Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[CH:2].N1C2C(=CC=CC=2)C=CC=1>C(OCC)C.[Pd]>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[CH2:2]
Reactant: C#Cc1ccc(O)c(C(=O)OC)c1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: C=Cc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 5-ethynyl-2-hydroxybenzoate (8 g, 45.4 mmol), prepared according to Example 1 b, was dissolved in a mixture of diethyl ether and light petroleum (200+200 ml) in a hydrogenation flask. Quinoline (1.7 ml) and palladium on CaCO3, poisoned with Pb (Lindlax catalyst; 200 mg) were added, and the flask was attached to an atmospheric pressure hydrogenation apparatus. The mixture was stirred for 2 h at room temperature, by then the calculated amount of hydrogen had been consumed. The catalyst was filtered off and the solution was evaporated to dryness. The product was purified by flash column chromatograpy on silica, using toluene as an eluent. A nearly quantitative yield was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:39]O.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:39]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)CCC(C(=O)c2ccc(OCc3ccccc3)cc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: COc1ccc(-c2ccc(-c3ccc(OC)cc3)c(-c3ccc(OCc4ccccc4)cc3)n2)cc1
Yield: 37.5 %

Procedure:
The 1-(4-benzyloxyphenyl)-2,5-bis(4-methoxyphenyl)pentan-1,5-dione (9 g, 18 mmol), hydroxylamine hydrochloride (1.8 g, 26 mmol), and 0.8 mL concd H2SO4 were stirred in 250 mL of 1-butanol at 95°-100° C. for 18 h. The reaction mixture was neutralized with solid NaHCO3, worked up, purified, and recrystallised (EtOAC/ hexane) to give 3.2 g (37% yield) of white solid: mp 99°-102° C.; 1H NMR (CDCl3) d 3.82 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 5.06 (s, 2H, OCH2Ar), 6.83-6.89 (m, 4H, ArH), 6.99-7.02 (d, 2H, J=9, ArH), 7.14-7.17 (d, 2H, J=9, ArH), 7.32-7.45 (m, 7H, ArH), 7.64-7.71 (m, 2H, ArH), 8.08-8.11 (d, 2H, J=9, ArH); MS(FD) 473(M+). Anal. Calcd for C32H27NO3 : C, 81.16; H, 5.75; N, 2.96. Found: C, 81.10; H, 5.92; N, 2.98.
Reaction SMILES: [OH:1][CH:2]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6](CCCCCCC(OCC)=O)[S:7]([CH3:10])(=[O:9])=[O:8].[OH-].[Na+].O>C(O)C>[OH:1][CH:2]([CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8]
Reactant: CCOC(=O)CCCCCCN(CCCC(O)COc1ccc(F)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)NCCCC(O)COc1ccc(F)cc1
Reaction time: 20 h

Procedure:
A solution composed of ethyl 7-{N-[4-hydroxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido}heptanoate (4.7 g., 0.11 mole), sodium hydroxide (1.0 g.), water (13 ml.) and ethanol (130 ml.) is kept at room temperature for 20 hours. Most of the solvent is removed in vacuo, water (150 ml.) is added and the solution extracted with ether (100 ml.). The aqueous layer is acidified (hydrochloric acid) and extracted with ethyl acetate (2 × 100 ml.). The organic layer is dried over sodium sulfate then concentrated in vacuo to obtain the subject compound. The yield is 3.7 g. (84%) of heavy oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>>[N:12]1([C:18]([O:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([C:18]([N:12]3[CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)=[O:19])[N:7]=2)=[O:19])[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: Oc1n[nH]c2cc(F)ccc12
Reactant: O=C(Cl)N1CCSCC1
Product: O=C(Oc1nn(C(=O)N2CCSCC2)c2cc(F)ccc12)N1CCSCC1

Procedure:
In analogy to example 1, 200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were reacted with 261.4 mg (1.578 mmol) of thiomorpholine-4-carbonyl chloride. Yield: 39 mg (7%), M+H+: 411.17.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16](I)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.O.[C:34]([O:37][CH2:38][CH3:39])(=[O:36])C>CN(C1C=CN=CC=1)C.C(O)C.[Pd]>[CH2:38]([O:37][C:34]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:36])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2I)CC1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(OC2CCNCC2)ccc2cnccc12

