Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH:19]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])C)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:44]>>[ClH:44].[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:34])[C@@H:9]([NH:7][CH3:6])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:25][CH:24]=1
Reactant: ClCCl
Reactant: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](CC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Product: Cl
Reaction time: 0.42 h

Procedure:
To a solution of (S)-{1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester in CH2Cl2 (15 mL) was added trifluoroacetic acid (5 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 25 minutes, then concentrated in vacuo. The viscous oil obtained was dissolved in 60 mL of CH2Cl2 and successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The CH2Cl2 solution of free amine was concentrated in vacuo to afford the crude product as a viscous oil which was further purified by flash chromatography (10% methanol in chloroform). The free amine isolated was dissolved in 10 mL of ethyl ether. To this solution was added saturated HCl solution in ethyl ether until no more white precipitate formed. Filtration and drying overnight under vacuum afforded 0.65 g (89%) of pure titled compound as a white foam: mp 70-84° C. APCI-MS m/z 389.0 (MH+).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[C:20]([CH3:21])=[CH:19][S:18][C:17]=1[C:22]([O:24][CH3:25])=[O:23]>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[CH3:21][C:20]1[C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[C:17]([C:22]([O:24][CH3:25])=[O:23])[S:18][CH:19]=1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1scc(C)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1scc(C)c1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.1 %

Procedure:
A solution of 1-adamantaneacetyl chloride (0.2 g) prepared as described in Example 1a) was added to a solution of methyl 3-amino-4-methylthiophene-2-carboxlate (0.16 g) in pyridine (2 ml) and dichloromethane (4 ml). The reaction mixture was stirred at ambient temperature for 2 days before being diluted with ethyl acetate. The organic phase was then washed with dilute hydrochloric acid and water, dried over magnesium sulphate (MgSO4) and finally concentrated under reduced pressure to give an oil. Purification of the residue by silica gel chromatography, eluitng with 10% ethyl acetate in isohexanes, gave the title compound as a white solid (0.049 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=O.[CH:13]([NH2:15])=O.C(Cl)Cl.CO.[NH4+:21].[OH-]>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:3]2[NH:15][CH:13]=[N:21][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC=O
Reactant: [NH4+]
Reactant: COc1cccc(C(=O)CBr)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(-c2cnc[nH]2)c1
Yield: 43 %

Procedure:
Reaction of 2-bromo-1-(3-methoxy-phenyl)-ethanone (2.5 g, 10.90 mmol), and formamide (3.1 mL, 76.40 mmol), followed by chromatography (CH2Cl2/MeOH/NH4OH 48:1:1) gave the title compound (820 mg, 43%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 3.83 (s, 3H), 6.78–6.82 (m, 1H), 7.26–7.28 (m, 3H), 7.42 (s, 1H), 7.72 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:6][C:5]1=S.[O:24]1CCOCC1.[K]>C(O)=O.O>[F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:5]1=[O:24]
Reactant: FC(F)(F)CN1C(=S)NC(c2ccccc2)c2cc(Cl)ccc21
Reactant: C1COCCO1
Agent: [K]
Solvent: O
Solvent: O=CO
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinethione in 50 ml. of dioxane was added dropwise a solution of 3 g of potassium permangenate in 20 ml. of water. The mixture was stirred at room temperature for 2 hours and then a few drops of formic acid was added. The resultant brown precipitate was filtered off and washed with chloroform. The filtrate was concentrated under reduced pressure and the residue was dissolved in 30 ml. of chloroform. The chloroform solution was combined, washed successively with dilute sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was recrystallized from isopropyl alcohol to give 1 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone, m.p. 184.0°-185.0° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1.[O:17]=[C:18]1[N:22]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[NH:19]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[N:1]1[CH:6]=[C:5]([C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:26]3[CH2:25][CH2:24][CH:23]([N:22]4[C:21]5[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=5[NH:19][C:18]4=[O:17])[CH2:28][CH2:27]3)[CH2:12][CH2:11]2)([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CC(C)(c1cncnc1)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(c1cncnc1)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.3 %

