Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([C:25](O)=[O:26])[N:15]([CH3:24])[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1>>[CH2:1]([NH:4][C:25]([C:14]1[N:15]([CH3:24])[C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][CH:10]=2)[N:13]=1)=[O:26])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: CCCNC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 9, Step B, but using n-propylamine (0.015 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[NH:7]([CH2:11]CO)[CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][N:7]1[CH2:11][CH2:5][O:4][C:1]1=[O:6]
Reactant: OCCNCCO
Reactant: COC(=O)OC
Product: O=C1OCCN1CCO

Procedure:
In a preferred embodiment of this invention, equimolar amounts of dimethyl carbonate and diethanolamine are mixed and heated to reflux. The mixture is maintained at reflux until essentially all of the reactants are consumed as measured by gas chromatography. The product mixture consists of methanol and 3-(2-hydroxyethyl)-2-oxazolidinone. The methanol is removed by distillation leaving essentially pure 3-(2-hydroxyethyl)-2-oxazolidinone as confirmed by gas chromatography.
Reaction SMILES: C(OC)(=O)C1C=CC(C([O-])=O)=CC=1.[K+:14].[C:15]([O:30]CCCC)(=[O:29])[C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:18][CH:17]=1.[OH-].[K+].C1(C)C=CC=CC=1>C(O)CCC>[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:21])[C:19]1[CH:27]=[CH:28][C:16]([C:15]([O-:30])=[O:29])=[CH:17][CH:18]=1.[K+:14]
Reactant: CCCCOC(=O)c1ccc(C(=O)OCCCC)cc1
Agent: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1ccc(C(=O)[O-])cc1
Yield: 96 %

