Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]2[CH:22]=[N:23][N:24]=[C:11]2[C:10]([CH3:26])([CH3:25])[N:9]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]3[CH:22]=[N:23][N:24]=[C:11]3[C:10]([CH3:26])([CH3:25])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2-n2cnnc21
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: CC1(C)N=C(c2ccccc2F)c2cc(N)ccc2-n2cnnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
22.6 g (64.5 mmol) of 6-(o-fluorophenyl)-4,4-dimethyl-8-nitro-4H-s-triazolo[4,3-a][1,4]benzodiazepine, dissolved in 200 ml of concentrated hydrochloric acid, are treated portionwise with a total of 43.66 g (0.19 mol) of tin chloride in such a manner that the temperature does not exceed 85° C. The mixture is stirred at room temperature for a further 1 hour, cautiously neutralised with 10 N sodium hydroxide while cooling with ice and extracted with chloroform/ethanol (9:1) in a perforator. After removing the solvent, the residue is suspended in hot ethyl acetate and filtered off, there being obtained 8-amino-6-(o-fluorophenyl)-4,4-dimethyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 288° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:15]1[C:27]2[N:26]([C:28]3[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:15]1[C:27]2[N:26]([C:28]3[CH:33]=[CH:32][C:31]([C:2]4[CH:3]=[CH:4][C:5]5[NH:6][C:7]6[C:12]([C:13]=5[CH:14]=4)=[CH:11][CH:10]=[CH:9][CH:8]=6)=[CH:30][CH:29]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: c1ccc2c(c1)[nH]c1ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)cc12
Temperature: 90 °C
Yield: 66.1 %

Procedure:
5.0 g (20 mmol) of 3-bromo-9H-carbazole, 5.8 g (20 mmol) of 4-(9H-carbazol-9-yl)phenylboronic acid, and 308 mg (1.0 mmol) of tri(ortho-tolyl)phosphine were put into a 300 mL three-neck flask. The air in the flask was replaced with nitrogen. To the mixture were added 100 mL of ethyleneglycoldimethylether and 20 mL of an aqueous solution of potassium carbonate (2.0 mol/L). This mixture was stirred to be degassed under reduced pressure. After the degassing, 46 mg (0.20 mmol) of palladium(II) acetate was added the mixture. This mixture was refluxed at 90° C. for 4.5 hours. After the reflux, the organic layer of the mixture was washed with water twice, and the aqueous layer was extracted with acetate ether. The extract was combined with the organic layer and then washed with a saturated saline solution. The obtained organic layer was dried with magnesium sulfate. After the drying, the mixture was subjected to gravity filtration. The obtained filtrate was condensed to give an oily light brown substance. The obtained oily substance was purified by silica gel column chromatography (a developing solvent was a mixed solvent of hexane:toluene=1:1) to give 5.4 g of a white powdered solid, which was the object of the synthesis, at a yield of 65%. A synthesis scheme of Step 3 is shown in (f-3) given below.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Fc1cccc(Br)c1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1cccc(Nc2ccccc2)c1F
Temperature: 110 °C
Yield: 96.6 %