Procedure:
A mixture of 1-(2-(5-pyrimidinyl)-prop-2-yl)-4-oxopiperidine (117 mg), 4-(2-oxo-1-benzimidazolinyl)piperidine (128 mg), 1,2-dichloroethane (2.5 mL), glacial acetic acid (0.031 mL) and sodium triacetoxyborohydride (170 mg) was stirred at room temperature for 48 h. The reaction mixture was poured into dichloromethane (15 mL) and saturated aqueous Na2 CO3 (8 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (2×15 mL) and the combined organic layers dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography, eluting with a gradient of methylene chloride; 0-6% methanol; 1% NH4OH, followed by trituration with diethyl ether gave 104 mg of 1,3-dihydro-1-(1-{1-[2-(5-pyrimidinyl)-prop-2-yl]piperidin-4-yl}piperidin-4-yl)-2H-benzimidazol-2-one as a colorless solid: 1H NMR (400 MHz, CDCl3) 10.37 (br s, 1H), 9.10 (s, 1H), 8.88 (s, 2H), 7.30 (m, 1H), 7.12-7.01 (m, 3H), 4.37 (m, 1H), 3.11 (d, 2H), 2.86 (d, 2H), 2.53-2.30 (m, 5H), 2.18 (t, 2H), 1.85 (m, 4H), 1.57 (m, 2H), 1.40 (s, 6H). Treatment with citric acid in ethanol yielded the citrate salt, analysis calculated for C24H32N6O.0.1 H2O.1.5 C6H8O7 : C: 55.78, H: 6.27, N: 11.83 found C: 55.82, H: 6.56, N: 11.68.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][S:8]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[CH:24]2.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C=O>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([NH:20][C:17]([CH:14]3[CH2:13][CH2:12][N:11]([S:8]([CH3:7])(=[O:9])=[O:10])[CH2:16][CH2:15]3)=[O:19])=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CS(=O)(=O)N1CCC(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(C(=O)Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A catalytic amount of N,N-dimethylformamide and a solution of oxalyl dichloride (0.367 g, 2.89 mmol) in methylene chloride (3 ml) were added to a solution of 1-(methylsulfonyl)-4-piperidinecarboxylic acid (500 mg, 2.41 mmol) in methylene chloride (7 ml), and the resulting mixture was stirred at room temperature for three and a half hours. The reaction solution was distilled under reduced pressure to remove the solvent, and a solution of the resulting residue in methylene chloride (5 ml) was added to a solution of 5-aminoindazole (322 mg, 2.42 mmol) and triethylamine (0.67 ml, 4.8 mmol) in methylene chloride (10 ml) at 0° C. and stirred overnight at room temperature. Then, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and the organic solvent was distilled off under reduced pressure. The solid precipitated was collected by filtration and suspended in methanol, and the resulting suspension was stirred at 50° C., followed by filtration. The solid collected by this filtration was dried under reduced pressure to obtain N-(1H-indazol-5-yl)-1-(methylsulfonyl)-4-piperidinecarboxamide (670 mg, 86%).
