Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[F-].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][CH:10]([CH3:12])[CH2:9][CH:8]([C:5]1[CH:4]=[N:3][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=2)=[N:7][CH:6]=1)[OH:13]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)CC(O)c1cnc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 14.9 %

Procedure:
To a solution of the 1-(2-chloropyrimidin-5-yl)-3-methylbutan-1-ol (600 mg, 2.99 mmol) in toluene (15.0 mL) was added Pd(PPh3)4 (346 mg, 0.299 mmol), 4-(trifluoromethyl)phenyl boronic acid (682 mg, 3.59 mmol), potassium fluoride (521 mg, 8.97 mmol) and water (3.7 mL). The reaction mixture was purged with nitrogen and heated to reflux for 5 h. The phases were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were concentrated under reduced pressure. The crude solid was purified by silicas gel chromatography to give 3-methyl-1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)butan-1-ol (138 mg) as a yellow solid. 1HNMR (400 MHz, CDCl3) δ 8.77 (s, 2H), 8.55 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 4.81-4.84 (m, 1H), 1.92-1.65 (m, 2H), 1.53-1.47 (m, 1H), 0.94 (d, J=6.4 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[C:4]([CH3:11])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc([N+](=O)[O-])c(N)n1
Agent: O=S(=O)(O)O
Product: Cc1nc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred solution of 2-amino-3-nitro-6-methylpyridine (8.5 g, 55 mmol) in conc. H2SO4 (100 mL) at 0° C. was added HNO3 (2.74 mL, d=1.49, 58.3 mmol) dropwise over 10 min. The mixture was warmed to r.t. for 30 min then heated to 50° C. for 90 min. The reaction mixture was cooled and poured into 200 g of ice. The resulting percipitate was filtered and air dried to give 2-amino-3,5-dinitro-6-methylpyridine as a yellow solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[S:18]1[CH2:22][CH2:21][N:20]=[CH:19]1>>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([CH2:2][CH:19]3[N:20]=[CH:21][CH2:22][S:18]3)[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: C1=NCCS1
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CC1N=CCS1)C2
Temperature: 150 °C
Reaction time: 4 h
Yield: 38.4 %

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (4.802 g) and thiazoline (5.815 g) was stirred at 150° C. in the stream of argon gas for 4 hours. The solvent was distilled off under reduced pressure. Chloroform was added to the residue, and extracted with 1N-HCl. After the extract was washed with chloroform, 1N-NaOH was added to bring the pH basic. Extraction was performed with chloroform, followed by washing with water. After dried, the residue was crystallized from methanol to obtain 1.885 g of a free base of the title compound as pale yellow powder (mp.: 196°-199° C.).
Reaction SMILES: C1(CO[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][CH:13]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]2)[C:14]3=[O:19])C=CC=CC=1.F[C:35](F)(F)[C:36]([O-:38])=O>>[CH3:14][CH:15]([C:10]1[CH:11]=[CH:12][C:35]([CH2:36][O:38][C:18]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:19])[CH:13]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]2)[CH2:12][CH2:11]3)=[CH:18][CH:9]=1)[CH3:16]
Reactant: O=C1c2cccc(OCc3ccccc3)c2CCC1CCN1CCC(c2ccccc2)CC1
Reactant: O=C([O-])C(F)(F)F
Product: CC(C)c1ccc(COc2ccc3c(c2)CCC(CCN2CCC(c4ccccc4)CC2)C3=O)cc1

Procedure:
3,4-Dihydro-5-(phenylmethoxy)-2-[2-(4-phenyl-1-piperidinyl)ethyl]-1(2H)-naphthalenone, trifluoroacetate (1:1);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=O.Cl.[NH2:16][OH:17]>CO.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[N:16][OH:17]
Reactant: CC1(C)CC(=O)c2cc(F)ccc2O1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC1(C)CC(=NO)c2cc(F)ccc2O1

Procedure:
By heating 10 mmol of 6-fluoro-2,2-dimethyl-4-chromanone with 12 mmol of hydroxylamine hydrochloride in 5 ml of methanol and 5 ml of pyridine for 2 hours to 80° C., after distilling off the solvent and precipitating with water, 6-fluoro-2,2-dimethyl-4-chromanone oxime is obtained; m.p. 108-110° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[CH:18].C(N(CC)CC)C.C1C=CC=CC=1>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][N:9]=1
Reactant: NNc1ccccc1I
Reactant: C#Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccccc1Cc1n[nH]c2ccccc12

Procedure:
Under argon, 200 mg (0.86 mmol) of 2-iodophenylhydrazine, 133 mg (1.11 mmol) of 2-fluoro-phenylacetylene, 30 mg (0.04 mmol) of bis(triphenylphosphine)palladium(II) chloride and 8 mg (0.04 mmol) of copper(I) iodide are introduced into a mixture of 1.5 ml of triethylamine and 3.5 ml of benzene. The mixture is heated to reflux for 4 h and then diluted with ethyl acetate and filtered. The filtrate is concentrated and the residue is purified by preparative HPLC. 36 mg (18% of theory) of the desired product are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([CH3:16])[N:3]=2)[CH:21]=[CH:20][N:19]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example A.41) (0.4 g, 1.46 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.3 g, 1.9 mmol) according to the general procedure IVb. Obtained as a light brown solid (0.15 g, 29%). MS (ISP) 350.2 [(M+H)+]; mp 155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[CH2:18][CH2:17][NH:16][CH2:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:26][C:25]1[C:20]([N:16]2[CH2:17][CH2:18][C:10]3[C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:14][CH:13]=[N:12][C:11]=3[CH2:15]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccnc1Cl
Reactant: Fc1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: Fc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 150 °C
Yield: 29.3 %

