Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[N:15]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(Nc2ccccc2)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc([C@H](C)NC(=O)OC(C)(C)C)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103 %

Procedure:
A mixture of 4-methyl-N1-phenylbenzene-1,2-diamine (500 mg, 2.52 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (524 mg, 2.77 mmol), HOAt (377 mg, 2.77 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (532 mg, 2.77 mmol) and 4-methylmorpholine (0.609 mL, 5.54 mmol) in anhydrous DCM (20 mL) was stirred at RT for 20 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (10 mL) and heated to 70° C. for 20 h. After cooling to RT, volatiles were removed in vacuo and the residue was dissolved in EtOAc and washed with a saturated solution of NaHCO3 (2×100 mL). The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 10-60% EtOAc in cyclohexane) affording [(S)-1-(5-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (912 mg, quantitative). LCMS: RT 3.02 min [M+H-tBu]+ 352.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:18])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(C(=O)Nc2ccccc2O)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2OC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
A solution of N-(2-hydroxyphenyl)-4-methoxybenzamide (0.486 g, 2.00 mmol) in methylene chloride (35 mL) was cooled to 0° C. Triethylamine (0.281 mL, 2.00 mmol) was added followed by the dropwise addition of a solution of 4-tert-butylbenzoyl chloride (0.393 mL, 2.00 mmol) in methylene chloride (15 mL). The reaction mixture was allowed to warm to room temperature over 16 h and washed with cold water, dried (magnesium sulfate), filtered, and concentrated in vacuo. Crystallization of the residue from diethyl ether provided 0.563 g (70%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: CCOC(=O)Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]-pyridine (15 g) in tetrahydrofuran (150 mL) was added 1M sec-butyllithium in tetrahydrofuran (97 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 1 hour. To the mixture was added ethyl chloroformate (9.29 mL) and the mixture was stirred at −78° C. for 0.5 hour. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with EtOAc. The extract was wash with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (120 mL) and to the solution was added 1M tetra-n-butylammonium fluoride in tetrahydrofuran (56 mL). The mixture was stirred at ambient temperature for 1 hour and then extracted with EtOAc. The extract was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was with diisopropyl ether to give ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[C:3]=1[C:12]1[CH2:16][N:15]([CH2:17][C:18]([NH2:20])=[O:19])[C:14](=[O:21])[CH:13]=1.[OH:22][CH2:23]C(CO)(CO)N.C[OH:31]>>[OH:22][CH2:23][N+:15]([CH2:14][OH:21])([CH2:16][OH:31])[CH3:17].[OH:1][C:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[C:3]=1[C:12]1[CH2:16][N:15]([CH2:17][C:18]([NH2:20])=[O:19])[C:14](=[O:21])[CH:13]=1
Reactant: NC(CO)(CO)CO
Reactant: CO
Agent: NC(=O)CN1CC(C2=C(O)CN(CC(N)=O)C2=O)=CC1=O
Product: C[N+](CO)(CO)CO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.0 g (0.010 mol) of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid diamide are suspended in 70 ml of methanol; 2.4 g of tris-(hydroxymethyl)-aminomethane are added and the whole is stirred at room temperature for 12 hours, during which time the free acid goes into solution and precipitates again in the form of a salt. The resulting precipitate is filtered off, washed with cold methanol and dried under greatly reduced pressure at 60°. The tris-(hydroxymethyl)-methylammonium salt of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid diamide is obtained in the form of white crystals having a melting point of 203° (decomposition).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1CS/[C:13](=[N:15]\[C:16](=[O:22])[CH2:17][C:18](OC)=[O:19])/[CH3:14].[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>C1COCC1>[OH:22][C:16]1[N:15]=[C:13]([CH3:14])[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=2)[C:18](=[O:19])[CH:17]=1
Reactant: COC(=O)CC(=O)/N=C(/C)SCc1ccc2ccccc2c1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2c(C)nc(O)cc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a solution of methyl 3-({(1Z)-1-[(2-naphthylmethyl)thio]ethylidene}amino)-3-oxopropanoate (1.9 g, 0.006 mol, from step 1) in THF (25.0 mL), at 0° C., is added methyl-4-aminomethylbenzoate (1.1 g, 0.0067 mol). The reaction mixture is stirred at room temperature for 1 hour, and then concentrated to dryness. The resulting residue is dissolved in dioxane (20.0 mL), DBU (0.1 mL) is added, and the resulting reaction mixture is heated at 70° C. for 1 h under an argon atmosphere. After removing the solvent under reduced pressure, the residue is purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=275) are combined and freeze-dried to afford the title compound (0.33 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.99 (d 2H, J=8.4 Hz), 7.29 (d, 2H, J=8.4 Hz), 5.42 (s, 1H), 5.36 (s, 2H), 3.88 (s, 3H), and 2.42 (s, 3H); ES-HRMS m/z 275.1021 (M+H calcd for C14H15N2O4 requires 275.1026).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29](Cl)=[O:30])[CH:22]=[N:21]2)=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:29]([C:23]1[CH:22]=[N:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[C:24]=1[C:25]([F:28])([F:26])[F:27])=[O:30]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Fluoro-3-trifluoromethyl-phenylamine (0.007 g; 0.039 mmol) was added to a suspension of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.010 g; 0.032 mmol) and PS-DIEA (0.1 g) in acetonitrile (2 mL). The reaction mixture was shaken at room temperature for 12 h at which time PS-TSCl (0.2 g) high loading was added to remove the excess amine. After an additional 12 h of shaking, the reaction mixture was filtered and concentrated to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2-fluoro-3-trifluoromethyl-phenyl)-amide. LCMS m/z=449.9 (M−H)−.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=O)=[O:4].Cl.[NH2:21][C@H:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:24][CH2:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([NH:21][C@H:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:9])=[O:4]
Reactant: CCCC[C@H](N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Boc-Gly-Pro-OH (3.85 g, 0.014 mol), the HCl salt of Nleu-OEt (2.76 g, 0.014 mol) and HOBt (2.8 g, 0.02 mol.) were dissolved in 100 ml DMF and the solution was chilled to 0° C. on a water-ice bath. TEA (2.8 ml, 0.02 mol.) was added to the solution. After stirring the solution for 10 minutes, EDC (4.0 g, 0.021 mol.) was added. The stirring was continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 200 ml ethyl acetate. The organic layer was washed by H2O 2×30 ml, saturated NaHCO3 3×10 ml, brine 2×10 ml, saturated NaHSO4 3×15 ml and brine again until the pH value of the brine layer was approximately 7. The ethyl acetate solution was dried using Na2SO4 and the solvent was removed by distillation under reduced pressure. Column chromatography (elution solvents: E/H, 2:1) was performed to obtain the pure product (yellowish oil, 4.7 g, 81%). TLC Rf=0.54 (developing solvents: CMA, 85:15:3) and Rf=0.34 (developing solvents: E/H, 2:1).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN1CCCC1=O.[Cu]I>[C:18]1([N:1]2[C:5](=[O:6])[CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][CH:2]23)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Ic1ccccc1
Reactant: O=C1CN2C(=O)CCC2N1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1CCC2N1CC(=O)N2c1ccccc1
Yield: 11.7 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1 g, 7.14 mmol; prepared as described in J. Med. Chem. 36, 4214-4220, 1994,) in N-methylpyrrolidone (NMP, 12 cc), CuI (0.2 g, 1.05 mmol), K2CO3 (1 g, 7.14 mmol) and Iodobenzene (5 g, 24.5 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 45 min. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with isopropyl ether. The solid was filtered, triturated with water and filtered to yield 0.18 g of the title compound, mp=185-188° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])[NH:11][C:10]=1[C:24]([OH:26])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:27]([O:34][CH2:35][CH2:36][NH:37][CH:38]([CH3:40])[CH3:39])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Si:27]([O:34][CH2:35][CH2:36][N:37]([CH:38]([CH3:40])[CH3:39])[C:24]([C:10]1[NH:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])=[N:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:26])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: O=C(O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Yield: 51 %

Procedure:
5-(Benzyloxy)-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (68) (1 g, 2.41 mmol, Eq: 1.00) was dissolved in pyridine (20 ml) and N-(2-(tert-butyldimethylsilyloxy)ethyl)propan-2-amine (8b) (576 mg, 2.65 mmol, Eq: 1.1) was added. Precipitate formed and gave a thick slurry. Additional 5 ml of pyridine were added to ease stirring. The suspension was cooled in an ice/NaCl bath. POCl3 (1.11 g, 673 μl, 7.22 mmol, Eq: 3) was added dropwise, keeping the inside temperature below 0° C. After the addition was complete the mixture was stirred for 45 minutes at 0° C. The reaction was quenched with ice and the organic solvent was mostly removed. The remaining aqueous layer was extracted three times with ethyl acetate. The organic layers were washed with brine, combined, dried over Na2SO4, filtered and concentrated. The remaining oil was taken up in a little dichloromethane, was filtered through Celite and then purified by SiO2 flash chromatography (80 g SiO2, hexanes/ethyl acetate 0-50% ethyl acetate) to afford 5-benzyloxy-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (69) (0.758 g, 1.23 mmol, 51.2% yield) as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:22])[CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[N:12]=[CH:13][CH:14]=[CH:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1cccc2cccnc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzene sulfonylchloride (1.10 g, 4.32 mmol) in pyridine (5 mL) was added 8-quinolinamine (1, 623 mg, 4.32 mmol) and the reaction mixture was stirred overnight at 25° C. Ethyl acetate was added to the reaction mixture and the organic layer was washed with saturated sodium carbonate (X 3), dried over magnesium sulfate, filtered and concentration under reduced pressure to afford a light brown solid (2, 1.57 g, 3.80 mmol). MS(ESI) [M+H+]+=363.1; 365.1 (1:1)
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].O[N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C:8]1=[O:13].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Br:1][CH2:2][C:3]([O:5][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C:8]1=[O:13])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CBr)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