Procedure:
This compound was prepared by the procedure described for potassium monomethyl terephthalate. Typical reagent levels were as follows: dibutyl terephthalate (10.0 g, 0.036 mole), potassium hydroxide (2.1 g, 0.036 mole), 50 ml of toluene and 20 ml of 1-butanol. After workup 9.4 g was recovered which represented a 96% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH:17][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: O=C(Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1)c1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
4-[(E)-2-(4-Nitrophenyl)ethenyl]-1,3-thiazol-2-amine (300 mg) and N,N-dimethylaniline (4 ml) were combined under nitrogen atmosphere, and then benzoyl chloride (0.31 ml) was added dropwise to the suspension. The reaction mixture was stirred at 110° C. for 2 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate. The organic solution was washed with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with ethyl ether to give N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}benzamide (298.6 mg) as a yellow solid.
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:50])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][C:20](=[O:31])[C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][N:15]2[C:32]([CH:34]2[CH2:39][N:38]([C:40](=[NH:42])[CH3:41])[CH2:37][CH2:36][N:35]2C(OC(C)(C)C)=O)=[O:33])[CH:3]=1.CO>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:50])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][C:20](=[O:31])[C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][N:15]2[C:32]([CH:34]2[CH2:39][N:38]([C:40](=[NH:42])[CH3:41])[CH2:37][CH2:36][NH:35]2)=[O:33])[CH:3]=1
Reactant: CC(=N)N1CCN(C(=O)OC(C)(C)C)C(C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=N)N1CCNC(C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4 N Hydrochloric acid in 1,4-dioxane (10 mL) was added to crude (1-tert-butoxycarbonyl-4-acetimidoylpiperazin-2-ylcarbonyl)-trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (D) at 0° C. After stirring at 0° C. for 10 min and at room temperature for 10 min, methanol (2 mL) was added until insoluble materials were disappeared. After stirring for 1 hr, the solvents were removed in vacuo. The residue was purified by HPLC (Shiseido, Capcell Pak C18 UG120, 3 cm×25 cm, 0.02 N hydrochloric acid:methanol=70:30 to 60:40, v/v) and freeze-dried from water to afford the title compound (37 mg) as a pale yellow powder. The compound appears as a mixture of rotamers: 1H NMR (400 MHz, D2O) δ 1.78-2.00 (2H, m), 2.26 and 2.32 (each s, total 3H), 2.20-2.43 (m, 1H), 2.52-2.66 (m, 2H), 3.18-3.72 (m, 6H), 3.87-4.13 (m, 3H), 4.30-4.44 (m, 2H), 4.52-4.66 (m, 1H), 4.73-4.82 (m, 1H), 7.04-7.27 (m, 5H), 7.77 (t, J=7.8 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 8.00-8.12 (m, 2H), 8.91 (s, 1H), and 9.25 (s, 1H); IR (KBr) 3064, 1658, 1612, 1571, 1550, 1494, and 1454 cm−1; mass spectrum (FAB+) m/e 572 (M+1); Anal.Calcd for C31H37N7O4.3HCl.6.1H2O: C, 47.07; H, 6.65; N, 12.40. Found: C, 46.68; H, 6.11; N, 12.02.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([O:22][CH3:23])=[O:21].[H-].[Na+].[CH3:26]OS(OC)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[N:15]([CH3:26])[C:14]([CH3:19])=[C:13]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1F
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
The product of Example 21, Step 1 (3.0 g, 9.056 mmol, 1.0 equiv) was dissolved in 100 mL DMF and NaH (725 mg, 18.11 mmol, 2.0 equiv) was added slowly to the reaction mixture. Me2SO4 (1.72 mL, 18.11 mmol, 2.0 equiv) was added and the reaction was stirred at room temperature for 45 min. The reaction was quenched with water and diluted with EtOAc. After the phases were separated, the organic phase was washed once with satd. NaHCO3 and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was triturated with Et2O and filtered to provide 1.5 g (48%) of the title compound as a light yellow solid. MS (ES+) m/e 346 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C(#N)C.[Cl:18]N1C(=O)CCC1=O>CCCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[Cl:18]
Reactant: CCOC(=O)c1ccc(N)c(OC)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC#N
Product: CCOC(=O)c1cc(Cl)c(N)c(OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To ethyl 4-amino-3-methoxybenzoate (17.8 g, 91.2 mmol), were added acetonitrile (170 mL) and N-chlorosuccinimide (13.4 g, 100 mmol) in this order, and the mixture was stirred at 60° C. for two hours. The mixture was returned to room temperature, and the solvent in the mixture was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate:n-heptane/ethyl acetate=8/1 then 4/1) to obtain the title compound (158 g, 68.8 mmol).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]([C:15]1[S:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.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>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[S:19][C:15]([C:12](=[O:14])[CH3:13])=[CH:16][CH:17]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1

Procedure:
A mixture of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (620 mg, 2.9 mmol), 5-acetyl-2-thiopheneboronic acid [206551-43-1] (634 mg, 3.7 mmol), potassium carbonate [584-08-7] (792 mg, 5.7 mmol), and bis(triphenylphosphine)palladium(II) dichloride [13965-03-2] (100 mg, 0.1 mmol) was suspended in a microwave reaction vial with a 25% (v/v) solution of water in acetonitrile (4.5 mL) then stirred and irradiated to an internal temperature of 145° C. for 15 minutes. The cooled reaction mixture was diluted with ethyl acetate, filtered, and partitioned between 1N aqueous sodium hydroxide and additional ethyl acetate. The organic extract was flash chromatographed (silica gel, eluted with 20% (v/v) ethyl acetate/hexanes) to provide 1-[5-(6-fluoro-imidazo[1,2-b]pyridazin-3-yl)-thiophen-2-yl]-ethanone as 300 mg of yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.63 (s, 3H) 7.00 (d, J=9.35 Hz, 1H) 7.75 (d, J=4.04 Hz, 1H) 7.83 (d, J=4.04 Hz, 1H) 8.13 (dd, J=9.60, 7.07 Hz, 1H) 8.21 (s, 1H). LRMS (ESI) m/z 262.1 [(M+H)]+, calc'd for C12H8FN30S: 261.28.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:10]=[C:9]([Br:13])[CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1C(C)(C)C
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 2-(t-butyl)anisole (16.38 g, 0.0997 mol) in CH2Cl2 (350 mL) was added pyridinium tribromide (35.09 g, 0.110 mol). The resulting mixture was allowed to stir at RT overnight. The mixture was diluted with CH2Cl2 and H2O and the layers were separated, the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with H2O, brine and dried with MgSO4. The mixture was filtered and the solvents evaporated to give 2-(t-butyl)-4-bromoanisole as an oil (23.16 g, 95%). 1H NMR (300 MHz, CDCl3): δ 1.35 (s, 9H), 3.82 (s, 3H), 6.74 (d, J=8.7 Hz, 1H), 7.28 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:21]Br>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:21][CH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reaction time: 0.5 h
Yield: 995.8 %