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)=[O:6].[NH4+].[Cl-].C(Cl)Cl.C1[CH2:23][O:22][CH2:21]C1>CCCCCC.O>[CH3:3][O:4][C:5]([CH:7]1[CH2:12][CH2:11][C:10](=[CH:21][O:22][CH3:23])[CH2:9][CH2:8]1)=[O:6]
Reactant: C1CCOC1
Reactant: COC(=O)C1CCC(=O)CC1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: COC=C1CCC(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A 2 L three-necked flask equipped with thermometer, stirrer, liquid sealing, N2 protection and drying tube was used. 285.4 g of MTC and 400 ml of THF were added. The flask was placed into a tank with cold bath at −15° C., to obtain a white suspension. The temperature was controlled to be between −5° C. and −10° C., and a solution of 93.3 g of t-BUOK in 400 ml of THF was added dropwise. The colour was changed into bright orange firstly, and then changed gradually into dark. After the completion of addition by dropwise, the reaction was conducted for 0.5 hour. A solution of 100 g of 4-keto-cyclohexyl formic acid methyl ester in 100 ml of THF was added dropwise at a temperature of between −5° C. and −10° C., with the colour faded gradually. After the completion of addition, the cooling was shut off, the temperature was raised naturally to about 0° C. and the reaction was conducted for 1 hour under thermal retardation. A 200 ml aqueous solution of 10 g NH4Cl was added, and the temperature was controlled to be less than 10° C. 500 ml of CH2Cl2 was added for extraction. If there is undissolved substance, a small amount of water was added to dissolve it, and washed with water till neutrality. The organic phase was tan in color, dried with anhydrous Na2SO4, and the solvent was removed by a rotary evaporator, so as to obtain a liquid-solid mixture. 500 ml of n-hexane was added, pumping filtrated, and leached with 100 ml of n-hexane twice. The filtrate was passed through a silicagel column, and the solvent was removed by a rotary evaporator, to obtain 113.5 g of pale yellow liquid. Yield: 96%, GC purity: 95.9%.
Reaction SMILES: [Na].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([NH2:14])=[NH:13])=[CH:6][CH:5]=1.[CH:15]([CH:17]([CH2:23][CH3:24])[C:18](OCC)=O)=[O:16]>C(O)C>[CH2:23]([C:17]1[C:15](=[O:16])[N:13]=[C:12]([CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[NH:14][CH:18]=1)[CH3:24]
Reactant: CCOC(=O)C(C=O)CC
Reactant: N=C(N)CCc1ccc(F)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCc1c[nH]c(CCc2ccc(F)cc2)nc1=O
Temperature: 25 °C
Yield: 79.8 %

