Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:18])C>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:16]=[O:18])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CC(=O)O
Product: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1

Procedure:
It has now been found that reaction of 2,4-di-tert-butylphenol with hexamethylenetetramine in glacial acetic acid followed by quenching with water or aqueous acid, extraction with a water insoluble non-polar solvent and filtration through silica gel provides 3,5-di-tert-butylsalicylaldehyde in more than 60% yield and of a purity suitable for the production of chiral Mn-Salen catalysts. Alternatively, reaction of 2,4-di-tert-butylphenol with HMT in glacial acetic acid followed by quenching with an aqueous acid, separating the aqueous phase from the organic phase and recrystallizing the organic phase in methanol provides 3,5-di-tert-butylsalicylaldehyde in more than 40% isolated yield and a purity suitable (>95%) for the production of the catalyst.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:14][C@@H:15]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:16]([NH:18][C@@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20]1)=[O:17]>ClCCl>[CH2:24]([N:21]1[CH2:22][CH2:23][C@@H:19]([NH:18][C:16](=[O:17])[C@@H:15]([NH:14][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)=[O:11])[C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)[C@H](N)C(=O)N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)Nc1cccc(C(F)(F)F)c1)C(=O)N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.5 %

Procedure:
3-(Trifluoromethyl)phenyl isocyanate (0.093 g, 0.50 mmole) was slowly added to a solution of 2a (0.12 g, 0.42 mmole) in dichloromethane (20 mL) at 0° C. The solution was allowed to warm to room temperature and stirred for 18 h. The reaction was then quenched with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The organic residue was purified by flash chromatographey on silica gel, eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4) to give 3a (0.045 g, 34%) as a white solid; MS (EI)=476 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]#[C:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CN(C)CC#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
The mixture of (3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-prop-2-ynyl)-dimethyl-amine (200 mg, 0.43 mmol), 10% Pd/C (20 mg) in MeOH (20 mL) was stirred under H2 atmosphere (50 psi) at room temperature for overnight. Filtered and concentrated to give 246 (26 mg, yield: 13%). 1H NMR (CDCl3, 400 MHz): δ8.08 (s, 1H), 7.58-7.52 (m, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.15-7.07 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.90 (s, 1H), 4.29 (t, J=4.4 Hz, 2H), 3.12 (t, J=4.4 Hz, 2H), 2.82-2.77 (m, 4H), 2.57 (s, 6H), 2.15-2.08 (m, 2H). ESI− MS: (m/z)=468 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]2[C:25]=1[O:24][C:23]([CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]3[C:25]=2[O:24][C:23]([CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cc3ccco3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(Cc3ccco3)nc2c1C#N
Temperature: 95 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (88 μl, 0.695 mmol) and triethylamine (97 μl, 0.695 mmol) were added to a dimethyl sulfoxide (4 ml) solution of 7-fluoro-2-(2-furylmethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-271) (154 mg, 0.463 mmol), followed by stirring in an oil bath at 95° C. for 1 hour. The reaction liquid was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography and preparative TLC (eluent, chloroform:methanol=20:1, v/v) to obtain the entitled compound (27 mg, 14%) as a pale brown foamy substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24].S(=O)(=O)(O)O>O>[OH:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[C:5]([Cl:9])[C:4]=1[CH:23]=[O:24]
Reactant: Oc1cc(Cl)c(F)cc1Br
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1c(O)c(Br)cc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
A mixture of 90.4 gm (0.40 mole) 2-bromo-4-fluoro-5-chlorophenol (containing 10% 2-bromo-3-chloro-4-fluorophenol) and 64 gm (0.45 mole) hexamethylenetetramine was cooled in an ice bath. To this cooled mixture were added 306 mL trifluoroacetic acid. After stirring at about 0° C. for 15 minutes, the reaction mixture was heated at reflux for 1.5 hours. The reaction mixture was then cooled in an ice bath and treated with 439 mL of water followed by 220 mL 50% sulfuric acid. The reaction mixture was stirred without cooling for two hours. The reaction mixture was then diluted with 500 mL water and the resulting solid collected by filtration. The solid was washed with water until the wash was neutral (pH about 7). The solid was dried under reduced pressure and was then subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0–2% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 57 gm (62%) 2-hydroxy-3-bromo-5-fluoro-6-chlorobenzaldehyde.
Reaction SMILES: Br[C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C([Li])(C)(C)C.CN(C)[CH:20]=[O:21].Cl>O1CCCC1.CCCCC>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2]([CH:20]=[O:21])[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4]1
Reactant: Cc1c(Br)c(C(F)(F)F)nn1C
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1c(C=O)c(C(F)(F)F)nn1C
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
Dissolve 4-bromo-1,5-dimethyl-3-trifluoromethyl-1H-pyrazole (0.30 g, 1.23 mmol) in tetrahydrofuran (14.7 mL). Cool to −78° C. and add 1.7 M t-butyllithium in pentane (2.9 mL) dropwise. Stir for 3 min. at −78° C. and then add dimethylformamide (669 μL, 8.64 mmol). Stir for thirty min. at −78° C., then warm to 0° C. over 2 hr. Add 2 N hydrochloric acid (12.3 mL) and stir at room temperature for one hr. Separate layers and extract aqueous layer 2 times with DCM. Dry combined organic layers (magnesium sulfate), filter, concentrate and purify (silica gel chromatography eluting with 0:100 to 15:85 ethyl acetate:hexanes), to give the title preparation (79 mg, 33%). GC-MS: m/z=192 [M+].
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:6][C:7]=1[CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH3:9])[CH3:2].[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35]>>[CH2:1]([C:3]1[O:4][C:5]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=2)=[CH:6][C:7]=1[CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:16])=[CH:13][CH:12]=1)[CH3:9])[CH3:2]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(C)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCNC
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(C)Oc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 99 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethoxy)benzoic acid (121 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (145 mg, 99%) as an oil.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.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>[NH2:20][C:4]1[N:3]=[C:2]([C:22]2[O:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1nc(-c2cc3ccccc3o2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 2.5 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 2-benzofuranylboronic acid (99 mg, 0.61 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 15 s) for 40 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (15 mL) and washed with sat. aq. NaHCO3 (15 mL×2) and brine (15 mL) and dried over MgSO4. Purification by flash column chromatography (normal phase, ICN silica, 20 g, 18-32μ, gradient 0-20% ethanol in DCM, residue dry loaded, product eluted in 15% ethanol) and by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10%, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 35% acetonitrile) afforded the title compound 13 as a white solid (4.9 mg, 3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1.C(COC)OC>O>[C:19]([C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(C)c1cc(-c2ccccc2N)cc(C(C)(C)C)c1O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1cc(-c2ccccc2NC(=O)CCCC(=O)O)cc(C(C)(C)C)c1O

