Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH2:29][CH3:30])=[CH:8][C:7]=1[CH3:31].[OH-].[Na+].C1COCC1>CO>[CH2:29]([C:15]1[N:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=2)[O:18][C:14]=1[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]([CH3:31])[CH:8]=1)[CH3:30]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1COc1ccc(CCC(=O)OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1COc1ccc(CCC(=O)O)c(C)c1

Procedure:
3-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-methyl-phenyl}-propionic acid methyl ester (0.100 g, 0.223 mmole) is treated with a mixture of NaOH(aq) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight. The organic solvents are removed on rota-vapor. The residue is diluted with water (10 mL), acidified to pH=2 with 6N HCl(aq). The precipitate is collected through filtration, washed with cold water (30 mL) and dried to provide the titled compound as a white solid. Mass [EI+] 434 (M++H), 432 (M+−H).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[H-].[Na+].[CH:37]1([CH2:40][O:41][C:42]2[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:43]=2[CH:44]=O)[CH2:39][CH2:38]1>CS(C)=O.C(OCC)(=O)C>[CH:37]1([CH2:40][O:41][C:42]2[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:43]=2/[CH:44]=[CH:15]/[C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:13]=[CH:12][S:11]3)[CH2:38][CH2:39]1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC)c2OCC2CC2)nc2sccn12
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Step 3 intermediate (2.0 g, 3.626 mmol) was added NaH (0.160 g, 3.989 mmol) in anhydrous DMSO (10 mL) and stirred for 30 min. A solution of 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (0.82 g, 3.989 mmol) in anhydrous DMSO (10 mL) was added drop wise to this solution at room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), brine and dried (Na2SO4) to yield a crude solid which was purified by column chromatography using 5% ethyl acetate in petroleum ether to afford 0.776 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 2H), 0.50-0.53 (m, 2H), 1.17-1.23 (m, 1H), 1.39 (t, J=7.5 Hz, 3H), 3.75 (d, J=7.2 Hz, 2H), 3.79 (s, 3H), 4.37 (q, J=6.9 Hz, 2H), 6.95-6.99 (m, 2H), 7.08 (t, J=7.8 Hz, 1H), 7.18-7.22 (m, 1H), 7.43 (d, J=4.5 Hz, 1H), 7.69 (d, J=16.2 Hz, 1H), 7.92 (d, J=16.5 Hz, 1H), 8.10 (d, J=4.2 Hz, 1H); ESI-MS (m/z) 399.20 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Under a nitrogen stream, 4-bromo-2-fluorophenol (14.9 g, 78 mmol) and potassium carbonate (13.0 g, 94 mmol) were dissolved in N,N-dimethylformamide (100 mL), followed by addition of benzyl bromide (10.2 mL, 86 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the solvent was concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (ethyl acetate/hexane:0/100-5/95) to give the title compound (21.9 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:4]([CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:16])[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(N)nc(O)c1CCC#N
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(N)nc(Cl)c1CCC#N
Reaction time: 5 h
Yield: 48 %

Procedure:
A mixture of 3-(2-amino-4-hydroxy-6-methylpyrimidine-5-yl)propanenitrile (2 g, 11.2 mmol) and phosphorous oxychloride (13 ml) was kept at 90° C. for 5 hours. The procedure according to pro-treatment of Reference-example 6 was carried out to give the object compound (1.06 g, 48%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]([CH3:14])[C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:20](Cl)Cl>>[C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([C:9]([O:11][CH3:20])=[O:10])=[C:12]([CH3:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1C(=O)O
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(C)cc(C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To 50 g (0.26 moles) of 4-t-butyl-2,6-dimethylbenzoic acid in 250 ml methylene chloride was added 25 ml (0.34 mole) of thionyl chloride at 25° C. After stirring overnight at 25° C. the solvent and remaining thionyl chloride were evaporated in vacuo. The resulting white solid was dissolved in 50 ml tetrahydrofuran and added dropwise to 250 ml of methanol containing 2 ml of pyridine. After heating the reaction mixture to reflux for 30 minutes the solvents were evaporated in vacuo and the residue was dissolved in 200 ml ethyl acetate and 100 ml of water was added. The organic phase was separated and washed with 100 ml saturated aqueous sodium bicarbonate, 50 ml water and 25 ml brine; then dried over anhydrous magnesium sulfate and evaporated to an oil. The oil was distilled in vacuo at 104°-8° C. at 1.2 mm of mercury to obtain 43 g (81% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]([F:19])([F:18])C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:18][CH:14]([F:19])[O:12][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(O)C(F)(F)Cl
Reactant: COC(=O)c1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(F)c1OC(F)F
Yield: 41.3 %