Procedure:
A solution of 200 mg (0.44 mmol) 4-(5-iodo-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (12), 107 mg (0.88 mmol) of DMAP, 4.7 mg (0.1 eq) of Pd on charcoal (10%), 150 μL (0.88 mmol) of triethyl amine and 58 mg (0.22 mmol) of Mo(CO)6 in 3 mL of ethanol was heated to 135° C. for 1 h in a microwave reactor (CEM Discovery). Then water and ethyl acetate were added and the mixture was filtered through a Celite cartridge. After removal of the solvents the remainder was subjected to preparative HPLC to give the 7.4 mg Boc-protected intermediate. To remove the Boc group the intermediate was treated with 2 mL 5-6 N HCl in isopropanol at room temperature for 2 h. Purification by preparative HPLC gave 2.5 mg of compound 30 as TFA salt.
Reaction SMILES: Cl[CH2:2][C@@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH2:4]1.O.O.O.C([O-])(=O)C.[Na+]>[C].[Pd].C(O)(C)C>[CH3:16][C:5]1([CH3:17])[C:6]2[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=2)[C:12]([CH3:14])([CH3:13])[C@@H:3]([CH3:2])[CH2:4]1
Reactant: Cc1ccc2c(c1)C(C)(C)[C@@H](CCl)CC2(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc2c(c1)C(C)(C)[C@@H](C)CC2(C)C
Yield: 99.8 %

Procedure:
Into an autoclave, (S)-3-(chloromethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene 200 mg; 0.798 mmol), isopropanol (10 ml), sodium acetate trihydrate (120 mg; 0.882 mmol) and 10 % palladium carbon (160 mg) were charged, and the resultant mixture was stirred at 50° C. under a hydrogen pressure of 80 kg/cm2 for 12 hours. After cooling, the reaction mixture was filtered to separate palladium carbon, admixed with water and extracted with n-hexane. The extract was washed with saturated sodium hydrogen carbonate solution, dried and concentrated to give (S)-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (172 mg; 0.796 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[C:16]([F:25])([F:24])[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18].O>CC(N(C)C)=O.C1(C)C=CC=CC=1>[F:24][C:16]([F:25])([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18]
Reactant: Oc1cccc(F)c1
Reactant: CCN(CC)C(=O)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)C(F)(F)Oc1cccc(F)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-fluoro-phenol (4.9 g, 43.5 mmol), and K2CO3 (6.6 g, 47.8 mmol) in 43 g of DMAC at 100° C. was added 2-bromo-2,2-difluoro-N,N-diethyl-acetamide (10 g, 43.5 mmol). The mixture was kept at that temperature for 1 h and then heated to 120° C. for 2 h. The reaction mixture was then cooled to room temperature and poured on 120 mL of H2O and 50 mL of toluene. The aqueous phase was extracted with 25 g of toluene. The combined organic layers were extracted with 5% NaOH (20 g) and H2O (2×20 g) and dried over Na2SO4. The product (10.2 g, >90% purity by NMR) was obtained after removal of all volatiles under reduced pressure as a slightly yellow liquid. The material could be used in subsequent steps without further purification.
Reaction SMILES: [CH:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16].C([OH:20])C.O.[OH-].[Na+]>O>[C:1]([OH:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCO
Reactant: CCCC/C=C\CCCCCCCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC/C=C\CCCCCCCCCC(=O)O

