Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O.ClCCCl>[CH:16]([C:10]1[CH:15]=[CH:14][C:13]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:12][CH:11]=1)([CH3:18])[CH3:17]
Reactant: CCC(=O)Cl
Reactant: CC(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)c1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
525 ml of 1,2-dichloroethane and 209 g of aluminium chloride are added to a round flask, which is fitted with a stirrer, thermometer, condenser and dropping funnel. The mixture is cooled to 0° C. and 127 g of propionic acid chloride are allowed to drop in at 0°-5° C. within 3/4 hour. After the addition, the temperature is allowed to rise to +18° C. and then 157 g of cumene are added within 2 hours at 30° C. The mixture is left to stand for 12 hours and the product is then poured into a mixture of 800 g of ice, 130 ml of water and 130 ml of concentrated hydrochloric acid. The aqueous phase is separated and extracted with two 250 ml portions of dichloroethane. The combined organic phases are washed with three 200 ml portions of 2% sodium hydroxide and with 250 ml of water. The solvent is removed by evaporation under a vacuum and the residue (244 g) is distilled over a 10 cm column. There are obtained 192.1 g of p-isopropyl-propiophenone (yield: 83.2% of theory). B.p.=76°-77° C./0.15 mmHg; nD20 =1.5150; d420 =0.9645.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1>O>[CH:10](=[N:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(F)cc1F
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(N=Cc2ccccc2)c(F)c1
Yield: 95.2 %

Procedure:
322.8 g (2.5 mol) of 2,4-difluoroaniline, 265.3 g (2.5 mol) of benzaldehyde and 1000 ml of toluene are heated to reflux, and the water formed is removed for 5 hours at 90°-105° C. using a water separator. The toluene is removed by distillation on a vacuum rotary evaporator, and the product is recrystallized from hexane, to give 516.9 g (92.5 % of theory) of N-benzal-2,4-difluoroaniline, which melts at 51°-52° C.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(=O)C)[CH2:14][C@H:13]2[CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN>ClCCl.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:21][NH2:22])=[O:11])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 104.1 %

Procedure:
To a solution of (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (4.92 g: 10.18 mmole) in a mixture of dichloromethane (15 ml) and methanol (75 ml), hydrazine hydrate (1.53 ml: 3 eq.) is added. The mixture is warmed to remove dichloromethane and heated to reflux for 1 hour and 10 minutes. The reaction mixture is concentrated in vacuo. The residue is diluted with dichloromethane and filtered. The filtrate is washed with water, dried over magnesium sulfate, and concentrated in vacuo to give crude (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-aminomethyl-4-mercaptopyrrolidine (3.3 g). Yield: Quantitative.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24]C(=O)C)[C@@H:7]([CH2:8][CH:9]=[C:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:35])[CH2:12][CH2:13][C@@H:14]2[O:28]C(=O)C(C)(C)C)[CH2:6]1)(=O)C.[OH-].[K+].C(O)(=O)C.O>C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][OH:24])[C@@H:7]([CH2:8][CH:9]=[C:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:35])[CH2:12][CH2:13][C@@H:14]2[OH:28])[CH2:6]1
Reactant: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C[C@@H]1CC=C1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)C(C)(C)C)CC[C@]12O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H]3C(=CC[C@H]4C[C@@H](O)CC[C@@]43CO)[C@@]1(O)CC[C@@H]2O