Procedure:
N-(4-Fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.47 g, 1.92 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (3 mL). To the mixture was added 2,3-dichloropyridine (420 mg, 2.86 mmol) and N,N-diisopropylethylamine (0.38 mL, 2.2 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified by silica gel chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (200 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]1(=O)[O:20][C:18](=[O:19])[CH:17]=[CH:16]1>C(O)(=O)C>[F:12][C:11]([F:14])([F:13])[C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:1]3[C:18](=[O:19])[CH:17]=[CH:16][C:15]3=[O:20])[C:7]=2[N:8]=1
Reactant: Nc1cccc2oc(C(F)(F)F)nc12
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1c1cccc2oc(C(F)(F)F)nc12
Yield: 57.2 %

Procedure:
Compound 476B (0.500 g, 2.48 mmol) was dissolved in acetic acid (10 mL) and maleic anhydride (0.267 g, 2.72 mmol) was added. The mixture was heated at reflux for 3 h, cooled and the solvent removed in vacuo to give a tan solid. The crude product was purified by flash chromatography on silica gel eluting with 2% MeOH/CH2Cl2 to give compound 476C (0.40 g, 57%) as an off-white solid. HPLC: 89.7% at 2.38 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 283.21 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].[CH2:13](N)/[CH:14]=C/C.C(O)(=O)C(O)=O.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29]C1CNC1.C(N(CC)CC)C>C(Cl)Cl>[CH2:12]([NH:8][C:1]([N:3]1[CH2:4][CH:6]([O:29][C:28]2[CH:34]=[CH:35][CH:36]=[C:26]([C:25]([F:24])([F:37])[F:38])[CH:27]=2)[CH2:7]1)=[O:2])/[CH:11]=[CH:13]/[CH3:14]
Reactant: C/C=C/CN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C/CNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.7 %

Procedure:
A solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 60 ml of methylene chloride was cooled in an ice bath while stirring under nitrogen while 1.6 g (0.022 mole) of trans-crotylamine was added dropwise. After warming to ambient temperature, 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 0.25 hr by 5 ml of triethylamine with stirring continued for 72 hr. The reaction solution was washed with 2×50 ml of water, dried over magnesium sulfate and concentrated on a rotary evaporator to a solid residue, 7 g. Recrystallization from methanol-water gave 5.5 g of slightly yellow product. A second recrystallization with charcoal treatment from isopropyl ether yielded 3.75 g (59.7%) of fine white crystals, m.p. 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:17](=[O:19])[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(=O)Cl
Reactant: Nc1cnc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5,6-dichloropyridin-3-amine (commercially available) and triethyl amine (3 eq) in CH2Cl2 (0.2 M) at 0° C. was added acetyl chloride (2 eq). After stirring at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford N-(5,6-dichloropyridin-3-yl)acetamide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[Li]CCCC.[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[CH2:24])[CH:19]=2)[CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH2:23][CH2:24][N:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[CH3:1])[CH:17]=[CH:16]2
Reactant: C=Cc1ccc2cc(Br)ccc2c1
Reactant: CC1CCCN1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CCCN1CCc1ccc2cc(Br)ccc2c1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a cooled solution of 2-methylpyrrolidine (2.0 mL, 20 mmol) in THF (30 mL) at −15° C. was added n-BuLi (1.6 M in hexane, 4.0 mL, 6.4 mmol) dropwise keeping the temperature below −10° C. The resulting mixture was stirred at −15° C. for 10 min. To the cooled solution was added a solution of 2-bromo-6-vinyl-naphthalene (3) (2.33 g, 10.0 mmol) in THF (30 mL) dropwise keeping the temperature below −15° C. The resulting mixture was stirred at −15° C. for 5 min. and quenched with H2O (1 mL) and then poured into 5% Na2CO3 (80 mL). To the mixture was added EtOAc (80 mL), and organic was separated, the aqueous layer was extracted with EtOAc (30 mL). The combined organic layer was washed with brine and treated with activated carbon, dried over Na2SO4 and concentrated. The residue was then further dried under high vacuum to give 2.47 g product. The crude product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) d 7.86 (d, 1H), 7.53–7.59 (m, 3H), 7.40–7.42 (dd,1H), 7.28–7.30 (dd, 1H), 3.04–3.22 (m, 1H), 3.98–3.04 (m, 1H), 2.85–2.91 (m, 2H), 2.23–2.33 (m, 2H), 2.14 (q, 1H), 1.81–1.88 (m, 1H), 1.62–1.78 (m, 2H), 1.32–1.39 (m, 1H), 1.04 (d, 3H). 13C NMR (400 MHz, CDCl3) d 138.50, 132.75, 131.65, 129.29, 128.90, 128.76, 128.21, 126.63, 126.34, 118.72, 60.11, 55.88, 54.15, 35.78, 32.93, 21.98, 19.28. [M+H]+ at m/z 319.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26]I)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOCC>[C:11]([N:18]1[CH2:19][CH2:20][CH:21]([CH2:24][CH2:25][CH2:26][O:1][C:2]2[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-hydroxy-5-isoxazolecarboxylate (Aldrich) (3-5) (286 mg, 2.0 mmol), 3-4 (706 mg, 2.0 mmol), Cs2CO3 (650 mg, 2.0 mmol), and DMF (10 mL) was stirred at ambient temperature. After 72 hours the reaction mixture was diluted with ether and then washed with H2O and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 4% acetone/CH2Cl2) gave 3-6 as a colorless solid. Rf 0.54 (silica, 40 %EtOAc/hexanes).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([CH2:29][C:30]#[N:31])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:59])(=O)=O)CCCCCCCCCCCCCCC>>[C:30]([CH2:29][CH:10]([CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:59])(=[O:7])=[O:6])#[N:31]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)CNS(=O)(=O)CCCCl
Product: CCCCCCCCCCCCCCCCOCC(CC#N)CNS(=O)(=O)CCCI