Procedure:
(Z)-11-hexadecenoic acid was prepared as described in Example VII but starting with Z-11-hexadecenal (1.115 g, 4.68 mmol) and (0.875 g, 5.15 mmol) in 15 ml. of ethanol/water, 2/1, and NaOH (0.880 g, 22 mmol) in water (10 ml); purification by flash chromatography (H/EA/A), 8/2/1, gave 0.478 g (40%) of the acid; Rf (H/EA,7/3), 0.64; IR (film) 2800-3300 (CODH), 2850-2950 (alkane, alkane C--H), 1700 cm-1 (C=O), 1H NMR 0.95 (t, J=6 HZ, 3H), 1.20-1.50 (br S, 18 H), 2.05 (br d, J=6 HZ, 4H), 2.38 (t, J=6HZ, 2H), 5.32 (t, J=6HZ, 2H), 10.6-10.8 (br S, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[O:9][C:10]3[C:15]([C:16]([O:18][CH2:19][C:4]=2[CH:3]=1)=[O:17])=[C:14]([O:20][CH3:21])[C:13]([C@@H:22]([OH:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=3.F[B-](F)(F)F.[O:33]=[N+:34]=[O:35]>C(Cl)Cl>[OH:8][C:6]1[C:5]2[O:9][C:10]3[CH:11]=[CH:12][C:13]([CH:22]([OH:27])[CH2:23][CH:24]([CH3:25])[CH3:26])=[C:14]([O:20][CH3:21])[C:15]=3[C:16](=[O:17])[O:18][CH2:19][C:4]=2[C:3]([N+:34]([O-:35])=[O:33])=[C:2]([CH3:1])[CH:7]=1
Reactant: O=[N+]=O
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1c(C(O)CC(C)C)ccc2c1C(=O)OCc1c(c(O)cc(C)c1[N+](=O)[O-])O2
Temperature: -68 °C
Reaction time: 1 h

Procedure:
150 mg (0.4 mmol) of penicillide are dissolved in 15 ml of methylene chloride and stirred for 1 h under inert gas at a bath temperature of -68° C. after addition of 0.8 ml of a 0.5 molar solution of nitronium tetrafluoroborate. The reaction mixture is added to ice. After extraction with methylene chloride, washing with water and bicarbonate, drying and evaporating, the residue is chromatographed on silica gel in petroleum ether:ether=1:1. After evaporating, 86 mg (51% of theory) of yellowish solid are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O.CN(C)C=O.O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:9])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
3,4-Dinitrobenzoic acid (1.000 Kg, 4.71 mol, 1.O wt), tetrahydrofuran (10.00 L, 1O.O vol), and dimethylformamide (0.010 L, O.O1 vol) were charged to a flask under nitrogen. Thionyl chloride (0.450 L, 6.16 mol, 0.45 vol) was added at 20 to 3O° C. and the reaction mixture was heated to 65 to 7O° C. Reaction completion was determined by 1H NMR analysis (d6-DMSO), typically in 3 hours. The reaction mixture was cooled to 0 to 5° C. and triethylamine (1.25 L, 8.97 mol, 1.25 vol) was added at 0 to 10° C. Morpholine (0.62 L, 7.07 mol, 0.62 vol) was charged to the reaction mixture at 0 to 10° C. and the slurry was stirred for 30 minutes at 0 to 10° C. Reaction completion was determined by 1H NMR analysis (d6-DMSO). The reaction mixture was warmed to 15 to 2O° C. and water (4.00 L, 4.0 vol) was added. This mixture was then charged to a 40 L flange flask containing water (21.0O L, 21.0 vol) at 15 to 25° C. to precipitate the product. The flask contents were cooled to and aged at 0 to 5° C. for 1 hour and the solids were collected by filtration. The filter-cake was washed with water (4×5.00 L, 4×5.0 vol) and the pH of the final wash was found to be pH 7. The wet filter-cake was analysed by 1H NMR for the presence of triethylamine hydrochloride. The filter-cake was dried at 40 to 45° C. under vacuum until the water content by KF<0.2% w/w, to yield (3,4-dinitrophenyl)-morpholin-4-yl-methanone (1.286 Kg, 97.0%, KF 0.069% w/w) as a yellow solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12].ClCCl.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[CH:39]=[C:38]([O:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[N:37]=[CH:36][N:35]=1)[CH2:29][CH2:28]2)(=[O:24])=[O:23]>O>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[N:35]=[CH:36][N:37]=[C:38]([O:40][CH:41]3[CH2:46][CH2:45][N:44]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:43][CH2:42]3)[CH:39]=1)[CH2:29][CH2:28]2)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
Diisopropylethylamine (186 μL, 1.07 mmol) and butyl chloroformate (51 μL, 0.40 mmol) were added at 0° C. to a dichloromethane (5 mL) solution of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline (100 mg, 0.267 mmol) produced in Reference Example 28, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-1:2, V/V) to obtain the title compound as white powder (53.9 mg, yield: 43%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C:21]3[CH:22]=[C:23]([CH:28]=[C:29]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[CH:30]=3)[C:24]([O:26][CH3:27])=[O:25])=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1cc(N)cc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Nc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Y using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.300 g, 1.100 mmol), methyl 3-amino-5-morpholinobenzoate (0.260 g, 1.100 mmol), XPhos precatalyst (CAS 1028206-56-5; 0.074 g, 0.110 mmol), XPhos (0.052 g, 0.110 mmol), sodium tert-butoxide (0.26 g, 2.75 mmol), and toluene (2.2 mL). Purification by column chromatography (silica; 0-90% EtOAc in hexanes) afforded methyl 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzoate as a yellow amorphous solid. Mass Spectrum (ESI) m/e=473.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][CH2:13][OH:14])[N:9]=[C:10](I)[C:3]=12.[CH3:15][O:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[NH:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=1[F:44].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][CH2:13][OH:14])[N:9]=[C:10]([C:21]3[CH:20]=[CH:19][C:18]([NH:32][C:33](=[O:45])[C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][C:35]=4[F:44])=[C:17]([O:16][CH3:15])[CH:22]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2CCO
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(CCO)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 85 °C
Yield: 64.6 %