Procedure:
A mixture of 20 mg of 3β ,19-diacetoxy-14β-hydroxy-17β-pivaloxy-5α-androst-7-ene and 1.0 ml of 0.2 N methanolic potassium hydroxide was heated under nitrogen at 70° C. for 20 hours whereupon a solution of 0.2 N acetic acid in ethyl acetate was added and the mixture was evaporated. The residue obtained was treated with water and the mixture was then extracted with ethyl acetate. Evaporation of the ethyl acetate solution gave 3β ,14β ,17β ,19-tetrahydroxy-5α-androst-7-ene as indicated by tlc analysis.
Reaction SMILES: [Cl-:1].[Cl-].[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[CH3:11][O:12]COC>Cl>[OH2:12].[ClH:1].[ClH:1].[N:10]1[C:6]2[CH2:5][CH2:4][NH:3][CH2:11][C:7]=2[NH:8][CH:9]=1
Reactant: NCCc1c[nH]cn1
Reactant: COCOC
Reactant: [Cl-]
Agent: Cl
Product: O
Product: c1nc2c([nH]1)CNCC2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Histamine dichloride (5.0 g, 27 1 mol) was dissolved in concentrated hydrochloric acid (20 ml), dimethoxymethane (7.0 ml, 79 mmol) was added dropwise to the solution, and the mixture was stirred overnight at 100° C. By evaporating the solvent from the reaction solution and purifying the thus obtained crystals by their recrystallization from methanol, 4.6 g (22 mmol, 79% in yield) of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][OH:22])=[CH:12][C:7]=2[O:6][CH2:5]1.N1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>ClCCl>[CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]([OH:22])[C:30](=[O:31])[O:32][CH3:33])=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)Cl
Reactant: CON=C1COc2cc(OCc3ccccc3NO)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON=C1COc2cc(OCc3ccccc3N(O)C(=O)OC)ccc21
Reaction time: 8 h
Yield: 35.8 %

Procedure:
A solution of 4.8 g of N-[2-(3-methoxyimino-2,3-dihydro-benzofuran-6-yloxymethyl)phenyl]-N-hydroxyamine and 1.3 g of pyridine in 50 ml of dichloromethane was cooled to 0° C. 1.4 g of methyl chloroformate was dropped into the solution. The temperature was slowly elevated to room temperature, and the reaction was further carried out for 8 hours. After the completion of the reaction, the reaction liquid was washed with a dilute aqueous hydrochloric acid solution and aqueous NaCl solution and then dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the obtained residue was dissolved in a mixed solution of 30 ml of methanol and 20 ml of tetrahydrofuran. 1.4 g of anhydrous potassium carbonate was added to the obtained solution, and they were stirred for 4 hours. Water and diethyl ether were added to the reaction solution, and the resultant mixture was neutralized with a dilute aqueous hydrochloric acid solution. After the extraction with diethyl ether, the extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (hexane:ethyl acetate) to obtain 1.9 g of methyl N-[2-(3-methoxyimino-2,3-dihydrobenzofuran-6-yloxymethyl)phenyl]-N-hydroxycarbamate [1H-NMR (CDCl3) (ppm): 3.77 (3H, s), 3.93 (3H, s), 5.03 (2H, s), 5.13 (2H, s), 6.49-7.50 (m)].
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][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][C:19]([CH3:25])([CH3:24])[C:20]([O:22]C)=[O:21])=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1.[C:40]([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C>[CH3:40][CH:18]([C:8]1[N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:15]2[C:10]([C:9]=1[CH3:17])=[CH:11][C:12]([O:16][CH2:29][C:30]1[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=1)=[CH:13][CH:14]=2)[C:19]([CH3:25])([CH3:24])[C:20]([OH:22])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(C)C(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4c3)cc12

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (Preparation 1) (200 mg), 2-bromomethynaphthalene (138 mg), K2CO3 (89 mg), and Cs2CO3 (34 mg) in 5 mL DMF was stirred at room temperature under nitrogen for 24 hours. The mixture was poured onto 1N HCl, extracted 2× EtOAc, washed 2× brine, dried (MgSO4), and evaporated. Purification of the residue by chromatography (silica gel; hexane/EtOAc 4:1) gave the title compound, used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)c(Cl)c1
Temperature: 50 °C
Yield: 99.7 %