Procedure:
A solution of 1.9 g (6.4 mmole) of the known compound 2'-amino-3,5-di-tertiary-butyl-4-hydroxybiphenyl, 0.8 g (7.0 mmole) of glutaric anhydride and 50 ml of glyme was heated on a steam bath for three hours, then an additional 0.20 g of glutaric anhydride was added. The mixture was heated at reflux for six hours, then poured into water. The aqueous mixture was extracted with diethyl ether, and the ether extracts were then washed with 10% hydrochloric acid and water. The ether solution was extracted with dilute sodium carbonate solution, and the aqueous extracts were acidified to about pH 1 with 10% hydrochloric acid. An oil separated and crystallized after scratching to initiate crystal formation. Recrystallization of the residue from aqueous ethanol provided tan crystals of N-(3',5'-di-tertiary-butyl-4'-hydroxy-2-biphenylyl)-glutaramic acid, m.p. 132°-134° C. Anaylsis: Calculated for C25H33NO4 : % C, 73.0; % H, 8.1; % N, 3.4; Found: % C, 73.0; % H, 8.0; % N, 3.3.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1.[CH3:22][O:23][C:24](Cl)=[O:25]>O.C(Cl)Cl>[CH3:22][O:23][C:24]([NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:25]
Reactant: COC(=O)Cl
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 6 h
Yield: 64 %