Procedure:
1-(3-Chloropropylsulfonylamino)-2-cyanomethyl-3-hexadecyloxypropane IIIn1 is allowed to react by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH2:13]([C:15]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16]1)[CH3:14].[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:43][C:1]([N:22]4[CH2:14][CH2:13][C:15]5([CH2:16][O:17][CH2:18][CH2:19]5)[CH2:20][CH2:21]4)=[O:12])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC1(CCN)CCOC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCC2(CCOC2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 2-(3-ethyl-tetrahydro-furan-3-yl)-ethylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=443.7 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[NH:44]1[CH2:48][CH2:47][CH:46]([OH:49])[CH2:45]1.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22]([N:44]3[CH2:48][CH2:47][CH:46]([OH:49])[CH2:45]3)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: OC1CCNC1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1N=C(NCC(=O)N2CCC(O)C2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and pyrrolidin-3-ol (0.23 mL) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (90 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1)[CH3:22]
Reactant: CCN1CCNCC1
Reactant: COc1ccccc1OCC(C)Oc1nccnc1Cl
Product: CCN1CCN(c2nccnc2OC(C)COc2ccccc2OC)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51 mmol) and N-ethylpiperazine (222 mg, 1.94 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 127 mg (67%) of the title product. HRMS m/z calcd for C20H28N4O3 (M)+372 2161, found 372.2174. Anal. (C20H28N4O3) C, H, N
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13]([C:15]1[CH:22]=[C:21]([O:23]C2CCCCO2)[CH:20]=[C:19]([B:30]2[O:34][C:33](C)(C)C(C)(C)[O:31]2)[C:16]=1C=O)[CH3:14].Cl>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:33]1[O:34][B:30]([OH:31])[C:19]2[CH:20]=[C:21]([OH:23])[CH:22]=[C:15]([CH2:13][CH3:14])[C:16]1=2)[CH3:12]
Reactant: CCc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(CC)c21
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
To a suspension of zinc dust (5.35 g, 82.3 mmol) in THF (10 mL) was added trimethylsilyl chloride (1.1 g, 10.15 mmol) at 40° C. The mixture was heated to 55° C. and stirred for 45 minutes. After cooling down to 37° C., ethyl bromoacetate (7.58 mL, 74.87 mmol) was slowly added to the reaction mixture at 37-40° C. After addition, the resulting mixture was allowed to cool to room temperature over 30 minutes. This solution was added to a solution of 2-ethyl-4-(tetrahydro-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (2.07 g, 5.39 mmol) in THF (6 mL) at 0° C. The mixture was stirred for 10 minutes before treating with 3 N HCl and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and lyophilized to give (4-ethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester(0.380 g, 27%). 1H NMR (400 MHz, DMSO-d6δ 9.30 (s, 1H), 9.02 (s, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 5.40 (m, 1H), 4.00 (m, 2H), 3.00 (m, 1H), 2.50 (m, 2H), 2.20 (m, 1H), 1.20 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[O:40][C:41]4[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:42]=4[N:43]=3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:39]4[O:40][C:41]5[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:42]=5[N:43]=4)=[CH:36][CH:37]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
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: O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Yield: 198.7 %

Procedure:
To a solution of rac-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate (0.412 g, 0.958 mmol) in ethylene glycol dimethyl ether (6 mL) and water (3 mL) was added N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.436 g, 1.20 mmol), tetrakis(triphenylphosphine)palladium (0) (0.055 g, 0.048 mmol), and sodium carbonate (0.254 g, 2.39 mmol). The solution was heated at 80° C. for 18 h, and then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate as an orange solid (1.029 g), which was used in the next step without further purification.