Procedure:
To methyl 2-chloro-4-methylbenzoate (1.00 g, 5.42 mmol) in tetrahydrofuran (10 mL) methyl alcohol (5 mL) and water (2.5 mL) is added 2N lithium hydroxide (8.12 mL, 16.2 mmol). The reaction mixture is heated at 50° C. for 2.5 hr, cooled to room temperature, and then quenched with 5N hydrochloric acid (3.24 mL). The mixture is concentrated to remove the tetrahydrofuran and methyl alcohol. A white precipitate is formed and is filtered. After drying, 0.922 g (100%) of 2-chloro-4-methylbenzoic acid is isolated. ES(−)MS m/z 169, (M−H)− consistent with 1 Cl.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[I:11]([O-])(=O)=O.[K+].[I-].[K+]>S(=O)(=O)(O)O.O>[OH:1][C:2]1[C:7]([I:11])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: [O-][I+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(I)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 236.3 %

Procedure:
2-Hydroxy-5-nitropyridine (7.0 g, 50 mmol) was suspended in 100 mL of 20% sulfuric acid and then treated with potassium iodate (4.2 g, 19.6 mmol) dissolved in 10 mL of water. The mixture was heated to 100° C. and potassium iodide (8.0 g, 48.2 mmol) dissolved in 20 mL of water was added dropwise over one h. The reaction mixture turns a purplish-red and a precipitate forms. After 0.5 h, the reaction mixture is cooled and filtered. The solid is stirred for 15 min with 10% sodium meta-bisulfite solution, filtered, washed with water and dried at 80° C. overnight on a vacuum pump to give the desired compound 765A (12.32 g, 92%) as a yellow solid. The product was characterized by 1H NMR.
Reaction SMILES: C(=O)(OC(C)(C)C)[NH2:2].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.Cl[C:54]1[CH:55]=[N:56][CH:57]=[C:58]([F:76])[C:59]=1[N:60]1[CH2:65][CH2:64][CH:63]([S:66]([N:69]2[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]2)(=[O:68])=[O:67])[CH2:62][CH2:61]1.C(O)(C(F)(F)F)=O>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1(C)C=CC=CC=1.C(Cl)Cl>[F:76][C:58]1[C:59]([N:60]2[CH2:65][CH2:64][CH:63]([S:66]([N:69]3[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]3)(=[O:68])=[O:67])[CH2:62][CH2:61]2)=[C:54]([NH2:2])[CH:55]=[N:56][CH:57]=1
Reactant: CN1CCN(S(=O)(=O)C2CCN(c3c(F)cncc3Cl)CC2)CC1
Reactant: CC(C)(C)OC(N)=O
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)C2CCN(c3c(N)cncc3F)CC2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Tert-butyl carbamate (211.3 mg, 1.804 mmol), sodium tert-butoxide (173.4 mg, 1.804 mmol), BrettPhos Pre-catalyst (143.7 mg, 0.1804 mmol) and BrettPhos (96.83 mg, 0.1804 mmol) were degassed by vacuum/nitrogen cycles (×5). A solution of 1-[[1-(3-chloro-5-fluoro-4-pyridyl)-4-piperidyl]sulfonyl]-4-methyl-piperazine (340 mg, 0.9022 mmol) in dry toluene (9.884 mL) was added and the resulting mixture was heated to 80° C. After 5 minutes at 80° C. the reaction was cooled to RT and partitioned between ethyl acetate and water. The combined organics was dried with MgSO4 and concentrated in vacuo to a yellow solid. The yellow solid was purified by column chromatography using 1% MeOH/DCM to elute side products and then 5-10% MeOH/DCM to elute product. Relevant fractions combined and concentrated in vacuo to yield a light yellow solid. It was dissolved in DCM (10 mL) followed by the addition of TFA (1.029 g, 695.3 μL, 9.022 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to yield 5-fluoro-4-(4-((4-methylpiperazin-1-yl)sulfonyl)piperidin-1-yl)pyridin-3-amine as a light orange solid. MS (ES+) 358.1.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br>CN(C)C=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: BrCc1cccc(Br)c1
Solvent: CN(C)C=O
Product: OC1CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine and 0.55 g (0.0022 mol) of 3-bromobenzyl bromide were dissolved in 5 ml of dimethylformamide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with saturated bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.52 g (96%) 1-(3-bromo-benzyl)-piperidin-4-ol was obtained as a brown oil. MS: me/e (% basic peak)=271, 269 (C12H16BrNO+, 26, 26.6), 270, 268 (25.5, 22), 171, 169 (47, 48.3), 114 (76.6), 100 (100).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:26][C:20]1[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1
Reactant: [H][H]
Reactant: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Yield: 55.7 %

Procedure:
7-Benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (16.11 g, 46.6 mmol), 10% palladium on carbon (4.96 g), and ethanol (380 mL) were combined. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen and then filtered. The solids were washed with ethyl acetate, and the filtrate was concentrated. Diethyl ether was added to the residue and a green solid formed. The solid was recrystallized from acetonitrile to give 6.63 g of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol as a beige solid.
Reaction SMILES: ClC1N=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])[N:5]2[N:14]=[C:15]([C:17]3[C:26]([CH3:27])=[N:25][C:24]4[C:19](=[CH:20][C:21]([F:28])=[CH:22][CH:23]=4)[N:18]=3)[CH:16]=[C:4]2C=1.Cl.[F:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.[N:36]12CCCN=C1CCC[CH2:38][CH2:37]2.O>CN1CCCC1=O>[F:28][C:21]1[CH:20]=[C:19]2[C:24]([N:25]=[C:26]([CH3:27])[C:17]([C:15]3[CH:16]=[C:4]4[N:36]=[C:37]([N:33]5[CH2:34][CH2:35][C@@H:31]([F:30])[CH2:32]5)[CH:38]=[C:6]([NH:8][CH2:9][C:10]([CH3:11])([OH:12])[CH3:13])[N:5]4[N:14]=3)=[N:18]2)=[CH:23][CH:22]=1
Reactant: Cc1nc2ccc(F)cc2nc1-c1cc2cc(Cl)nc(NCC(C)(C)O)n2n1
Reactant: F[C@@H]1CCNC1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc2ccc(F)cc2nc1-c1cc2nc(N3CC[C@@H](F)C3)cc(NCC(C)(C)O)n2n1
Temperature: 70 °C

Procedure:
A suspension of 1-{[5-chloro-2-(7-fluoro-3-methylquinoxalin-2-yl)pyrazolo[1,5-c]pyrimidin-7-yl]amino}-2-methylpropan-2-ol (170 mg, 0.424 mmol), (R)-3-fluoropyrrolidine hydrochloride (268 mg, 2.12 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (387 mg, 2.54 mmol) in N-methylpyrrolidinone (5.0 mL) was heated at 70° C. overnight. After being cooled to ambient temperature, the reaction mixture was diluted with ice-cooled water. The resulting precipitate was collected and washed with water to give 1-({2-(7-fluoro-3-methylquinoxalin-2-yl)-5-[(3R)-3-fluoropyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)-2-methylpropan-2-ol. MS (APCI): m/z 454 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[OH:13][CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>COCCOC.O.C(Cl)Cl.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>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([C:16]#[C:15][CH2:14][OH:13])=[CH:18][CH:19]=1
Reactant: OCC#Cc1ccc(B(O)O)cc1
Reactant: Brc1ncccn1
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: O
Solvent: ClCCl
Solvent: COCCOC
Product: OCC#Cc1ccc(-c2ncccn2)cc1
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A mixture of 2-bromopyrimidine (1.00 g, 6.29 mmol) and Pd(Ph3P)4 (220 mg, 0.19 mmol) in ethylene glycol dimethyl ether (25 mL) was stirred for 10 min, a slurry of sodium bicarbonate (1.58 g, 18.81 mmol) and [4-(3-hydroxy-1-propynyl)phenyl]boronic acid (1.32 g, 7.50 mmol, prepared as described in Reference Example 235) in water (25 mL) was added, and the mixture was heated to reflux for 4 h. The cooled reaction mixture was diluted with methylene chloride (100 mL) and washed with water (100 mL). The aqueous layer was extracted with dichloromethane (25 mL) and the combined organic layers were dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 3:2 hexane/ethyl acetate) provided 1.04 g (79%) of the title compound as a yellow solid. MS 211 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:20]4[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]4[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=23)=[CH:4][CH:3]=1.[C:55]([OH:60])(=[O:59])[CH2:56][CH:57]=[CH2:58].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:55]([CH2:56]/[CH:57]=[CH:58]/[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:20]4[O:46][C@H:45]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:42])([CH3:43])[CH3:41])[C@@H:47]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C@H:21]4[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26])[C:11]=23)=[CH:4][CH:3]=1)([OH:60])=[O:59]
Reactant: C=CCC(=O)O
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(Br)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(/C=C/CC(=O)O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Yield: 69.9 %