Procedure:
A mixture of 1-bromo-2,3-difluorobenzene (0.232 mL, 2.073 mmol), aniline (0.208 mL, 2.280 mmol), Pd2(dba)3 (95 mg, 0.104 mmol), BINAP (194 mg, 0.311 mmol), sodium tert-butoxide (299 mg, 3.11 mmol), and toluene (3 mL) in a sealed vessel under argon was heated in an oil bath at 110° C. overnight. The reaction mixture was filtered through a plug of celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography to give the title compound as a light brown oil (411 mg). LCMS m/z=206.1 [M+H]+; 1H NMR (400 MHz, Methanol-d4) δ ppm 6.53-6.64 (m, 1H), 6.80-6.88 (m, 2H), 6.88-6.95 (m, 1H), 6.95-7.03 (m, 2H), 7.11-7.19 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11](=[O:12])[CH:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1Cl)C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
2-Chlorobenzaldehyde (1z, 2.00 ml, 17.8 mmol) and acetone (19, 0.65 ml, 8.8 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.00 g, 25.0 mmol) and water (20 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 1.80 g (67%) of a yellow solid: mp 119-121° C. [expected mp 110° C.]; 1H NMR: δ 7.04 (d, 2H, J=16.1 Hz), 7.29 (m, 4H), 7.41 (m, 2H), 7.67 (m, 2H), 8.11 (d, 2H, J=16.1 Hz); 13C NMR: δ 127.0, 127.5, 127.6, 130.1, 131.1, 132.9, 135.3, 139.2, 188.4.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([O:17]CC)=O)=[N:12][N:11]=2)=[CH:6][CH:5]=1.[NH:21]1[CH2:24][CH:23]([O:25][C:26]2[CH:39]=[CH:38][C:29]([CH2:30][N:31]3[CH2:37][C:33]4([CH2:36][O:35][CH2:34]4)[CH2:32]3)=[CH:28][CH:27]=2)[CH2:22]1>>[CH2:36]1[C:33]2([CH2:32][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([O:25][CH:23]4[CH2:22][N:21]([C:15]([C:13]5[O:14][C:10]([C:7]6[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:20])=[CH:9][CH:8]=6)=[N:11][N:12]=5)=[O:17])[CH2:24]4)=[CH:39][CH:38]=3)[CH2:37]2)[CH2:34][O:35]1
Reactant: c1cc(OC2CNC2)ccc1CN1CC2(COC2)C1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC(F)F)cc2)o1
Product: O=C(c1nnc(-c2ccc(OC(F)F)cc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Yield: 68.6 %