Bromoacetic acid (4.30 g) and N-hydroxysuccinimide (4.03 g) were dissolved in DCM (25 ml). The mixture was stirred on a magnetic stirrer at room temperature. DCC was added (7.42 g) in one portion and the mixture was reacted overnight. The reaction mixture was filtered to remove dicyclohexylurea. The filter cake washed several times with DCM. The combined filtrates were washed three times with saturated aqueous sodium chloride solution (30 mL/each wash), dried over anhydrous magnesium sulfate, and filtered. The title compound was obtained as a white solid (5 g) after rotary evaporation in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]([Cl:18])=[CH:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[CH:11]=[C:10]([Cl:18])[Cl:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C=C(Cl)Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOCCOC
Product: CC(C)(C=C(Cl)Cl)CCOc1ccc(Cl)cc1
Yield: 86 %

Procedure:
128 g (1 mol) of 4-chlorophenol, 201 g (1 mol) of 1,1,5-trichloro-3,3-dimethyl-1-pentene (II) and 138 g (1 mol) of potassium carbonate in 1 liter of diethylene glycol dimethyl ether are heated under reflux for 10 hours. The mixture is then diluted with methylene chloride and extracted by shaking several times with water. The organic phase is freed of solvent on a rotary evaporator and then distilled at a boiling point of 135°-140° C./0.1 mbar. 252 g (0.86 mol, which is 86% of theory) of 5-(4-chlorophenoxy)-1,1-dichloro-3,3-dimethyl-1-pentene are obtained.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:31]2[CH2:33][CH2:32]2)[CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:34])[CH:2]=[CH2:3].[H-].[Na+].I[CH2:39][CH3:40]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:31]2[CH2:33][CH2:32]2)[CH2:25][N:26]([CH2:39][CH3:40])[S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(C)(=O)=O)C2CC2)C1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CN(CC)S(C)(=O)=O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)methanesulfonamide (Example 289, Step A, 86 mg, 0.161 mmol) in DMF (1.5 ml) was added sodium hydride (16.06 mg, 0.401 mmol) at rt and the reaction was stirred at rt for 30 minutes. To this reaction was added iodoethane (0.058 mL, 0.723 mmol) and the reaction was stirred at rt for 2 hours. The reaction was diluted with EtOAc, washed with water and sat. NaCl, dried with Na2SO4 and then concentrated. The crude was used on next reaction.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:14]Br.C(Cl)(Cl)Cl.[OH-].[Na+]>CO>[Br:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,6-diisopropylaniline (2.0 mL, 11 mmol) in methanol (80 mL) was treated dropwise with bromine (543 μL, 10.6 mmol). The solution was stirred at room temperature for 15 min. Chloroform and 0.1 N NaOH were added and the organic layer was dried (Na2SO4), filtered and concentrated to an orange liquid. Kugelrohr distillation (110° C. @ 0.06 Torr) afforded a colorless liquid (2.22 g 79%): 1H NMR (400 MHz) δ1.25 (d, J=6.4 Hz, 12H), 2.88 (m, 2H), 3.70 (brs, 2H), 7.11 (s, 2H); 13C NMR δ22.1, 27.9, 111.0, 125.6, 134.5, 139.3; Anal calcd for C12H19BrN: C, 56.26; H, 7.08; Br, 31.19; Found, C, 56.24; H, 7.07; Br, 30.98.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[Cl:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[O:22][C:21]([CH2:23][NH:15][CH2:14][CH:13]([O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])[CH3:16])=[CH:20][CH:19]=1
Reactant: CC(CN)Oc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)o1
Product: CC(CNCc1ccc(Cl)o1)Oc1ccc2ccccc2c1Cl
Yield: 77 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]propan-1-amine and 5-chlorofuran-2-carbaldehyde in 77% yield as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([NH:18]C(=O)OC(C)(C)C)=[CH:17][C:11]=3[CH:10]=2)[O:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1([CH3:26])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:11]=3[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2sc(B3OC(C)(C)C(C)(C)O3)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OB(c2cc3cc(N)ccc3s2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)carbamate (7.51 g, 20 mmol, 1 eq) in anhydrous dichloromethane (40 mL under nitrogen atmosphere at 0° C. was added dropwise trifluoroacetic acid (15.4 mL, 10 eq) and the reaction was stirred at 0° C. for 30 minutes followed by at room temperature for about two hours. The reaction was then slowly poured into an ice-cold saturated aqueous sodium bicarbonate solution with stirring and the white solid that appeared during the process was filtered, washed with water, to give a first batch of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine in the amount of 2.792 g. The pH of the filtrate was adjusted to 8 by addition of solid sodium bicarbonate with stirring and then extracted using chloroform (3×). All organic layers were combined, dried with anhydrous sodium sulfate, and concentrated down to give brown oil. After the oil was placed in vacuo for two hours, it was treated with EtOAc-Hex (1:9) and the mixture was stirred at room temperature for 30 minutes. A second batch of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine was isolated as a pale pink solid in the amount of 1.883 g upon filtration. The total amount of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine is 4.675 g with a yield of 85%.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2C=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>C(Cl)Cl.C1COCC1>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH2:48][CH3:49])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and ethylamine (0.19 mL, 0.37 mmol, 2.0M soln in THF). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (17 mg, 40%). LC-MS m/z 549 (M+H)+.