Procedure:
Sodium bicarbonate (2.073 g, 24.68 mmol) was dissolved in a mixture of water (20.00 mL) and DCM (20 mL), and phenylmethyl (3S)-3-amino-1-pyrrolidinecarboxylate (2.88 g, 11.22 mmol) was added followed by methylchloroformate (0.953 mL, 12.34 mmol). This mixture was stirred for 6 h. The biphasic mixture was then separated, and the aqueous phase was extracted once with DCM. The combined organics were dried over sodium sulfate, filtered and evaporated. The residual material was then purified via silica gel chromatography (0-100% EtoAc in hexane) yielding phenylmethyl (3S)-3-{[(methyloxy)carbonyl]amino}-1-pyrrolidinecarboxylate (2 g, 64%) as a clear oil. LCMS: (M+H)+: 278.9.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C@H:3]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:27](=[O:28])C1.C(N(CC)CC)C>ClCCCl>[CH3:1][C:2]([CH3:24])([CH3:23])[C@H:3]([N:11]1[CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[C:27]1=[O:28])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Cc1cccc(CNCCN[C@H](C(=O)OC(C)(C)C)C(C)(C)C)n1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
A solution containing the product from Example 10A (1.76 g, 5.25 mmol) in 1,2-dichloroethane (210 mL) was treated with N,N-disuccinimidyl carbonate (1.61 g, 6.28 mmol) and triethylamine (0.75 mL, 5.38 mmol), stirred at 25° C. for 16 hours, and partitioned with 10% Na2CO3. The aqueous phase was extracted with additional dichloromethane. The combined organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% methyl tert-butyl ether/dichloromethane to give the title compound (1.33 g, 70% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)cc1Cl

Procedure:
4-Bromo-2-chloro-benzoic acid (0.64 g, 2.7 mmol) and DMF (50 μl) were added to dichloromethane (9 ml). Oxalyl chloride (0.47 ml, 5.4 mmol) was then added to the mixture and the resultant solution stirred at room temperature for 2 hours. The reaction was monitored to completion by LC-MS. The reaction was concentrated in vacuo to afford crude 4-bromo-2-chloro-benzoyl chloride.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([Br:23])[N:22]=2)=[O:17])[CH2:3]1.C[Si]([N:28]=[C:29]=[O:30])(C)C.C(N(CC)CC)C.CO>O1CCCC1>[NH2:28][C:29]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([Br:23])[N:22]=2)=[O:17])[CH2:3]1)=[O:30]
Reactant: C[Si](C)(C)N=C=O
Reactant: N[C@@H]1CCCN(c2c(F)cccc2NC(=O)c2nc(Br)c[nH]2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)N[C@@H]1CCCN(c2c(F)cccc2NC(=O)c2nc(Br)c[nH]2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of imidazole 12 (29 mg, 0.076 mmol), trimethylsilyl isocyanate (18 mg, 0.15 mmol) and triethylamine (31 mg, 0.30 mmol) in tetrahydrofuran (1 mL) was stirred at r.t. for 4 h. Methanol (1 mL) was added and the mixture was stirred at r.t for 1 h. The solvents were removed in vacuo and chromatographic purification (ethyl acetate-hexane) of the residue gave urea 15 (21 mg, 64%) as a colorless oil. LCMS m/e (M+H+)=425.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([CH3:12])[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[CH:25]=[C:24]([NH2:26])[N:23]=[CH:22][N:21]=2)=[CH:18][N:17]=[CH:16][N:15]=1.NC1N=C[C:31]2[N:36]=[CH:35][N:34]=[CH:33][C:32]=2N=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([CH3:12])[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[CH:25]=[C:24]([NH:26][C:2]3[CH:3]=[CH:4][C:32]([CH2:31][N:36]4[CH2:35][CH2:9][O:8][CH2:7][CH2:6]4)=[CH:33][N:34]=3)[N:23]=[CH:22][N:21]=2)=[CH:18][N:17]=[CH:16][N:15]=1
Reactant: COc1cc(OC)c(Cl)c(Nc2ncncc2-c2cc(N)ncn2)c1C
Reactant: Nc1ncc2ncncc2n1
Product: COc1cc(OC)c(Cl)c(Nc2ncncc2-c2cc(Nc3ccc(CN4CCOCC4)cn3)ncn2)c1C

Procedure:
Compound 32 is carried out the same reaction as in Scheme 1 for compound 10 to afford N4′-(2-Chloro-3,5-dimethoxy-6-methyl-phenyl)-N6-(5-morpholin-4-ylmethyl-pyridin-2-yl)-[4,5′]bipyrimidinyl-6,4′-diamine as final product.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:23]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH2:35][CH3:36])(=O)=O.Cl.C[O:39][C:40]([CH:42]1[CH2:45][NH:44][CH2:43]1)=[O:41]>>[CH:30]1([C:24]2[CH:23]=[C:22]([C:20]3[O:19][N:18]=[C:17]([C:13]4[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:44]5[CH2:45][CH:42]([C:40]([OH:39])=[O:41])[CH2:43]5)=[C:11]([CH2:35][CH3:36])[CH:12]=4)[N:21]=3)[CH:27]=[C:26]([O:28][CH3:29])[N:25]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCOS(C)(=O)=O
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCN1CC(C(=O)O)C1
Yield: 19.1 %