Procedure:
A mixture of methyl 3-fluoro-2-hydroxy-benzoate (1.5 g, 8.8 mmol), 2-chloro-2,2-difluoro-acetic acid (1.62 g, 1.05 mL, 10.6 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were heated in DMF (5 mL) at 120° C. for 5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ether (2×10 mL). The organics were separated and washed sequentially with water (5 mL) and brine solution (5 mL). The organics were dried (MgSO4) and concentrated in vacuo to give residue which was purified by silica gel column chromatography using 0-30% EtOAc/hexanes as eluent to give methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 39%). To methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 3.64 mmol) was added 12% aq. NaOH (3 mL) and the reaction mixture was heated at 50° C. for 1 hour. The aqueous layer was extracted with 1:1 ether/hexane (2×5 mL). The aqueous layer was acidified to pH 1 with 6 N HCl solution to give a suspension. The solid was filtered and washed with water, then dried in vacuo to give 2-(difluoromethoxy)-3-fluoro-benzoic acid (555 mg, 31%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.8 Hz, 1H), 7.43 (dd, J=13.1, 4.8 Hz, 1H), 7.35 (td, J=8.1, 4.9 Hz, 1H), 6.68 (t, J=74.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH:12][CH3:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N:12]([CH3:13])[C:29]([NH:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[F:20])=[O:30])=[C:5]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNc1cnc2ccc(Cl)cc2c1-c1ccccc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: CN(C(=O)Nc1ccc(F)cc1F)c1cnc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
A mixture of 6-chloro-3-methylamino-4-phenylquinoline (0.54 g), 2,4-difluorophenyl isocyanate (0.48 ml) and anhydrous toluene (10 ml) was refluxed for 22 hrs. and then concentrated. The residue was purified by a column chromatography on silica gel and recrystallized from a mixture of ethyl acetate and ethanol to give 6-chloro-3-[3-(2,4-difluorophenyl)-1-methylureido]-4-phenylquinoline as colorless crystals. Yield 0.56 g (66%). m.p. 200°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:21]([C@H:23]1[O:25][CH2:24]1)Cl>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:20][CH2:21][C@H:23]3[CH2:24][O:25]3)=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: ClC[C@@H]1CO1
Reactant: CC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1O
Product: CC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1OC[C@H]1CO1

Procedure:
(R)-(−)Epichlorhydrin (1.93 g; 0.021 mol) was added to a suspension of 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone (1.92 g; 0.007 mol) and potassium carbonate (1.44 g; 0.011 mol) in acetonitrile (5 mL). The mixture was heated under reflux for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 7:3) to give 1-(5-benzene sulfonyl-2-(S)-oxiranylmethoxy-phenyl)-ethanone as a white solid (1.456 g; 63%). A sample was recrystallized from diethyl ether-hexane: M. p. 115.1-116.8° C. Similarly, but replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin, 1-(5-benzene sulfonyl-2-(R)-oxiranylmethoxy-phenyl)-ethanone was prepared. M. p. 111.9-113.5° C. Similarly, but replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone, the above procedure gave 1-[5-(3-fluoro-benzenesulfonyl)-2-(S)-oxiranylmethoxy-phenyl]-ethanone: M. p. 112.7-114.9° C. Replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-Fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone and replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin gave 1-[5-(3-Fluoro-benzenesulfonyl)-2-(R)-oxiranylmethoxy-phenyl]-ethanone. M. p. 118.3-120.5° C.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[O:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)oc1Cl
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (116 mg, 0.44 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (171 mg, 0.44 mmol) [prepared according to Preparation 6] and n,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (228 mg, 0.49 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide (116 mg, 0.19 mmol, 42% yield) as a yellow oil: LCMS (ES) m/e 591, 593 (M, M+2)+.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([CH:79]=O)=[CH:75][CH:74]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:79]([C:76]3[CH:77]=[CH:78][C:73]([O:72][CH3:71])=[CH:74][CH:75]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(C(F)(F)F)nc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccc(C(F)(F)F)nc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 42.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.043 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.13 mmol, 0.13 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.048 mmol, 6.5 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 52%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.64 (s, br, 4H, piperazine N(CH2)2), 3.67 (s, br, 4H, piperazine N(CH2)2), 3.73 (s, 2H, NCH2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.8 Hz, 2H, methoxyphenyl H-2 & H-6), 7.91 (d, br, J=7.6 Hz, 1H, pyridine H-5), 8.09 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.13 (d, J=8.7 Hz, 2H, methoxyphenyl H-3 & H-5), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.77 (s, br, 1H, pyridine H-2), 13.58 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=3)[C:21]=12
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: COCCOC
Product: CC(C)n1nc(-c2cccc(CO)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 42.4 %

