Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1.[F-].[Cs+]>COCCOC.CO.CCOC(C)=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>[CH3:9][O:8][C:6]1[C:5]([NH2:10])=[CH:4][N:3]=[C:2]([C:15]2[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=2)[N:7]=1
Reactant: COc1nc(Cl)ncc1N
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CO
Product: COc1nc(-c2cnn(C)c2)ncc1N
Temperature: 150 °C
Yield: 92.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol) was added to a solution of 2-chloro-4-methoxypyrimidin-5-amine (41 mg, 0.257 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (107 mg, 0.514 mmol) and cesium fluoride (117 mg, 0.771 mmol) in DME/MeOH (2/1, 1.6 mL). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes. The reaction was then diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified via Biotage silica gel column chromatography eluting with DCM/EtOH 99/1 to 90/10 followed by filtration through a SCX-2 column to afford the title product as a white solid (49 mg, 93%). 1H NMR (500 MHz, CDCl3): δ 3.68 (br s, 2H), 3.93 (s, 3H), 4.06 (s, 3H), 7.88 (s, 1H), 7.92 (s, 1H), 8.04 (s, 1H). LC (Method B)-MS (ESI, m/z) tR 1.33 min, 206 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:37])[NH:28][CH2:29][CH2:30][O:31]C(=O)C(C)=C)[CH:21]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl.O>CO>[C:1]([C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][NH:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:28][CH2:29][CH2:30][OH:31])=[O:37])[CH:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=C(C)C(=O)OCCNC(=O)Nc1cc(CNc2ccccc2C(=O)NOCc2ccc(C#N)cc2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CONC(=O)c2ccccc2NCc2ccnc(NC(=O)NCCO)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 2-methyl-acrylic acid 2-[3-(4-{[2-(4-cyanobenzyloxy-carbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-ureido]-ethyl ester (Example 533, 500 mg) in methanol (10 ml) was added 2 M aqueous sodium hydroxide (5 ml). The reaction mixture was stirred at room temperature for 20 minutes. The pH of the mixture was adjusted to 5 by addition of 4 M hydrochloric acid and water (15 ml) was added. The resulting precipitated material was isolated by filtration and dried in vacuo, and gave the title compound. 13C-NMR (DMSO-d6) δ 167.4, 154.8, 153.8, 151.1, 148.6, 146.7, 141.8, 132.6, 132.1, 129.1, 128.0, 118.6, 115.1, 114.8, 113.0, 111.6, 110.8, 109.3, 76.0, 60.2, 45.3, 41.8.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O1CCOCC1.O>[F:27][C:12]([F:11])([F:26])[C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH2:18][CH2:17]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: COC(=O)c1cnc(Br)s1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 82.5 °C

Procedure:
A mixture of methyl 2-bromo-1,3-thiazole-5-carboxylate (10 g, 45 mmol) and 4-[2-(trifluoromethyl)phenoxy]piperidine (12.1 g, 50 mmol) in dioxane (160 mL) was heated at 80-85° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed twice with water, dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (eluting with 50% EtOAc/hexanes) to afford the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([CH3:17])[C:11](=O)[C:10]2[C:5](=[C:6]([CH3:15])[CH:7]=[C:8]([CH3:14])[C:9]=2[CH3:13])[C:4]1=O)[CH3:2].C1C=CC=CC=1>Cl.C(O)C>[CH2:1]([C:3]1([CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([CH3:15])[CH:7]=[C:8]([CH3:14])[C:9]=2[CH3:13])[CH2:4]1)[CH3:2]
Reactant: CCC1(C)C(=O)c2c(C)cc(C)c(C)c2C1=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: CCC1(C)Cc2c(C)cc(C)c(C)c2C1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a mixture of 60 g of 7% Zn/Hg in 200 ml of 20% hydrochloric acid and 70 ml of ethanol was added 27.92 g of the 2-ethyl-2,4,5,7-tetramethylindan-1,3-dione with stirring. After refluxing for 6 hours, the reaction mixture was added 100 ml of benzene and refluxed for 3 hour. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 17.77 g of the title compound as yellow oil.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[NH:27][C:28]([CH:31]([C:39]3[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=3)[CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][CH:30]=2)[CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:48][S:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:31]([C:28]2[NH:27][C:26]([C:22]3[CH:21]=[C:20]([CH2:19][OH:18])[CH:25]=[CH:24][N:23]=3)=[CH:30][CH:29]=2)[CH2:32][CH:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:40][CH:41]=1)(=[O:47])=[O:46]