Procedure:
Using a similar protocol as described in Example 6 but employing 7A (60 mg, 0.21 mmol) and 3B (50 mg, 0.19 mmol) as starting materials afforded 65 mg (68%) of 7 as a solid. 1H NMR (500 MHz, CDCl3): δ 3.0-4.2 (m, 6H), 4.34 (m, 1H), 4.66 (m, 1H), 4.76 (m, 5H), 5.10 (m, 2H), 6.62 (t, 1H), 6.76 (m, 2H), 7.27 (m, 4H), 8.18 (d, 2H), MS (APCI+) m/z 499 [M+H]+, LC purity: 96%.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([CH3:16])=[N:10]2.CO.O.[OH-].[Li+]>C(O)(=O)C>[Cl:15][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:25])=[C:8]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[C:9]([CH3:16])=[N:10]2)=[C:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:14]=1
Reactant: COC(=O)Cc1cc(Cl)cc2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2cc(Cl)cc(CC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of [7-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yl]acetic acid methyl ester (0.24 g), methanol (10 mL), water (2.0 mL) and saturated aqueous lithium hydroxide solution (1.0 mL) was stirred at room temperature for 17 hours. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol removed under reduced pressure. The resulting precipitate was collected by filtration and washed with water. Crystallisation of the solid from ethyl, acetate gave title compound as a fluffy white solid, 0.16 g
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.Cl>CN(C)C=O>[N+:25]([C:18]1[CH:17]=[CH:16][C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:20][C:19]=1[C:21]([F:22])([F:23])[F:24])([O-:27])=[O:26]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
Sodium hydride (60% oiliness) (0.33 g, 8.25 mmol) was added in the dimethylformamide (20 mL) solution of diethyl malonate (1.23 mL, 8.14 mmol) while cooling the solution with ice, and the mixture was directly stirred for 4 hours. 5-bromo-2-nitrobenzotrifluoride (2.0 g, 7.41 mmol) was added in the reaction mixture while cooling it with ice, and the temperature was raised to room temperature and then the mixture was further heated and stirred at 70° C. for 3 hours. After the reaction solution was poured into ice water and acidified with 2N hydrochloric acid, the solution was extracted with ethyl acetate. After the organic layer had been washed with 5% sodium hydrogencarbonate aqueous solution and then with water and dried over anhydrous sodium sulfate, the solvents were concentrated under reduced pressure. The residue was subjected to silica gel column chromatograph (45 g) and was eluted with the mixture of ethyl acetate and n-hexane of 1:5 in mixing ratio. The eluted liquid was concentrated under reduced pressure and yellow oily diethyl 2-(4-nitro-3-trifluoromethyl-phenyl)-malonate (1.1 g, 42%) was obtained.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1SC.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1>>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[NH:34][CH2:33][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][N:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH2:26][CH2:27]1
Reactant: CSc1nc2ccccc2c(=O)n1N
Reactant: NCCCN1CCN(c2ccc3ccccc3n2)CC1
Product: Nn1c(NCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2ccccc2c1=O
Temperature: 145 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
A mixture of 131 mg of 3-amino-2-methylthio-3H-quinazolin-4-one as synthesized in above Step 6-1-A and 172 mg 3-(4-quinolin-2-ylpiperazin-1-yl)propylamine was heated at 145° C. under stirring for 5 hours. The reaction mixture was cooled and purified on silica gel column chromatography (methanol:methylene chloride=1:19) to provide 198 mg (73%) of 3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylamino]-3H-quinazolin-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:30]#[CH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:31]#[C:30][CH2:29][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Reactant: C#CCN1CCCC1
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCN4CCCC4)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described above for Method O, 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) and 1-(prop-2-ynyl)pyrrolidine were converted to I-32 (42%): HRMS Calcd. for C27H27N5O3: 470.2192, Found 470.2192.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCC[CH2:15]2.CI>C1C=CC=CC=1>[CH3:15][O:12][C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Solvent: CI
Product: COC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo [5.4.0]-undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution was added 74.84 g (0.528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and then cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, saturated sodium bicarbonate solution, and brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4 %) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[C:9]([Cl:30])[CH:8]=1.[CH3:31][C:32]([CH3:55])([CH2:37][O:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]=1)[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[Cl:30][C:9]1[CH:8]=[C:7]([C:42]2[C:43]([CH3:45])=[CH:44][C:39]([O:38][CH2:37][C:32]([CH3:31])([CH3:55])[C:33]([O:35][CH3:36])=[O:34])=[N:40][CH:41]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)c(Cl)c2)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
N,N-dimethylformamide (2 mL) was added to 2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (297 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate (228 mg) and palladium chloride (dppf) methylene chloride complex (27 mg), and after adding 2N aqueous sodium carbonate solution (0.98 mL) to the mixture, the atmosphere was replaced with nitrogen and the resulting mixture was stirred at 60° C. for 5 hours. To the reaction mixture were added ethyl acetate and water, and the liquids were separated. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=94:6 to 82:18) to obtain methyl 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (278 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([F:29])([F:28])C(OC)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[O:14][CH:23]([F:29])[F:28]
Reactant: COC(=O)C(F)(F)Cl
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)F)cc1OC(F)F
Temperature: 65 °C
Yield: 73.2 %

Procedure:
To a solution of 500 mg (2.271 mmol) 2-hydroxy-4-trifluoromethyl-benzoic acid methyl ester (CAS: 345-28-8) in 5 ml N,N-dimethylformamide at room temperature, was added 470.8 mg (3.407 mmol) potassium carbonate, followed by dropwise addition of 293.4 ul (2.725 mmol) methyl chlorodifluoroacetate. The reaction mixture was heated at 65° C. oil bath for 22 hours. Water and ethyl acetate were added. The organic phase was washed 3 times with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to provide 449 mg of the title compound as a pink oil which was used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH2:12](O)[CH2:13][OH:14].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]2[O:14][CH2:13][CH2:12][O:8]2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: OCCO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccc(C2OCCO2)c1
Reaction time: 4 h
Yield: 101.2 %

Procedure:
A mixture of 3-nitrobenzaldehyde (100 g, 0.66 mole), ethylene glycol (49.3 g, 0.7 mole) and p-toluenesulfonic acid (0.8 g) and benzene (1 L) was heated at reflux with continuous removal of water via a Dean and Stark trap. After 4 hours, the mixture was cooled, filtered through a pad of neutral alumina and concentrated in vacuo to afford 2-(3-nitrophenyl)-1,3-dioxolane (130.4 g, 100%) as an amber oil used without further purification below.
Reaction SMILES: [C:1]1([CH3:8])[C:6](O)=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])(=[O:11])[CH3:10].C1(C=CC(O)=CC=1)[OH:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:8]1(=[O:22])[O:12][C:9](=[O:11])[CH:6]2[CH2:5][CH2:4][CH:3]=[CH:2][CH:1]12.[C:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])(=[O:11])[CH3:10]
Reactant: Oc1ccc(O)cc1
Reactant: Cc1ccccc1O
Agent: CCOCCOCCOC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1OC(=O)C2CCC=CC12
Temperature: 115 °C

Procedure:
A reflux condenser, a thermometer, a bleed tube, and a stirrer were set to a four-necked flask. In order to prepare a reaction solution, 212 parts by mass of cresol novolac epoxy resin (N-695 (item number) available from DIC Corporation, epoxy equivalent weight: 212), 221 parts by mass of diethylene glycol monoethyl ether acetate, 0.2 parts by mass of hydroquinone, 300 parts by mass of ω-carboxy-polycaprolactone monoacrylate (Aronix M-5300 (trade name) available from TOAGOSEI CO., LTD., the number average molecular weight: 290), and 3 parts by mass of triphenyl phosphine were added to the four-necked flask. The reaction solution was heated at 115° C. for 12 hours with air bubbled therein to cause the addition reaction. Subsequently, into thus-obtained solution in the four-necked flask, 76 parts by mass of tetrahydrophthalic acid anhydride and 97.3 parts by mass of diethylene glycol monoethyl ether acetate were added, and then thus-obtained solution was heated at 110° C. for 5 hours to react them. Consequently, a 65 mass % solution (carboxyl group containing resin solution C-2) of resin containing a carboxyl group was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3cc(F)ccc3F)cc2)OC1(C)C
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: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90° C. in an oil bath and then concentrated under vacuum. The residue was diluted with water and the resulting solution was extracted with dichloromethane and the organic layers were combined. The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel and eluted with dichloromethane/methanol (10/1) to give 510 mg (87%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:14]([F:17])([F:16])[F:15])=[C:9]([C:12]#[N:13])[C:10]=1N)=[O:5])[CH3:2].[I:18]C1CC(C(C)C)CCC1(I)C.N(OCCC(C)C)=O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:14]([F:17])([F:16])[F:15])=[C:9]([C:12]#[N:13])[C:10]=1[I:18])=[O:5])[CH3:2]
Reactant: CC(C)C1CCC(C)(I)C(I)C1
Reactant: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1N
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1I
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
Combine 3-amino-4-cyano-5-trifluoromethyl-thiophene-2-carboxylic acid ethyl ester, prepared in preparation 45, (1.12 mmol), diiodomenthane (3.92 mmol), and isoamyl nitrite (2.8 mmol) in CH3CN and heat to 80° C. After 45 minutes, cool to room temperature and concentrate in vacuo. Purify the dark residue by flash chromatography eluting with methylene chloride. Concentration of desired fractions and recrystallization from hexanes provides the title compound: 1H NMR (400 MHz, CDCl3) δ 4.45 (q, 2H, J=7.2 Hz) and 1.44 (t, 3H, J=7.3 Hz), 19F NMR (CDCl3) δ—57.6 ppm (s).
Reaction SMILES: [N:1]1[N:2]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:3]=[CH:4][CH:5]=1.NC1C=CC=CC=1>[Pd]>[N:1]1[N:2]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:3]=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCCn2nccn2)cc1
Agent: [Pd]
Solvent: Nc1ccccc1
Product: Nc1ccc(OCCn2nccn2)cc1

Procedure:
4-[2-(1,2,3-Triazol-2-yl)ethoxy]aniline was prepared from 4-[2-(1,2,3-triazol-2-yl)ethoxy]nitrobenzene (10.5 g, 44.8 mmol) and 10% palladium on charcoal (1.5 g) in a manner similar to the aniline intermediate of Example 12 to give the desired material (4.91 g) as a yellow solid m.p. 159°. δH (CDCl3) 7.62 (2H, s), 6.73-6.58 (4H, m), 4.77 (2H, t, J 5.8 Hz), 4.40 (2H, t, J 5.8 Hz) 3.43 (2H, s).