouring the reaction mixture into saturated/solid aqueous sodium bicarbonate solution and stirring overnight. The mixture was then extracted with three 100 mL portions of EtOAc. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to afford a yellow oil. The oil was diluted with hexanes and passed through a pad of silica gel in a 600 mL funnel eluting with hexanes to afford a white solid which was diluted with cold (dry ice-acetone) hexanes and collected by filtration to afford 4.7 g (28%) of 5-bromo-2,3-dihydrobenzofuran as a white solid, mp 45° C.-48° C. The filtrate was concentrated to afford 5.1 g of 5-bromo-2,3-dihydrobenzofuran which was 70% pure.
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[C:12]=1[NH:19][C:20](=[O:36])[CH2:21][CH:22]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:29][C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)(C)(=O)=O.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>CN(C)C=O.C(OCC)(=O)C>[N:37]1([CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[C:12]=2[NH:19][C:20](=[O:36])[CH2:21][CH:22]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[O:29][C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: CSc1cccc(COCCCOS(C)(=O)=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cccc(COCCCn2ccnc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 90 °C
Reaction time: 5.5 h
Yield: 68 %

Procedure:
251 mg of the crude crystals of N-{2-[3-(mesyloxy)propoxy]methyl-6-methylthiophenyl}-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (i) above] were suspended in 3 ml of dimethylformamide. 162 mg (2.39 mmol) of imidazole were added to the suspension, and the mixture was stirred for 5.5 hours at 90° C. At the end of this time, the reaction mixture was allowed to return to room temperature, after which it was diluted with ethyl acetate and washed several times with water. The solvent was then removed by distillation under reduced pressure, and the resulting residue was subjected to column chromatography through 15 g of silica gel. Fractions eluted with mixtures of methylene chloride and methanol ranging from 100:2 to 100:7 by volume were collected. Recrystallization from a mixture of methylene chloride and methanol afforded 162 mg (yield 68%) of the title compound as crystals, melting at 176.5°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:17])([F:16])[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:9]([F:17])([F:16])[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(Cl)cc1C(F)(F)c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(F)(F)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the preparation of N-Aryl-benzenesulfonamides using 4-chloro-2-(difluoro-pyridin-4-yl-methyl)-phenylamine and 4-tert-butyl-benzenesulfonyl chloride. MS: (M+H)=451.
Reaction SMILES: C[O:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(=O)n3nc(C(=O)O)cc3[nH]c12
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cc2[nH]c3c(O)cccc3c(=O)n2n1
Yield: 76.2 %

Procedure:
From 4,9-dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid (1.04 g), 48% hydrobromic acid (25 ml) and acetic acid (25 ml), following the procedure of Example 3, there is obtained the desired product (0.75 g) as the quarter hydrate. mp 326°-330° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1.[Br:17]Br.C(=O)([O-])O.[Na+]>ClCCl>[Br:17][C:4]1[O:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: BrBr
Reactant: Cc1nc(-c2ccc3c(c2)CCCC3)co1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(-c2ccc3c(c2)CCCC3)c(Br)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)oxazole (9.0 g) in dichloromethane (90 mL) was added dropwise a solution of bromine (2.2 mL) in dichloromethane (5 mL) at room temperature. After stirring the mixture at room temperature for 30 min, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 5-bromo-2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)oxazole (11.7 g, yield 95%) as crystals. Recrystallization from ethanol gave colorless plate crystals. melting point: 97–98° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[N:11]=[C:12]([C:15]([OH:17])=O)[S:13][CH:14]=1)([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[CH3:27][C:28]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([C:37](=[O:39])[CH3:38])[C:29]=1[NH2:30]>C1(C)C=CC=CC=1>[C:37]([C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:28]([CH3:27])[C:29]=1[NH:30][C:15]([C:12]1[S:13][CH:14]=[C:10]([CH:7]([CH3:8])[CH3:9])[N:11]=1)=[O:17])(=[O:39])[CH3:38]
Reactant: COc1ccc(C(C)=O)c(N)c1C
Reactant: CC(C)c1csc(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Oxalyl chloride (5.71 g, 45 mmol., 3.0 eq) was added dropwise, at ambient temperature, to a solution of 4-isopropyl-thiazole-2-carboxylic acid (3.85 g, 22.5 mmol., 1.5 eq) in toluene (40 mL). Stirring was continued at ambient temperature until the bubbling stopped. The reaction mixture was then heated under reflux for a further 1 hour. LCMS analysis of an aliquot quenched with methanol revealed full conversion of the acid to the acid chloride. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was diluted with dry dioxane (40 mL). Diisopropylethylamine (3.9 g, 30 mmol., 2 eq.) was added dropwise followed by 2-methyl-3-methoxy-6-acetyl-aniline (2.7 g, 15.0 mmol., 1.0 eq). The reaction mixture was stirred at ambient temperature for 15 hours. LCMS analysis showed full conversion of the starting material to product. The solvent was removed under vacuum and the residue dissolved with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), water (50 mL), and brine (50 mL), dried over sodium sulphate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography using a gradient of heptanes:ethyl acetate (4:1 to 6:4). The relevant fractions were combined and the solvent removed under vacuum to give 4.55 g (91%) of the title compound as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 11.28 (br. s, 1 H), 7.76 (d, J=8.70 Hz, 1 H), 7.17 (s, 1 H), 6.79 (d, J=8.70 Hz, 1 H), 3.94 (s, 3 H), 3.23 (spt, J=6.89 Hz, 1 H), 2.59 (s, 3 H), 2.17 (s, 3 H), 1.42 (d, J=6.87 Hz, 6 H). LC-MS: 99% (UV), tR 2.24 min, m/z [M+1]+ 333.05.