Reactant: CC(C)(C)[Si](OCc1ccnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(CO)ccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (870 mg) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 1.54 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (533 mg, yield 95%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 441 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])[C:10](O)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])[C:10]([Cl:17])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)c1cc(Cl)cc(Br)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C(=O)Cl)c1cc(Cl)cc(Br)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-bromo-5-chloro-phenyl)-propionic acid (0.87 g, 3.3 mmol) in CH2Cl2 (10 mL) was added oxalyl chloride (0.63 mL, 6.6 mmol) and DMF (2 drops), and the reaction was stirred for 15 minutes and then concentrated to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]12([NH2:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C(#N)C>[C:14]12([NH:24][CH2:2][C:3]([N:5]3[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]3[C:12]#[N:13])=[O:4])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC12CC3CC(CC(C3)C1)C2
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.20 mmol ) in acetonitrile (3 mL ) at room temperature under nitrogen was added 1-adamantanamine(0.06 g, 0.408 mmol ). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the titled compound. MS (DCI) m/z 312 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])[NH:28][C:27]=1[C:37]([OH:39])=O.[NH2:40][CH2:41][C:42]1[C:43]([F:59])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:53]#[N:54])[C:45]([Cl:48])=[CH:46][CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH:34]2[CH2:35][CH2:36]2)=[O:32])[NH:28][C:27]=1[C:37]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([C:53]#[N:54])[CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:43]=1[F:59])=[O:39]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(NC1CC1)c1cc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(=O)NC4CC4)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 3-chloro-5-[(cyclopropylamino)carbonyl]-1H-pyrrole-2-carboxylic acid (0.037 g, 0.161 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. The residue was subjected to silica gel column chromatography (EtOAc/hexanes) to afford an impure solid. A second purification by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) afforded the title compound (0.0098 g, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10-8.26 (m, 1H), 7.82 (br. s., 1H), 7.39-7.62 (m, 5H), 7.33 (d, 1H), 6.35 (br. s., 1H), 4.42 (br. s., 2H), 2.62-2.79 (m, 1H), 0.61 (d, 2H), 0.45 (br. s., 2H). LCMS: m/z 521.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:31](=[O:33])[CH3:32])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1c(CCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)c(C)c(CCC(=O)O)n2Cc1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
Using the title compound of Example 23 as starting material, (1 g) was dissolved in CH2Cl2 (20 ml) at 0° C. and 1 ml pyridine added. 1.8 g acetic anhydride was added and the reaction let stir at 23° for 16 hours. The organic phase was washed with H2O (5×5 ml), evaporated and chromatographed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=1[Cl:20])[CH3:11])[NH2:5].[S-:21][C:22]#[N:23].[K+].BrBr>>[F:1][C:2]1[C:8]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=2[Cl:20])[CH3:11])=[CH:7][C:6]2[S:21][C:22]([NH2:23])=[N:5][C:4]=2[CH:3]=1
Reactant: N#C[S-]
Reactant: CC(Oc1ccc(N)cc1F)c1c(Cl)ccc(Cl)c1Cl
