Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[C:11]([N:22](S(C2C=CC(C(C)C)=CN=2)(=O)=O)[S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=2)(=[O:25])=[O:24])[N:10]([CH3:47])[N:9]=1)(=O)C.[OH-].[Na+]>C(O)C>[O:17]1[C:16]2[CH:20]=[CH:21][C:13]([C:12]3[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9][N:10]([CH3:47])[C:11]=3[NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=3)(=[O:25])=[O:24])=[CH:14][C:15]=2[O:19][CH2:18]1
Reactant: CC(=O)OCCOc1nn(C)c(N(S(=O)(=O)c2ccc(C(C)C)cn2)S(=O)(=O)c2ccc(C(C)C)cn2)c1-c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of 2-[(4-(1,3-benzodioxol-5-yl)-5-{bis[(5-isopropyl-2-pyridinyl)sulfonyl]amino}-1-methyl-1H-pyrazol-3-yl)oxy]ethyl acetate (Preparation 67) (9.0 g) in ethanol (200 ml) was added 2.0M aqueous sodium hydroxide (25 ml). The reaction was stirred for 30 min and concentrated under reduced pressure and the residue was poured onto 0.5M aqueous citric acid (300 ml). This was extracted with ethyl acetate (3×80 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude residue was purified by silica (230 g) chromatography eluting with a gradient of 50% ethyl acetate in hexane to 70% ethyl acetate in hexane to afford the title product as a white solid (5.0 g)
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:3]=1[O:4][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(OCC)C>[CH3:14][Si:13]([CH3:15])([CH3:16])[C:10]1[CH:11]=[CH:12][C:2]([CH3:1])=[C:3]([OH:4])[CH:9]=1
Reactant: Cc1ccc([Si](C)(C)C)cc1O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc([Si](C)(C)C)cc1O
Reaction time: 0.08 h
Yield: 53.2 %

Procedure:
To a solution of 2-methyl-5-(trimethylsilyl)phenoxytrimethylsilane (Intermediate 2; 5 g) in diethyl ether (40 mL) at room temperature was added tetrabutylammonium fluoride (TBAF; 19.3 mL, 1.0 M solution, 19.3 mmol). The reaction was stirred at this temperature for 5 minutes and then water (40 mL) was added. The mixture was extracted with diethyl ether (2×40 mL) and the combined organic extracts were dried (magnesium sulphate), concentrated under reduced pressure and purified by column chromatography (SiO2; light petroleum to 9:1 light petroleum-diethyl ether) to give the title compound as a colourless oil (1.9 g, 56%). Rf=0.32 (9:1 light petroleum-diethyl ether). 1H NMR δH 0.26 (9 H, s), 2.27 (3 H, s), 4.62 (1 H, s), 6.93 (1 H, d, J=1.0 Hz), 7.02 (1 H, dd, J=7.3, 1.0 Hz), 7.15 (1 H, d, J=7.3 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and benzoyl chloride: Anal. Calcd for C31H37N3O2+0.55CHCl3: C, 69.0; H, 6.89; N, 7.65. Found: C, 69.7; H, 6.73; N, 6.03; ESMS m/e: 484.4 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([SH:18])[CH:14]=[CH:15][C:16]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([S:18][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: Fc1ccc(S)cc1Cl
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(SCc2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Picolyl chloride hydrochloride (3.03 g) was added to a stirred suspension of 3-chloro-4-fluorobenzenethiol (3.0 g) and cesium carbonate (12.0 g) in DMF (50 ml) and the mixture stirred at RT overnight. Mixture poured into water, organics extracted into ether and the ether extracts washed (brine), dried (MgSO4) and evaporated under reduced pressure to a green oil (4.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:33]2[CH2:34][CH2:35][N:30]([C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=3)[CH2:31][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)c(OC)nc2c1
Yield: 94 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 94%). 1H NMR (300 MHz, CDCl3): δ 3.57-3.65 (m, 8H), 3.90 (s, 3H), 4.01 (s, 3H), 7.06 (d, J=9.4 Hz, 2H), 7.18-7.22 (m, 2H), 7.69 (d, J=8.6 Hz, 2H), 8.09 (d, J=9.4 Hz, 2H), 9.20 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15](=[O:21])[CH2:16][O:17]C(=O)C)=O)(C)(C)C.[ClH:22]>C(O)(C)C>[ClH:22].[CH:12]12[CH2:14][CH:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15](=[O:21])[CH2:16][OH:17]
Reactant: CC(=O)OCC(=O)N1CC2CC1CN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: O=C(CO)N1CC2CC1CN2
Temperature: 51 °C
Reaction time: 20 h

Procedure:
To a slurry of 5-(2-acetoxy-acetyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.2 g, 4 mmol) in isopropanol (16 mL) was quickly added 5 M HCl in isopropanyl (3.2 mL, 16 mmol). The mixture was warmed to 51° C. and stirred for 20 h. It was then concentrated to provide the title compound in 97 wt % purity (767 mg, 96%). MS (ESI): mass calcd. for C7H12N2O2, 156.1; m/z found, 157.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 9.9-9.2 (m, 2H), 4.73-4.71 (m, 1H), 4.42-4.37 (m, 1H), 4.1-3.9 (m, 2H), 3.79-3.77 (m, 0.5H), 3.55-3.48 (m, 1H), 3.37-3.35 (m, 0.5H), 3.25-3.07 (m, 2H), 2.00-1.82 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:42][Si](C(C)(C)C)(C)C)[CH2:25][C@@H:26]2[O:34][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[I-].[CH2:51]([Li])[CH2:52][CH:53]([CH3:55])[CH3:54].[Cl-].[NH4+]>C(OCC)C>[CH3:54][CH:53]([CH2:52][CH2:51][CH2:3][C@H:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([OH:42])[CH2:25][C@@H:26]2[OH:34])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH3:1])[CH3:55]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)[C@H]2CC[C@H]3C4=CC=C5C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]5(C)[C@H]4CC[C@]23C)cc1
Reactant: [Li]CCC(C)C
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 99 mg of 20-methyl-1α,3β-bis(t-butyldimethylsilyloxy)-21-p-toluenesulfonyloxypregna-5,7 -diene in 2 ml of diethyl ether was added dropwise, at -50° C. to -60° C., to a diethyl ether solution of iodide and 0.9 ml of a 1.1N diethyl ether solution of isoamyllithium in 2 ml of diethyl ether. After stirring at -30° C. for 1 hour, the reaction mixture was poured into a cold aqueous solution of ammonium chloride, followed by extraction with diethyl ether. The extract was washed with 10% aqueous ammonia, water and an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was dissolved in 2 ml of tetrahydrofuran, 1 ml of a 40% aqueous solution of tetra-n-butylammonium fluoride was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The extract was washed with an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was washed with cold ethyl acetate to give 45 mg of cholesta-5,7-diene-1α,3β-diol, whose 1H NMR spectrum was identical with that obtained in Reference Example 8.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH:17]12[O:22][CH:21]1[CH2:20][O:19][CH2:18]2>>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:21]2[CH2:20][O:19][CH2:18][C@H:17]2[OH:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C1OCC2OC12
Product: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (1.85 g, 0.0078 mole) and the compound of Example 1 (0.64 g, 0.0074 mole) were added to a degassed (Argon) solution of 50% sodium hydroxide (5 ml) and isopropyl alcohol (50 ml). The reaction was heated to reflux for 24 hours. The reaction was cooled to room temperature and poured into water (125 ml). The solution was made acidic with 1 N hydrochloric acid and extracted 3 times with 100 ml of diethyl ether. The combined diethyl ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oily solid in a rotary evaporator. The product was purified by silica gel chromatography and recrystallized from hexane (m.p. ca. 104° C.). The structure was supported by NMR and infrared spectroscopy and elemental analysis.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][N:11]=1.[C:17](=[O:19])=[O:18]>C1COCC1>[Cl:9][C:10]1[N:11]=[CH:12][CH:13]=[C:14]([Cl:16])[C:15]=1[C:17]([OH:19])=[O:18]
Reactant: Clc1ccnc(Cl)c1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)ccnc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Lithium diisopropylamide (2M in heptane/THF/benzene, 16.7 mL) was treated dropwise with 2,4-dichloropyridine (5 g, 33.8 mmol) at −78° C. in THF (25 mL). The mixture was stirred at −78° C. for 2 hours, treated with excess dry ice, allowed to warm up to room temperature, and partitioned between diethyl ether and an equal volume of 10% aqueous KOH. The basic extract was neutralized with 10% HCl and extracted with diethyl ether. The ethereal extract was dried (Na2SO4), filtered, and the filtrate wasconcentrated under reduced pressure to provide 9.5 g (70% yield) of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.32 (s, 1H), 7.74 (d, J=5.42 Hz,1H), 8.47 (d, J=5.42 Hz,1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[C:14]([NH:16][OH:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C([O:29]C1C=CC(CC(N)=O)=CC=1)C>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[C:14]([NH:16][OH:17])=[O:15])=[O:29])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CCOc1ccc(CC(N)=O)cc1