Procedure:
Sodium (0.23 g) in dry ethanol (10 ml) was treated with 3-(4-fluorophenyl)propionamidine hydrochloride (Int. A108) (1.02 g). Ethyl 2-formylbutyrate (0.72 g) was added and the mixture refluxed for 6 h then maintained at room temperature for a further 24 h. The reaction mixture was concentrated in vacuo, and the residue treated with water and acidified with conc. hydrochloric acid. The white precipitate was filtered off, washed with water and dried in vacuo at 40° C. overnight, to give the title compound, (982 mgs, 80%) 1H-NMR (CDCl3) δ 1.22 (3H, t), 2.52 (2H, q), 2.94 (2H, m), 3.09 (2H, m), 6.96 (2H, m), 7.24 (2H, m), 7.84 (1H, s) and 13.06 (1H, br. s). (APCI+) Found (M+1)=247, C14H15FN2O requires 246.
Reaction SMILES: C(OC([N:11]1[CH:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C:13]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:13]1[CH2:14][CH:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:11][N:12]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1CC(c2cccs2)=NN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CC(c2cccs2)=NN1

Procedure:
A solution of 5.0 g of (±)-4,5-dihydro-1-(benzyloxycarbonyl)-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid, t-butyl ester in 75 ml of ethanol containing 0.5 g of 5% palladium on carbon is hydrogenated at atmospheric pressure until the uptake of hydrogen ceases. The catalyst is removed by filtration through Celite and the filtrate is concentrated in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:22]=2)[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1C(=O)N([Br:42])C(=O)C1.O>C(Cl)(Cl)Cl.CC(O)=O>[Br:42][C:20]1[S:19][C:18]([C:15]2[S:16][CH:17]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=2)=[CH:22][C:21]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCc1csc(-c2cc(CCCCCCCCCCCC)cs2)c1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCc1csc(-c2cc(CCCCCCCCCCCC)c(Br)s2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 4,4′-didodecyl-2,2′-bithiophene (0.100 g, 0.199 mmol) in CHCl3/HOAc (1:1) (Vt=2.0 mL) at 0° C. was added N-bromosuccimide (NBS, 35.7 mg, 0.199 mmol) in portions over a period of 45 minutes. The reaction mixture was stirred for 1 hour at 0° C. and overnight at room temperature. The reaction mixture was poured into water (50.0 mL) and extracted with chloroform (3×50.0 mL). The combined organic phases were washed with water (50.0 mL), NaOH solution, and dried over MgSO4. After filtration through Celite, the filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (hexanes) to provide 5-bromo-4,4′-didodecyl-2,2′-bithiophene (29A) as a colorless oil (98.0 mg, 85% yield). 1H NMR (CDCl3): δ 0.84-1.54 (m, 46H), 2.57 (m, 4H), 6.81 (s, 1H), 6.84 (s, 1H), 6.94 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]([CH2:19]Cl)=[CH2:18].O>CN(C)C=O>[Cl:16][C:17](=[CH2:18])[CH2:19][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cl)COc1ccc(C#N)cc1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
10.0 g of 4-cyanophenol and 11.6 g of potassium carbonate were suspended in 100 ml of dimethylformamide, and 9.4 g of 2,3-dichloropropene was added dropwise. The reaction solution was stirred at 80 oC for 3 hours, allowed to cool, and poured into 200 ml of water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried. Ethyl acetate was evaporated under reduced pressure. The resulting oily product was purified by column chromatography (silica gel; developing solvent hexane/ethyl acetate (9:1)) to give 15.2 g of the desired 4-(2-chloro-2-propeneoxy)benzonitrile as an oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Br:30])[CH:19]=1>CN(C=O)C>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Br:30])[CH:19]=1
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Reactant: C=C(c1cc(Br)cc(Br)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Br)cc(Br)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.7 %

Procedure:
To a solution of (Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (850 mg, 3.55 mmol) and 1,3-dibromo-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.75 g, 5.32 mmol) in DMF (10 mL) at rt was added TEA (0.5 mL, 3.55 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the desired title compound 5-(5-(3,5-dibromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (600 mg; 32% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.06 (d, J=2.0 Hz, 1 H), 7.79 (m, 4H), 7.73 (dd, J=8.0 Hz, 0.8 Hz, 1H), 4.45 (d, J=18.8 Hz, 1H), 4.33 (d, J=18 Hz, 1H), 1.50 (d, J=2.8 Hz, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=534.0 (M+1, ESI+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14]Br)[CH3:2].[Br:17][C:18]1[C:19](=[O:34])[N:20]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[C:21]([CH3:25])=[CH:22][C:23]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][O:24][C:23]1[CH:22]=[C:21]([CH3:25])[N:20]([C:26]2[C:27]([F:33])=[CH:28][CH:29]=[CH:30][C:31]=2[F:32])[C:19](=[O:34])[C:18]=1[Br:17])[CH3:2]
Reactant: CCOC(=O)COc1cc(F)ccc1CBr
Reactant: Cc1cc(O)c(Br)c(=O)n1-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)ccc1COc1cc(C)n(-c2c(F)cccc2F)c(=O)c1Br
Reaction time: 2 h