Procedure:
13.2 Grams (0.006 mole) of tert-butyl 4-methylbenzoate, 0.3 g (0.0012 mole) of benzoyl peroxide and 6 g (0.006 mole) of sodium carbonate were suspended in 100 ml of carbon tetrachloride, and 9.6 g (0.06 mole) of bromine was added dropwise at 50° C. over 30 minutes with stirring. After completion of the addition, reaction was continued for further 30 minutes. The reaction solution was then cooled and filtered to remove carbon tetrachloride-insoluble matters. Carbon tetrachloride was then removed by evaporation under reduced pressure to obtain 16.2 g of tert-butyl 4-bromomethylbenzoate as crystals.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCCCCCCCl
Reactant: CCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Product: CCCCCCOc1ccc(-c2ncc(OCCCCCCO)cn2)cc1

Procedure:
0.013 mol of 2-(4-hexyloxyphenyl)-5-hydroxypyrimidine and 0.020 mol of 6-chlorohexan-1-ol are employed.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[N:22]=3)[CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To N-tert-butyl-3-[4′-methyl-6′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (example 299) (0.450 g, 0.856 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as an off-white solid (0.304 g, 76%). MS (ISP) 470.3 [(M+H)+]; mp 229° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 4-aminophenylboronic acid pinacol ester with reaction time of 24 h. Chromatography (hexane/ethyl acetate 6:4) gave the title compound as a yellow solid.
Reaction SMILES: [O:1]1CCC[CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[CH3:14][O:15][CH:16]([O:21][CH3:22])[CH2:17][CH2:18][C:19]#[N:20].C(OC)=O>C1COCC1>[CH:2]([CH:18]([CH2:17][CH:16]([O:21][CH3:22])[O:15][CH3:14])[C:19]#[N:20])=[O:1]
Reactant: C1CCOC1
Reactant: COC(CCC#N)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: COC=O
Product: COC(CC(C#N)C=O)OC
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (1.5 M in cyclohexane, 22.0 mL, 33.00 mmol) was added to THF (100 mL) at −30° C. and the resulting solution was stirred for 10 min before 3-cyanopropionaldehyde dimethyl acetal (3.90 mL, 29.90 mmol) was added dropwise over 5 min. After 15 min, methyl formate (2.80 mmol, 45.42 mmol) was added and the resulting solution was stirred at −20° C. to −15° C. for 2 h. The reaction mixture was quenched with water (100 mL) and washed with ether (2×50 mL, discarded). The aqueous layer was acidified with 10% HCl and extracted with ether (3×50 mL). The combined ether extracts were washed with brine (3×50 mL), dried (MgSO4), and concentrated. The residue was dissolved in dichloromethane and concentrated to remove traces of THF and provide 2.28 g (49%) of the title compound as a pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:24])[N:17]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH2:27][CH2:26]3)[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:23]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(O)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A solution of cis-3-[4-(benzyloxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrmidin-4-amine (0.500 g, 1.005 mmol) in absolute ethanol (25 mL) was treated with palladium 10 wt. % on activated carbon (0.100 g, 0.201 mmol) and ammonium formate (0.317 g, 5.03 mmol). The reaction mixture was stirred at 80° C. for 2 h; no starting material was seen by thin layer chromatography. The reaction mixture was filtered through a pad of celite, which was washed with ethanol (500 mL). The organic layer was removed under reduced pressure. The resulting solid was dried over night under high vacuum to give 0.406 g (99%) of cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol. 1H NMR (DMSO-d6, 400 MHz) δ 8.204-8.194 (m, 2H), 7.472-7.437 (m, 2H), 6.947-6.912 (m, 2H), 4.791-4.744 (m, 1H), 2.418 (m, 9H), 2.249-2.243 (m, 2H), 2.193(s, 3H), 2.077-2.050 (m, 2H), 1.688-1.666 (m, 2H), 1.656-1.578 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 3.47 min (99%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[OH:29][C:30]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:31]=1[C:32](Cl)=[O:33].[OH-].[Na+].Cl>C(Cl)Cl>[OH:29][C:30]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:33]
Reactant: COc1ccc(O)c(C(=O)Cl)c1
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(O)c(C(=O)Nc2ccccc2C(=O)NCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 1.00 g (4.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 ml of dry methylene chloride, add 4.50 g (38.50 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.58 g (5.70 mmol) of triethylamine and a solution of 0.71 g (38.5 mmol) of 2-hydroxy-5-methoxybenzoyl chloride dissolved in 10 mL of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 0.791 g (56%) of 4-[2-(2-hydroxy-5-methoxybenzoylamino)benzoylamino]butanoic acid as a cream-coloured solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:17]=1)[NH2:14].C(N(CC)CC)C>C1COCC1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:14][C:13]1[CH:15]=[C:16]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH:17]=[C:11]([F:10])[CH:12]=1
Reactant: Nc1cc(F)cc(N2CCOCC2)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)cc(N2CCOCC2)c1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
2,2,2-Trichloroethyl chloroformate (1.05 mL, 7.65 mmol) was added to an ice cold solution of 3-fluoro-5-morpholin-4-ylaniline (reference procedure see EP1102743; 1.0 g, 5.10 mmol) and triethylamine (1.77 mL, 10.2 mmol) in THF (25 mL). The reaction mixture was stirred at RT for 1.5 h, then quenched with water. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (1.89 g, 99%) as a clear oil. LCMS (Method 3): Rt 3.75 min, m/z 371, 373 [MH+].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([CH3:22])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][OH:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]([CH3:22])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:13]=[O:14]
Reactant: CC(C)(CO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 107 %