Procedure:
The title compound (29 mg) is prepared as a white solid in analogy to the procedures given in Example 1 starting from 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propyl methanesulfonate (150 mg, 0.291 mmol) and azetidine-3-carboxylic acid methyl ester hydrochloride (220 mg, 1.46 mmol); LC-MS: tR=0.96 min, [M+H]+=521.39; 1H NMR (CD3OD): δ 7.89 (d, J=1.4 Hz, 1H), 7.87 (d, J=1.4 Hz, 1H), 7.55 (d, J=1.0 Hz, 1H), 7.31 (d, J=1.1 Hz, 1H), 4.24-4.40 (m, 4H), 4.01 (s, 3H), 3.97 (t, J=5.8 Hz, 2H), 3.53-3.60 (m, 2H), 3.43-3.48 (m, 1H), 3.26-3.31 (m, 1H), 2.78 (q, J=7.5 Hz, 2H), 2.41 (s, 3H), 2.06-2.19 (m, 4H), 1.86-1.97 (m, 4H), 1.72-1.83 (m, 2H), 1.33 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([O:16][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=C(C)C(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 5.11 grams of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-ol, 2.0 ml of methacryloyl chloride and 3.10 ml of triethylamine in methylene chloride. The above-named product is isolated as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].[Br:6][C:7]1[NH:8][C:9]([C:16]([O:18][CH3:19])=[O:17])=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]=1.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[Br:6][C:7]1[N:11]([CH2:2][C:3]#[C:4][CH3:5])[C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([C:16]([O:18][CH3:19])=[O:17])[N:8]=1
Reactant: COC(=O)c1nc(Br)[nH]c1C(=O)OC
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc(C(=O)OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.06 g 1-bromo-2-butyne are added dropwise to a mixture of 6.00 g of dimethyl 2-bromo-1H-imidazole-4,5-dicarboxylate and 3.80 g of potassium carbonate in 40 ml of dimethylformamide. The mixture is stirred for 12 h at ambient temperature and then added to an aqueous saturated solution of sodium thiosulphate. The organic phase is separated off and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, the solvent is removed and the residue is chromatographed over silica gel (cyclohexane/ethyl acetate 4:1>1:1).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=3[CH3:33])[CH2:22][CH2:21]2)=[O:19])=[C:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:13]=1>>[CH3:33][C:27]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:26]=1[N:23]1[CH2:22][CH2:21][N:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:5]3[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]3(=[O:10])=[O:9])=[CH:13][C:14]=2[S:34]([CH3:37])(=[O:36])=[O:35])=[O:19])[CH2:25][CH2:24]1
Reactant: CC(C)[C@H]1CCS(=O)(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@@H](C(C)C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 7.7 %

Procedure:
Using (R)-3-isopropylisothiazolidine 1,1-dioxide (300 mg) described in Preparation Example 8 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 4, the title compound (41 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH:6]2[C:9]([OH:11])=O)[O:3]1.[NH2:12][CH:13]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:14]([NH:16][CH:17]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:18](=[O:21])[NH:19][CH3:20])=[O:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:22]1([C@H:17]([NH:16][C:14]([C@@H:13]([NH:12][C:9]([C@@H:6]2[CH2:5][C@@H:4]3[CH2:8][C@H:7]2[C:2](=[O:1])[O:3]3)=[O:11])[C:28]([CH3:30])([CH3:29])[CH3:31])=[O:15])[C:18]([NH:19][CH3:20])=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CNC(=O)C(NC(=O)C(N)C(C)(C)C)C1CCCCC1
Reactant: O=C(O)C1CC2CC1C(=O)O2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1C[C@@H]2C[C@H]1C(=O)O2)C(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of compound 32 (53 mg, 0.34 mmol) in DMF (9 mL) was added compound 65 (80 mg, 0.28 mmol) and DIEA (290 □L, 1.66 mmol). The solution was cooled to 0° C. and HATU (127 mg, 0.33 mmol) was added. After stirring at 0° C. for 1 h and at rt for 1 h the solvent was evaporated, and the crude product was purified by flash column chromatography (EtOAc/toluene 2:1) to give compound 72 (110 mg, 92%) as a white solid.