Procedure:
To a solution of ethyl[2-(bromomethyl)-5-fluorophenoxy]acetate (from Step 2) (0.59 g, 2.03 mmol) and 3-bromo-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.61 g, 1.93 mmol) in DMF (3.0 mL) was added K2CO3 (0.34 g, 2.43 mmol). After 2 h at RT, DMF was removed by distillation. The crude product was washed with 5% citric acid, extracted in DCM, dried over Na2SO4, filtered, and concentrated onto silica gel. Purified by flash column chromatography using 50% EtOAc/hexane as the eluent. Obtained product as a pale yellow solid (0.45 g, 42%). 1H NMR (CD3OD/400 MHz) δ7.21 (q, 3H, J=8.4 Hz), 6.80 (m, 2H), 6.69 (s, 1H), 6.15 (s, 1H), 5.40 (s, 2H), 4.84 (s, 2H), 4.23 (q, 2H, J=6.8 Hz), 2.08 (s, 3H), 1.26 (t, 3H, J=6.8 Hz). ESHRMS m/z 526.0446 and 528.0414 (M+H calculated for C23H20BrF3NO5 requires 526.0471 and 528.0454).
Reaction SMILES: C(O)[CH2:2][CH2:3][CH2:4][OH:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-:12].[Na+]>C1(C)C=CC=CC=1>[CH2:7]([O:5][CH2:4][CH:3]1[O:12][CH2:2]1)[CH:9]1[O:11][CH2:10]1
Reactant: ClCC1CO1
Reactant: OCCCCO
Reactant: [OH-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C(OCC1CO1)C1CO1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A 750 ml sulfonation flask equipped with thermometer, reflux condenser, N2 inlet and metering device, is charged with 90.12 g (1.0 mol) of 1,4-butanediol and 1.66 g of catalyst A and the reaction mixture is heated to 100° C. With efficient stirring, 160.7 ml (2.05 mol) of epichlorohydrin are added over 1 h and the mixture is allowed to react for 1 h. Afterwards the reaction mixture is cooled to 50° C., 200 ml of toluene are added and to the solution are added 16 g (0.2 mol) of a 50% aqueous solution of NaOH over 5 minutes (min). Then 76 g (1.9 mol) of pulverised NaOH are added by increments over 5 min and the suspension is stirred for 30 min. The reaction mixture is filtered, washed with 100 ml of toluene and the phases are separated. The organic phase is dried over MgSO4, filtered and the filtrate is freed from solvent on a rotary evaporator (bath temperature 70° C.), giving 204.8 g (101% of theory) of colourless diglycidyl ether of 1,4-butanediol having the following properties: epoxy value: 8.59 eq/kg (87% of theory); total chlorine content: 3.8%; concentration of hydrolisable chlorine: 29 ppm (parts per million).
Reaction SMILES: [C:1](=[O:16])([O:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[O:2][CH3:3].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[C:1](=[O:16])([O:4][C:5]1[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]([Br:11])=[CH:7][C:6]=1[C:12]([CH3:13])([CH3:15])[CH3:14])[O:2][CH3:3]
Reactant: COC(=O)Oc1ccc(Br)cc1C(C)(C)C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
Methyl (2-tert-butyl-4-bromophenyl) carbonate (470 g, 1.67 mol) was dissolved in conc. H2SO4 (1000 ml) at 0° C. KNO3 (253 g, 2.5 mol) was added in portions over 90 min. The reaction mixture was stirred at 0° C. for 2 h and poured into ice-water (20 L). The resulting precipitate was collected via filtration and washed with water thoroughly, dried and recrystallized from ether to give methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate (332 g, 60% over 3 steps).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([C:30]3[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)[CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[N:34][CH:35]=3)[C:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:17]=4)[C:11]=3[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[CH3:55][S:56]([N:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:18]2[CH:17]=[C:16]([N:13]3[C:11]4[N:12]=[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[N:8]=[C:9]([C:30]5[CH:31]=[N:32][C:33]([N:36]([CH2:37][C:38]6[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=6)[CH2:46][C:47]6[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=6)=[N:34][CH:35]=5)[C:10]=4[CH2:15][CH2:14]3)[CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26]1)(=[O:58])=[O:57]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CCN4CCNCC4)c3)cn2)cc1
Reactant: CS(=O)(=O)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CCN4CCN(S(C)(=O)=O)CC4)c3)cn2)cc1

Procedure:
In the same manner as Example 1-D-134, using a crude product (80 mg) of 5-{2-morpholin-4-yl-7-[3-(2-piperazin-1-yl-ethyl)-phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine obtained in Example 1-D-134 and methanesulfonyl chloride (0.017 ml) instead of acetyl chloride, a crude product of 5-(7-{3-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as a pale yellow solid (82 mg, 93%). Using this crude product (82 mg) of 5-(7-{3-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2,5-(7-{3-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-ylamine was obtained as a colorless powder (28 mg, 49%).