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2ccc(OCC)cc2)cc1
Product: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2ccc(OCC)cc2)cc1
Yield: 73 %

Procedure:
Starting from 2-{[4-(2-butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-(4-ethoxyphenyl)acetamide (808 mg, 2.27 mmol) and following the procedure as outlined in Example 7, 640 mg of 2-{[4-(2-Butynyloxy)phenyl]sulfinyl}-N-hydroxy-2-(4-ethoxyphenyl acetamide was isolated as a brown powder. Yield: 73%; MS: 388.2 (M+H)+. Mp: 192-193.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19](=[O:30])[C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=3[Cl:29])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([Cl:29])=[C:20]([CH:25]=1)[C:19]([C:13]1[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:31]([F:34])([F:33])[F:32])[CH:4]=2)(=[O:10])=[O:9])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=1)=[O:30]
Reactant: Cc1cnc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cnc(C(=O)c2cc(N)ccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To Fe powder (61.3 mg, 1.09 mmol), AcOH (2 mL) was added dropwise and heated to 80° C. To it, a solution of 4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (136 mg, 0.255 mmol) in AcOH (2 mL) was added slowly. After 30 min, reaction mixture was allowed to cool to room temperature and diluted with EtOAc (25 mL), filtered through a pad of Celite. The filter cake was washed with EtOAc (25 mL) and the filtrate was concentrated. The residual liquid was slowly treated with saturated aqueous NaHCO3 solution, followed by small portions of solid NaHCO3 to neutralize the AcOH, extracted with EtOAc (2×25 mL) and the extracts were dried (anhydrous Na2SO4), concentrated under reduced pressure and purified (SiO2, EtOAc) to get N-[2-(5-amino-2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (118 mg) in 92.2% yield. ESMS m/z (relative intensity): 504 (M+H)+ (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:19]2=[CH:20][CH:21]=[N:22][CH:23]=[C:18]2[C:5]2[C:6]([OH:17])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:17][C:6]1[C:5]2[C:18]3[C:19]([C:2]([CH3:1])([CH3:24])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])[CH:7]=1)=[CH:20][CH:21]=[N:22][CH:23]=3)(=[O:27])[CH3:26]
Reactant: CCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(2-heptyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(2-heptyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[C:14]1[N:15]=[C:11]([C:10]2[C:2]([CH3:1])=[N:3][N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=23)[S:12][C:13]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: OB(O)c1c(F)cccc1F
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
To a mixture of Methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (500 mg, 1.2 mmol) obtained in Example 13-B(ii), 2,6-difluorophenylboronic acid (375 mg, 2.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (97 mg, 0.12 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in DME (20 mL), was added water (1 mL) and the mixture was stirred at 80° C. for 3 h. The reaction mixture was allowed to cool to room temperature, and then water (100 mL) was added. The aqueous mixture was extracted with EtOAc (100 mL×2) and the combined organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound (147 mg, 32%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[N:4]1)[CH3:2].[NH3:35]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([NH2:35])=[O:9])[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[N:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)Cl)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reactant: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCn1cc(C(N)=O)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reaction time: 16 h