Agent: BrBr
Agent: [K+]
Product: CC(Oc1cc2sc(N)nc2cc1F)c1c(Cl)ccc(Cl)c1Cl
Yield: 74.7 %

Procedure:
5-Fluoro-6-[1-(2,3,6-trichlorophenyl)ethoxy]-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 1.35 g of 3-fluoro-4-[1-(2,3,6-trichlorophenyl)ethoxy]aniline, 1.56 g of potassium thiocyanate and 0.207 cm3 of dibromine. We obtain 1.18 g of 5-fluoro-6-[1-(2,3,6-trichlorophenyl)ethoxy]-1,3-benzothiazol-2-amine in the form of an orange-coloured powder, which has the following characteristics:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:34])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH2:35]([C:42](Cl)=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:34])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][NH:33][C:42](=[O:43])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CNC(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Diisopropylethylamine (0.17 ml, 1.02 mmol) was added in one portion to a stirred solution of [1-(4-aminomethyl-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.25 g, 0.68 mmol) in DCM (10 ml) at room temperature. To this mixture was added benzyl carbonyl chloride (0.1 g, 0.68 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.32 g, 97% yield) as a white solid. δH (500 MHz, DMSO) 8.67 (t, J=5.99 Hz, 1 H) 7.66 (d, J=8.20 Hz, 2 H) 7.47 (d, J=8.35 Hz, 2 H) 7.19-7.36 (m, 5 H) 6.85 (d, J=7.25 Hz, 1 H) 4.38 (d, J=5.99 Hz, 2 H) 3.51 (s, 2 H) 3.46 (d, J=11.82 Hz, 2 H) 3.21 (br. s., 1 H) 2.33-2.43 (m, 3 H) 1.76 (d, J=10.56 Hz, 2 H) 1.30-1.45 (m, 12 H).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[C:36]([O:40][C:41](=[O:65])[CH2:42][N:43]([S:55]([C:58]1[CH:63]=[CH:62][C:61](Br)=[CH:60][CH:59]=1)(=[O:57])=[O:56])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:39])([CH3:38])[CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C>[C:36]([O:40][C:41](=[O:65])[CH2:42][N:43]([S:55]([C:58]1[CH:63]=[CH:62][C:61]([C:16]2[CH:15]=[CH:14][C:13]([C:12]3[C:11]4[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=4[O:9][C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:17]=2)=[CH:60][CH:59]=1)(=[O:57])=[O:56])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 80 °C
Yield: 23 %

Procedure:
A solution of 2-benzyl-3-[4′-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran (268 mg 0.653 mmol) in anhyd DMSO (5 mL) was added to a stirred suspension of tert-Butyl-[(4-bromobenzenesulfonyl)-(3-trifluoromethylbenzyl)amino]-acetate (296 mg, 0.58 mmol) and tripotassium phosphate (0.37 g, 1.76 mmol) in anhyd DMSO (5 mL). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (60 mg, 0.07 mmol) was added as a solid, and the resulting suspension was heated to 80° C. for 25 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered though celite, and washed with sat'd aq LiCl (3×10 mL), sat'd aq NaCl (1×10 mL), dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (heptane) afforded the title compound as a white solid (95 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:24]=[CH:23][C:13]2[NH:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH2:17][CH2:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:26][C:27]1[N:31]([C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]=[N:29][N:28]=1.[I-].[Na+].[H-].[Na+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]1[CH:24]=[CH:23][C:13]2[N:14]([CH2:26][C:27]3[N:31]([C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:30]=[N:29][N:28]=3)[C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH2:17][CH2:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)CCc1ccccc1N2
Reactant: ClCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)CCc1ccccc1N2Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 1.3 g of Compound 31-2b, 2.0 g of 5-chloromethyl-N-triphenylmethyltetrazole, 0.6 g of sodium iodide, 0.2 g of sodium hydride (60% oily) and 50 ml of DMF was stirred at 80° C. for 15 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (10/1)] to give 1.05 g of an oily substance containing the desired compound.