Procedure:
A solution of (3-Hydroxymethylphenyl)boronic acid (24 mg, 0.13 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA26 (8.4 mg, 42% yield). ESI-MS (M+H)+ m/z calcd 283.1, found 284.2.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(O)CCO
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-methylbutane-1,3-diol (2.13 mL, 20 mmol) in pyridine (20 mL) at 0° C. was added para-toluenesulfonyl chloride (3.8 g, 20 mmol) in pyridine (10 mL) drop-wise over 15 minutes. This mixture stirred at ambient temperature for 3 hours and 35 mL H2O was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organics were washed with H2O (2×50 mL), dried over MgSO4, filtered, concentrated under reduced pressure and dried under vacuum (˜1 mm Hg) to afford the title compound. MS (ESI) m/z 276 (M+18)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].O.O.Cl[Sn]Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C(C)C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Temperature: 55 °C
Yield: 71.6 %

Procedure:
To a solution of 4-chloro-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (0.18 g, 0.61 mmol) in ethanol (5.0 mL), was added SnCl2.2H2O (0.56 g, 2.44 mmol) and the mixture was heated at 55° C. overnight. The ethanol was evaporated and the residue was taken up in ethyl acetate (50 mL) and washed with 10% NaOH (10 mL). The organic layer was dried over MgSO4 and evaporated to yield a light yellow solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) to yield a pale yellow solid of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.116 g, 75%). LCMS m/z (%)=267 M+H+, (35Cl, 100), 269 (37Cl, 28.5)), 1H NMR (400 MHz, CDCl3) δ: 7.47 (s, 1H), 6.78 (d, J=8.08 Hz, 1H), 6.72 (dd, J1=8.01 Hz, J2=2.78 Hz, 1H), 6.54 (d, J=2.78 Hz, 1H), 4.14 (m, 1H), 3.63 (s, 3H), 1.4 (d, J=6.57 Hz, 3H), 1.23 (d, J=6.57 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][CH:10](I)[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.O1CCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH:9]=[CH:10][Sn:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](C=CC(C)(C)c1ccc(F)cc1)(CCCC)CCCC
Yield: 88.2 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 17.2 grams (0.030 mole) of 3-(4-fluorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane and 13.7 grams (0.090 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)in 100 mL of tetrahydrofuran is heated at reflux for about 18 hours. The reaction mixture is cooled and poured into about 500 mL of water. The mixture is then made acidic with aqueous 2N hydrochloric acid and extracted with three 200 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 5% methylene chloride in petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 12.0 grams of 3-(4-fluorophenyl)-3-methyl-1-tributylstannyl-1-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:43][CH:44]([CH3:46])[CH3:45])[C:7]([F:42])=[C:8]([CH:10]([C:12]2[N:13]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)O)[CH:9]=1)[CH3:2].CS([Cl:51])(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:51][CH:10]([C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[C:6]([O:43][CH:44]([CH3:46])[CH3:45])[C:7]=1[F:42])[C:12]1[N:13]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(OC(C)C)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc(OC(C)C)c(F)c(C(Cl)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.5 %

Procedure:
To a solution of Intermediate 25.1 (100 mg, 0.163 mmol) in 2 mL CH2Cl2, were added DMAP (2 mg, cat.), TEA (27 μL, 0.20 mmol) and MsCl (15.2 μL, 0.196 mmol). The mixture was stirred at rt for 30 min, then TEA (27 μL, 0.20 mmol) and MsCl (15.2 μL, 0.196 mmol) were added. The mixture was stirred at rt for 30 min, then was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. to afford 125 mg of Intermediate 25.2 as a yellow solid, which was used in the following step without further purification.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.N[C:19]1[C:23]([C:24]#[N:25])=C[NH:21][N:20]=1>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:21]3[N:20]=[CH:19][C:23]([C:24]#[N:25])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 3.15 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone and 1.40 g. of 3-aminopyrazole-4-carbonitrile in 25 ml. of glacial acetic acid is refluxed for 6 hours. The mixture is evaporated and the residue is treated as described in Example 1, giving the desired product, m.p. 144°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[N+:10]([C:13]1[CH:14]=[CH:15][C:16](O)=[N:17][CH:18]=1)([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][N:17]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)nc1
Temperature: 120 °C
Yield: 48 %

Procedure:
A mixture of 3-flouro-benzyl alcohol (1.07 g, 8.48 mmol), 5-nitro-pyridin-2-ol (1.34 g, 8.48 mmol) and K2CO3 (1.41 g, 10.2 mmol) in DMA (10 ml) was heated at 120° C. for 7 h. The mixture was cooled to rt, diluted with MeOH(10 ml), filtered and purified by preparative HPLC to give 13A (1.01 g, 48%).