Procedure:
To a solution of oxalyl chloride (10.1 g, 79.4 mmol) in methylene chloride (70 mL) at −78° C. was added dimethylsulfoxide (10.0 mL, 139 mmol). The solution was stirred at −78° C. for 10 minutes then a solution of 2,2-dimethyl-3-phenylpropanol (6.52 g, 39.7 mmol) in methylene chloride (15 mL) was added. After stirring the reaction at −78° C. for 30 minutes, triethylamine (20.1 g, 198 mmol) was added and the reaction mixture was stirred for 10 minutes, then at 0° C. for 5 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and the aqueous layer was extracted with diethyl ether (2×50 mL). The organic portions were individually washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was redissolved in diethyl ether and the resulting precipitate was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to provide the title compound (6.89 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:15])=[C:6]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.[CH2:16]1[CH2:26]CN2C(=NCCC2)C[CH2:17]1.BrC(C)C.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH:16]([CH3:26])[CH3:17])=[C:6]([O:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[CH:7]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)C(=O)Oc1cc(Br)ccc1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)Br
Product: CC(C)Oc1ccc(Br)cc1OC(=O)C(C)(C)C
Temperature: 40 °C
Yield: 60 %

Procedure:
2,2-dimethylpropionic acid 5-bromo-2-hydroxyphenylester (500 mg) was dissolved in dimethylformamide and stirred with 1,8-diazabicyclo[5.4.0]undece-7-ene (DBU; 0.32 ml) for 10 minutes. Then, 2-bromopropane (0.25 ml) was added and heated at 40° C. After the reaction was completed, water was added to dilute and extracted with ethylacetate. An organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/12, v/v). As a result, the present compound (340 mg, productive yield 60%) was obtained.