Reaction SMILES: C[Li].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:10].O1CCC[CH2:29]1>C1C=CC=CC=1.CCCCCC>[OH:10][C:9]([C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH3:29]
Reactant: C1CCOC1
Reactant: COc1ccc(C(=O)Nc2ccccc2C(=O)c2ccccn2)cc1
Agent: [Li]C
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2ccccc2C(C)(O)c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
Methyl lithium (0.24 mole, 142 ml. of 1.7 molar in ether) is added to 2'-(2-pyridinecarbonyl)-p-anisanilide (36.6 g., 0.11 mole) in 400 ml. of tetrahydrofuran in 15 min. with stirring at 10° -20° C. Stirring is continued for another 30 min., the reaction mixture hydrolyzed by addition of 300 ml. of water, concentrated under reduced pressure until the tetrahydrofuran solvent is substantially removed, and the mixture extracted with ethyl acetate. The ethyl acetate extract washed with water, brine, dried over sodium sulfate and concentrated affords a residual dark brown oil. The residue taken up in benzene and diluted with hexane affords 2'-[1-hydroxy-1-(2-pyridyl)ethyl] -p-anisanilide, m.p. 127° -128° C., from aqueous-methanol.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].C(N(CC)CC)C>C(O)CC>[OH:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: NCc1ccccc1O
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: CCN(CC)CC
Product: Oc1ccccc1CNc1ncnc2c1ncn2C1CCCCO1
Yield: 90 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 2-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-propanol for 3 hrs. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 90%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity >98%. 1H-NMR (400 MHZ, DMSO): 1.58m (2H); 1.70m (1H); 1.95m (2H); 2.26qq (1H, Ja=11.8 Hz, Jb=4.0 Hz); 3.67m (1H); 4.0d (1H, J=11.3 Hz); 4.64bs (2H); 5.63dd (1H, Ja=11.3 Hz, Jb=1.8 Hz); 6.73t (1H, J=7.5 Hz); 6.82 (d, 1H, J=7.9 Hz); 7.06t (1H, J=7.5 Hz); 7.14d (1H, J=7.5 Hz); 8.21 s (1H); 8.35bs (1H); 8.37bs (1H); 9.82bs (1H). MS (ES): [M+H]+=326 (100).
Reaction SMILES: C[O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[C:4]=1[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:4]=1[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)N(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-dimethoxy-N,N-dimethylbenzamide (100 mg, 0.48 mmol) in methylene chloride (2.5 mL) is added BBr3 (1.0M in methylene chloride, 1.4 mL) dropwise and the mixture is stirred at RT for 18 h. Water is added and the suspension is extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound: 1H NMR (DMSO-d6) δ 9.35 (s, 2H), 6.93-6.89 (t, J=8.34 Hz, 1H), 6.29-6.27 (d, J=8.09 Hz, 2H), 2.89 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:21][OH:22])[NH2:20])[CH:3]=1.[CH:23](OCC)(OCC)[O:24][CH2:25]C.[C:33](#N)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([N:1]=[CH:23][O:24][CH3:25])=[CH:3][C:4]([C:19]2[N:20]=[CH:33][O:22][N:21]=2)=[N:5]1
Reactant: CC#N
Reactant: NC(=NO)c1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC=Nc1cc(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 70 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-pyrazolecarboxamide oxime (4.00 g, 11.3 mmol) and triethyl orthoformate (2.45 g, 22.6 mmol) were dissolved in 40 ml of dry acetonitrile, and then p-toluenesulfonic acid monohydrate (0.02 g) was added with stirring at room temperature. After the mixture was stirred at 60° C. for 6 hours, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure and 50 ml of ethyl acetate was added to the concentrated residue. The organic layer was washed twice with 50 ml of an aqueous saturated sodium hydrogencarbonate solution, and then washed three times with 50 ml of an aqueous saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting concentrated residue was subjected to silica gel column chromatography [eluent: mixed solvent of ethyl acetate and hexane (volume ratio=1:3)] to obtain 3.21 g (7.91 mmol) of the title compound as a pale yellow crystal.