Procedure:
To a solution of the title A compound, 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carbonyl chloride (0.15 g, 0.3 mmol) in DCM is added a saturated solution of ammonia (3 mL) in DCM at RT. The reaction mixture is stirred for 16 h. The reaction mixture is diluted with ethyl acetate, washed with water, dried and evaporated to give 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzene-sulfonylamino}-1H-pyrazole-4-carboxylic acid amide as a solid: MS [m/z] 481.5 [M-1]−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O>>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccco1
Product: c1ccc(NCc2ccco2)cc1

Procedure:
The title compound was prepared from aniline and 2-furaldehyde by the same procedure as described in Example 32, part A. The product was obtained as an oil (3.43 g, 99%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:9]([N:3]1[CH2:4][C@@H:5]([CH3:8])[NH:6][CH2:7][C@@H:2]1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
50 g trans-2,5 dimethylpiperazine was dissolved in 300 mL ethanol and treated with 26.36 mL (½ equivalents) benzylbromide. The mixture was stirred at room temperature for 12 hours and concentrated. The residue was taken up in ethyl acetate and washed with 10% aqueous sodium bicarbonate and saturated sodium chloride; dried over anhydrous magnesium sulfate and concentrated to give crude 1-benzyl-trans-2,5-dimethylpiperazine, as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([Cl:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([Cl:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(Cl)cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cc(O)cc(Cl)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.9 %

Procedure:
To a solution of Example 86 (0.100 g, 0.184 mmoles) in dichloromethane (4 ml), BBr3 (1M in dichloromethane, 1 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as pale green solid (0.032 g, 33% yield). MP: 122-124° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.19(s,1H), 8.06(s, 1H), 8.04(dd, J=7.9,1.5 Hz, 1H), 7.86(m,1H), 7.67(d, J=8.3 Hz, 1H), 7.53(t, J=7.1 Hz, 1H), 7.28(br s,1H), 7.06-6.87(m,6H), 6.03(q, J=6.9 Hz, 1H),1.88(d, J=7.1 Hz, 1H). Mass: 528.11(M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2ccccn2)c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
2.96 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile were dissolved in 100 ml of ethanol and added at room temperature to 100 mg of 10% palladium-on-charcoal. The mixture was shaken at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was then removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution. There were obtained 2.44 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 114°-115° C.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:15])[NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[CH:2]=[CH2:3].O>C(O)C.O.N>[NH:10]=[C:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:6][C:5](=[O:15])[N:4]1[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCNC(=O)Nc1ccccc1C#N
Agent: N
Solvent: O
Solvent: CCO
Product: C=CCn1c(=O)[nH]c2ccccc2c1=N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
A mixture of 2-(3-allylureido)benzonitrile (10.0 g, 50 mmol) in ethanol (70 mL) and 28% of ammonia water (50 mL) was heated on a steam bath with occasional stirring for 15 minutes. The mixture was then cooled to room temperature and to the mixture was added water (100 mL). The solid was collected by filtration and was recrystallized from methanol with a few drops of ammonia water to give 8.4 g (84%) of 3,4-dihydro-4-imino-3-allyl-2(1H)-quinazolinone, mp 223°-224° C. IR (KBr): 3284, 3203, 3147, 1691, 1582 cm-1. 1H NMR (300 MHz, DMSO-d6): δ4.61 (d, 2H, =CH2), 5.08 (q, 2H, CH2), 5.85 (m, 1H, =CH), 7.07 (m, 2H, Ar--H), 7.46 (t, 1H, Ar--H), 8.04 (d, 1H, Ar--H), 8.85 (br s, 1H, NH), 10.74 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): δ42.54, 115.08, 115.81, 122.09, 126.13, 132.77, 133.15, 137.01, 149.76. Anal. Calcd for C11H11N3O; C, 65.63; H, 5.56; N, 20.87. Found: C, 65.67; H, 5.51; N, 20.86.