Procedure:
A mixture of 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-ethanol (Intermediate 3) (0.120 g, 0.393 mmol), N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-(trifluoromethyl)benzamide (0.190 g, 0.433 mmol), palladium tetrakis(triphenylphosphine) (0.045 g, 0.039 mmol), and sodium carbonate (0.100 g, 0.943 mmol) in DME (3.9 mL) and water (3.9 mL) was heated at 85° C. for 3 h. The reaction mixture was cooled to ambient temperature and the organic solvent was removed in vacuo. The precipitate was collected by filtration, rinsed with water (20 mL) and ether (20 mL), and dried in vacuo to afford N1-{4-[4-amino-1-(2-hydroxyethyl)-1H-pyrazolo [3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a brown solid (0.125 g, 0.254 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.89 (1H, d, J=4.0 Hz), 8.31 (1H, d, J=8.0 Hz), 8.25 (1H, s), 7.99 (1H, t, J=7.4 Hz), 7.89 (1H, d, J=10.4 Hz), 7.75 (1H, d, J=8.0 Hz), 7.34 (1H, s), 7.31 (1H, d, J=8.4 Hz), 4.89 (1H, s), 4.40 (2H, t, J=5.6 Hz), 3.94 (3H, s), and 3.86 (2H, t, J=5.6 Hz); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 9.85 min. MS: MH+491.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][CH2:13][CH3:14])[CH2:2]1.[OH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][C:23]([C:25]([O:27]CC)=[O:26])=[CH:22][C:21](=[O:30])[C:20]=2[CH:31]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(O)C.O.CN(C)C=O>[OH:1][CH:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH3:14])[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][C:21](=[O:30])[C:20]=2[CH:31]=1
Reactant: CCOC(=O)c1cc(=O)c2cc(O)ccc2o1
Reactant: CCCc1ccccc1OCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccccc1OCC(O)COc1ccc2oc(C(=O)O)cc(=O)c2c1