Procedure:
A mixture of 4-[2-(4-bromophenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]-pyridine (0.27 g), 3-butenoic acid (56 mg), triethylamine (0.23 mL), palladium (II) acetate (7 mg) and tris(2-methyl-phenyl)phosphine (20 mg) in acetonitrile (5 mL) was heated for reflux under an argon atmosphere overnight. The reaction mixture was diluted with dichloromethane, and the insoluble material was removed by filtration. The filtrate was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give the title compound (0.19 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.CN1C(=O)CCC1.[F:28][C:29]([F:37])([F:36])[C:30]([F:35])([F:34])C([O-])=O.[Na+].C(=O)([O-])O.[Na+]>[Cu](I)I.C1(C)C(C)=CC=CC=1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:30]([F:35])([F:34])[C:29]([F:37])([F:36])[F:28])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Temperature: 170 °C
Yield: 7.7 %

Procedure:
A mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (500 mg), NMP (24 ml), xylene (10 ml), copper iodide (1.1 g), and sodium pentafluoropropionate (1.1 g) was heated to 170° C., and stirred with heating for 3 days. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with tert-butyl methyl ether. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 43 mg of 2-(2-ethylsulfanylphenyl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine hereinafter referred to as Present Compound 55).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[CH:19][C:20]3[S:24][N:23]=[CH:22][C:21]=3[CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.COCCOC.O>[CH3:8][S:7][C:4]1[S:3][C:2]([C:18]2[CH:17]=[CH:25][C:21]3[CH:22]=[N:23][S:24][C:20]=3[CH:19]=2)=[N:6][N:5]=1
Reactant: CC1(C)OB(c2ccc3sncc3c2)OC1(C)C
Reactant: CSc1nnc(Br)s1
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: COCCOC
Solvent: CCO
Solvent: O
Product: CSc1nnc(-c2ccc3cnsc3c2)s1
Temperature: 140 °C
Yield: 87.4 %

Procedure:
To a stirred mixture of 2-bromo-5-(methylthio)-1,3,4-thiadiazole (0.22 g, 1.0 mmol) (prepared as described in WO 97/30981), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isothiazole (0.18 g 0.69 mmol), Na2CO3 (0.22 g, 2.1 mmol), and Pd(PPh3)4 (80 mg, 0.07 mmol) was added EtOH (1.0 mL), water (1.0 mL) and DME (3.0 mL). The resulting mixture was heated at 90° C. overnight and at 140° C. for 30 minutes. The mixture was cooled and passed through a short path of Celite, washing with DCM (3×10 mL). The combined organic phases were concentrated to give the crude residue. Purification by chromatography on silica gel (DCM—5% MeOH in DCM) gave the product as an off-white powder (0.16 g, 87%). LCMS (API-ES) m/z (%): 266.4 (100%, M+H+); 1H NMR (400 MHz, CDCl3): δ ppm 8.97 (s, 1 H) 8.48 (s, 1 H) 8.16 (d, J=8.53 Hz, 1 H) 8.00 (d, J=8.03 Hz, 1 H) 2.87 (s, 3 H).