Procedure:
A mixture of 19.2 parts of 1,2-epoxy-3-(2-propylphenoxy) propane, 23.4 parts of ethyl 6-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate and 0.1 parts of benzyl trimethylammonium hydroxide in 50 parts of dimethyl formamide was heated under reflux for 3 hours. The solvent was evaporated under reduced pressure and the oil remaining dissolved in ethyl acetate. The solution was washed with dilute sodium hydroxide and water, dried over magnesium sulphate, filtered and evaporated to leave an oil. The oil was dissolved in ethyl alcohol, 20.0 parts of sodium bicarbonate were added, and the mixture was boiled for 2 hours, during which time water was added and the ethyl alcohol allowed to boil off. The aqueous solution was washed with ethyl acetate and acidified with dilute hydrochloric acid to give a brown precipitate which was collected and crystallised twice from ethyl alcohol to yield 10.5 parts of 6-[2-hydroxy-3-(2-propylphenoxy)propoxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid, melting point 164°-166° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.Cl.[CH3:18][NH2:19].[OH-].[Na+]>C(O)(C)C.O>[CH3:18][NH:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CNc1ccnc2cc(-c3cn(C)cn3)sc12
Temperature: 130 °C
Yield: 99.7 %

Procedure:
A stirred suspension of 175 (500 mg, 2 mmol) and methylamine hydrochloride (15 g, 222 mmol) in iso-propanol (50 ml) was heated at 130° C. in a sealed flask for four days. It was then cooled to room temperature, poured in water, and the pH was adjusted to 10 with 1N NaOH. After extraction of the aqueous phase with AcOEt, the combined organic phase was concentrated and purified by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2: 10/90 to 40/60) to afford title compound 421 (487 mg, 99% yield, hydrate form) as a beige solid. LCMS: 245.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[N:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[CH2:1]([C:8]1[CH:12]=[N:11][N:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cnn(C3CCN(Cc4ccccc4)CC3)n2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc(Cc2cnn(C3CCNCC3)n2)cc1
Yield: 8.9 %

Procedure:
A mixture of 4-(4-benzyltriazol-2-yl)-1-benzylpiperidine (627 mg, 1.9 mmol, from Step B), 10% palladium on carbon (400 mg, 0.38 mmol) and ammonium formate (770 mg, 11.3 mmol) in 20 mL MeOH was refluxed for 1 h. The mixture was filtered through celite and concentrated. The residue was dissolved in chloroform and the solution was washed with 1M aqueous NaOH. The organic layer was dried over Na2SO4 and concentrated to afford 41 mg (9%) of product was obtained which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:18])[CH:10]=[CH:11]C1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl.N1C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]2[C:7]([CH:11]=[CH:10][C:9](=[O:18])[NH:1]2)=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1ccc2ccc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-aminophenol (1 g) in CH2Cl2 (25 mL) and pyridine (1 mL) at 5° C. was added dropwise a solution of cinnamoyl chloride (1.53 g) in CH2Cl2 (10 mL). The mixture was warmed to r.t. over 1 hr, and then EtOAc (150 mL) was added. The organics were washed with H2O, 1N, HCl, saturated aq. NaHCO3 and H2O, dried (MgSO4) and concentrated. To the residue was added AlCl3 (6.38 g) and the mixture heated at 180° C. for 5 min. and then at 115°-120° C. for 2 hr. To the mixture was added ice and then H2O. The solid that formed was collected by filtration, washed with 2N HCl and H2O (3×). The resulting solid was triturated in EtOAc to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[Cl-].CCCCCC>C(O)C.[Zn]>[F:24][C:22]([F:23])([F:25])[C:18]1[CH:17]=[C:16]([S:13]([CH2:12][CH2:11][S:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=2)(=[O:14])=[O:15])[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCO
Product: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 76 %

Procedure:
1.31 g (20 mmol) zinc was added to a solution of 1.96 g (5.0 mmol) 3-nitro-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]ethyl-sulfanyl]pyridine in ethanol (45 ml) and the mixture was cooled to 0° C. 200 ml (0.2 M, 40 mmol) of an aqueous NH4Cl solution were added at this temperature and then the mixture was heated for 30 min at 90° C. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with water and neutralised with NaHCO3. It was then extracted with EE and the organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) of the residue yielded 1.38 g (3.8 mmol, 76%) [2-[2-[[3-(trifluoromethyl)-phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine.