Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:41])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[CH:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:41])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[CH:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (54 mg, 0.091 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.28 ml, 3.63 mmol) was added. The dark red solution was stirred at room temperature for 2 h then concentrated. The residue was redissolved in dichloromethane (0.5 ml) and ethylenediamine (0.37 ml, 5.48 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 28 mg (63%) of 2-(6-chloro-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow powder.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[I-:23].[Na+]>CC(=O)CC>[I:23][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1
Reactant: ClCCOc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: ICCOc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Yield: 78.5 %

Procedure:
A solution of 2-[4-[[4-(2-chloroethoxy)phenyl]methyl]phenyl]oxazole (1.7 g, 4.4 mmol) in 2-butanone (18 mL) was stirred as sodium iodide (7 g, 44 mmol) was added. The reaction was heated at reflux for 2 days. The reaction was concentrated. The residue was dissolved in ethyl acetate and washed with water. The combined organic layers were dried and concentrated. The residue was recrystallized from methanol to give 1.4 g of 2-[4-[[4-(2-iodoethoxy)phenyl]methyl]phenyl]oxazole, 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.68 (s, 1H), 7.27 (d, 2H), 7.21 (s, 1H), 7.13 (d, 2H), 6.82 (d, 2H), 4.22 (t, 2H), 3.96 (s, 2H), 3.39 (t, 2H).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:40][CH:41]([CH3:43])[CH3:42])=[CH:30][C:31]=3[O:33][CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[N:26]=[CH:25][N:24]=2)=[C:20]2[O:44][CH2:45][O:46][C:19]2=[CH:18][CH:17]=1.C=O.C(O)(=O)C>CO.C(Cl)Cl>[Cl:15][C:16]1[C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:40][CH:41]([CH3:42])[CH3:43])=[CH:30][C:31]=3[O:33][CH:34]3[CH2:35][CH2:36][N:37]([CH3:1])[CH2:38][CH2:39]3)[N:26]=[CH:25][N:24]=2)=[C:20]2[O:44][CH2:45][O:46][C:19]2=[CH:18][CH:17]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)Oc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(C)Oc1cc(OC2CCN(C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Yield: 85.4 %

Procedure:
Sodium triacetoxyborohydride (0.087 g) was added portionwise to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-isopropoxy-5-piperidin-4-yloxyquinazoline (0.125 g), aqueous formaldehyde (13N, 0.042 ml), acetic acid (0.019 ml), methylene chloride (5 ml) and methanol (2 ml) and the resultant mixture was heated to reflux for 3 minutes. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulphate and evaporated to give the title compound (0.11 g); NMR Spectrum: (CDCl3) 1.42 (d, 6H), 1.95–2.1 (m, 2H), 2.15–2.25 (m, 2H), 2.3 (s, 3H), 2.3–2.4 (m, 2H), 2.7–2.8 (m, 2H), 4.6 (m, 1H), 4.72 (m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.75 (d, 1H), 6.82 (d, 1H), 6.99 (d, 1H), 8.52 (s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H+ 471 and 473.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:14][CH2:13][C@H:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11]2)=[N:7][CH:6]=1)[NH2:4].[C:26](OCC)(=O)[CH2:27][OH:28].[O-]CC.[Na+]>C(O)C.O>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:8]2[S:9][C:5]([C:3]3[N:4]=[C:26]([CH2:27][OH:28])[O:1][N:2]=3)=[CH:6][N:7]=2)[CH2:11]1
Reactant: NC(=NO)c1cnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1
Reactant: CCOC(=O)CO
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1nc(-c2cnc(N3CC[C@H](Oc4ccccc4C(F)(F)F)C3)s2)no1
Temperature: 25 °C

Procedure:
A mixture of N′-hydroxy-2-{(3S)-3-[2-(trifluoromethyl)phenoxy]-pyrrolidin-1-yl}-1,3-thiazole-5-carboximidamide (373 mg, 1 mmol), ethyl glycolate (380 μL, 4 mmol) and sodium ethoxide, (21 wt. % solution in ethyl alcohol, 1.6 mL, 4.2 mmol) in ethanol (10 mL) was refluxed for 30 min. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. The residue was triturated with Et2O to give the title compound as a pale yellow powder. 1H NMR (500 MHz, acetone-d6): δ 7.83 (s, 1 H), 7.69-7.65 (m, 2 H), 7.41 (d, 1 H), 7.16 (t, 1 H), 5.52 (m, 1 H), 5.05 (s, 1 H), 4.87 (s, 2 H), 3.98 (m, 1 H), 3.85-3.69 (m, 3 H), 2.60-2.44 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[C:15]([O-])(O)=O.[Na+]>CCO.CC(O)=O.O.[Fe]>[NH2:11][C:10]1[C:2]([Br:1])=[C:3]([CH:7]=[C:8]([F:14])[CH:9]=1)[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C([O-])c1cc(F)cc([N+](=O)[O-])c1Br
Reactant: O=C([O-])O
Agent: [Fe]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)cc(N)c1Br
Temperature: 85 °C
Yield: 87 %

Procedure:
To a solution of 2-bromo-5-fluoro-3-nitrobenzoate (20 g, 278 mmol) in EtOH/CH3COOH (200 mL/200 mL) was added iron powder (25 g, 55 mmol). The mixture was vigorously stirred and heated to 85° C. for 1 h. After cooling, the mixture was diluted with water and basified with NaHCO3 (PH=8), extracted with ethyl acetate (450 ml×3). The combined organic layer was washed with brine (500 ml), dried over MgSO4, filtered, and evaporated in vacuum. The residue was applied to flash column chromatography (silica gel) to give methyl 3-amino-2-bromo-5-fluorobenzoate (15.6 g, 87%) as red oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3cccc(O)c3)nc2N2CCOCC2)O1
Temperature: 120 °C

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (58 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by trituration with diethyl ether affording 109 as a white solid (38 mg, 63%). LCMS: RT=4.13 min, [M+H]+=344. 1H NMR (400 MHz, CDCl3): δ 7.87-7.82 (2H, m), 7.26 (1H, t, J=7.6 Hz), 6.91 (1H, dd, J=2.4, 7.6 Hz), 3.92 (2H, s), 3.90-3.80 (8H, m), 1.47 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Cl:13])[C:3]=1[NH:14][C:15]1[C:24]2[CH:25]=[CH:26][N:27]=[C:28]([O:29]C)[C:23]=2[C:22]2[C:17](=[CH:18][CH:19]=[N:20][CH:21]=2)[N:16]=1.ClC1C=C(SC(F)(F)F)C=C(Cl)C=1NC1C2C=CN=C(OCC)C=2C2C(=CC=NC=2)N=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[Cl:13][C:4]1[CH:5]=[C:6]([S:8][C:9]([F:10])([F:11])[F:12])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:14][C:15]1[C:24]2[CH:25]=[CH:26][NH:27][C:28](=[O:29])[C:23]=2[C:22]2[C:17](=[CH:18][CH:19]=[N:20][CH:21]=2)[N:16]=1
Reactant: COc1nccc2c(Nc3c(Cl)cc(SC(F)(F)F)cc3Cl)nc3ccncc3c12
Agent: BrB(Br)Br
Agent: CCOc1nccc2c(Nc3c(Cl)cc(SC(F)(F)F)cc3Cl)nc3ccncc3c12
Solvent: ClC(Cl)Cl
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(SC(F)(F)F)cc3Cl)nc3ccncc3c12
Temperature: 85 °C

Procedure:
A solution of N-{2,6-dichloro-4-[(trifluoromethyl)thio]phenyl}-10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (15 mg, 0.03 mmol), N-{2,6-dichloro-4-[(trifluoromethyl)thio]phenyl}-10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (15 mg, 0.03 mmol) and boron tribromide (0.256 ml, 0.26 mmol) in chloroform (10 ml) was stirred in a microwave vial. The vial was sealed and heated to 85° C. for 45 minutes. The crude reaction mixture was washed with sodium bicarbonate and extracted with 3:1 chloroform:isopropanol. Combined organics were concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]([C:14](O)=[O:15])[CH:12]3[CH2:17][CH2:18][CH:9]2[CH2:10][CH2:11]3)=[CH:5][CH:4]=1.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:13]([C:14]([NH:24][C:25]3([C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=4)[CH2:27][CH2:26]3)=[O:15])[CH:12]3[CH2:17][CH2:18][CH:9]2[CH2:10][CH2:11]3)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)C1C2CCC(CC2)N1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)C3C4CCC(CC4)N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 34.3 %

Procedure:
The title compound (D156) (12 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (D111) (22.5 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (18 mg). (Reaction time: 2 hrs; 60° C.)
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]([CH:27]=[O:28])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(N(CC)C)C>S(Cl)(Cl)=O.CO>[CH:27]([C:22]1[N:23]([CH:24]([CH3:25])[CH3:26])[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([S:2](=[O:5])(=[O:3])[NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:9][CH:8]=3)[N:18]=2)=[CH:20][N:21]=1)=[O:28]
Reactant: COCCN
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Agent: CCN(C)CC
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C=O)n3C(C)C)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
Chlorosulphonic acid (70 μl, 1.0 mmol) was added dropwise to solution of 2-anilino-4-(2-formyl-1-isopropylimidazol-5-yl)pyrimidine (Example 10; 75 mg, 0.24 mmol) in thionyl chloride (2 ml) cooled at 0° C. and the mixture was stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of 2-methoxyethylamine (100 μl, 0.5 mmol) and diethylmethylamine (0.5 ml, 7.5 mmol) in MeOH (1.5 ml) added. The mixture was stirred for 30 minutes and the volatiles were evaporated in vacuo. The residue was purified by chromatography eluting with DCM/MeOH (98:2) to give the title compound (26 mg, 24%) as glassy solid. NMR: 1.53 (d, 6H) 2.86 (q, 2H) 3.17 (s, 3H) 3.28 (t, 2H) 5.65 (m, H) 7.3 (t, 1H) 7.50 (t, 1H) 7.71 (d, 2H) 7.83 (s, 1H) 7.89 (d, 2H) 8.68 (d, 1H) 9.81 (s, 1H) 10.11 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:11][C:12](=[O:43])[C@@H:13]([CH:40]([CH3:42])[CH3:41])[NH:14][C:15](=[O:39])[C@H:16]([CH:28](CC1C=CC=CC=1)[C:29](=[O:31])[OH:30])[NH:17]C(OCC1C=CC=CC=1)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.O.[Pd].[C]>[CH3:1][O:2][CH2:3][C@H:4]([NH:11][C:12](=[O:43])[C@@H:13]([CH:40]([CH3:41])[CH3:42])[NH:14][C:15](=[O:39])[C@H:16]([CH2:28][C:29](=[O:30])[OH:31])[NH2:17])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(C)C)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)CC(=O)O)C(C)C)c1ccccc1
Temperature: 40 °C
Yield: 70.1 %

Procedure:
To a suspension of 6.20 g (10.5 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-valine (R)-α-methoxymethylbenzylamide in 200 ml of methanol and 50 ml of water was added 1.50 g of 10% Pd-carbon (water content 50%). The mixture was reduced under hydrogen under heat at 40° C. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to 15 ml. The crystal thus precipitated was removed by filtration and dried to obtain 2.69 g (7.36 mmols, 70.0% ) of α-L-aspartyl-D-valine (R)-α-methoxymethylbenzylamide.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25].N1C=CC=CC=1>ClCCl>[F:23][C:2]([F:22])([F:1])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)(=[O:34])=[O:35])[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.366 mmol, 810 mg), 3-nitrobenzene-1-sulfonyl chloride (2.366 mmol, 524 mg) and pyridine (4.73 mmol, 0.383 mL, 374 mg) were combined in dichloromethane (20 mL) and stirred at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer was separated, dried and concentrated under vacuum. The residue was purified by SCX chromatography to afford the title compound (875.3 mg). MS (ESI) m/z 528.0 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH2:10][Cl:11])[CH:7]=[C:6]([OH:12])[N:5]=1)[CH3:2].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>>[CH3:13][N:14]([CH3:18])[C:15](=[O:16])[O:12][C:6]1[N:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=[C:8]([CH2:10][Cl:11])[CH:7]=1
Reactant: CCOc1nc(O)cc(CCl)n1
Reactant: CN(C)C(=O)Cl
Product: CCOc1nc(CCl)cc(OC(=O)N(C)C)n1

Procedure:
2-Ethoxy-4-chloromethyl-6-hydroxy-pyrimidine is reacted with N,N-dimethylcarbamoyl chloride analogously to the process described in Example 87 in order to produce 2-ethoxy-4-chloromethyl-6-pyrimidinyl N,N-dimethylcarbamate which is required as the starting material in Example 33. This product is obtained in the form of a yellow oil, 1H-NMR (CDCl3): 1.43 (t, OCH2CH3), 3.08 and 3.14 (2×s, CON(CH3)2), 4.40 (q, OCH2CH3), 4.50 (s, CH2Cl), 7.00 (s, CH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].OC1CNC([CH2:29][C:30]2[N:35]=[C:34]3[CH2:36][O:37][C:38](=O)[C:33]3=[CH:32][CH:31]=2)CC1.Cl.[O:41]1[CH2:46][CH2:45]OCC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:38]1[C:33]2[C:34](=[N:35][C:30]([CH2:29][N:7]3[CH2:8][CH2:45][CH:46]([OH:41])[CH2:5][CH2:6]3)=[CH:31][CH:32]=2)[CH2:36][O:37]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: C1COCCO1
Reactant: O=C1OCc2nc(CC3CCC(O)CN3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CN3CCC(O)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (110 mg, 0.72 mmol) in THF (5 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.8 mL of a 1 M solution in THF, 1.8 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 2-(5-Hydroxy-piperidin-2-ylmethyl)-7H-furo[3,4-b]pyridin-5-one (90 mg, 0.36 mmol) in THF (2.5 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and is poured into a cold 4 M HCl solution in dioxane (4.5 mL) at 0° C. The resulting mixture is stirred at room temperature overnight. The reaction mixture is concentrated to partially remove the dioxane and is then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic phase is collected and the aqueous phase is extracted with additional EtOAc. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography (silica gel) MeOH-Chloroform). The product containing fractions are concentrated to give the title compound as a yellow solid (41 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:20]CCC.C[Si](C)(C)[O:26][C@@H:27]1[C@@H:32]([O:33][Si](C)(C)C)[C@H:31]([O:38][Si](C)(C)C)[C@@H:30]([CH2:43][O:44][Si](C)(C)C)[O:29][C:28]1=[O:49].CS(O)(=O)=O>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1.CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2([O:49][CH3:20])[C@H:27]([OH:26])[C@@H:32]([OH:33])[C@H:31]([OH:38])[C@@H:30]([CH2:43][OH:44])[O:29]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: [Li]CCCC
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (10 g, 0.031 mol) in anhydrous toluene/THF (78 mL, v/v=2:1) was added dropwise n-BuLi (2.5 M in hexane, 13.5 mL) at −65° C. and stirred for 30 minutes at −65° C. The mixture was transferred to a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (15.7 g, 0.034 mol) in toluene (78 mL) at −65° C. The mixture was stirred at −65° C. for 2 hours until starting material was consumed. The reaction was quenched with methanesulfonic acid (4.18 mL, 0.065 mol) in methanol (70 mL), and the mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated bicarbonate, then with water, then with brine, and were dried over sodium sulfate. After removal of the volatiles, the residue was slurried in toluene/hexane (120 mL, 1:5), filtered, and dried under vacuum to give compound 4 as a white solid (12.5 g). The crude product was used in the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11]O)[CH:6]=1>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:11][C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1cccnc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCc1cccnc1
Yield: 63.7 %

Procedure:
Thionyl chloride (9.60 g, 80.6 mmol) was added dropwise to a stirred solution of (pyridin-3-yl)methanol (2.20 g, 20.1 mmol) in 30 ml of CHCl3 at 0° C. and refluxed for 4 h. The reaction mixture was concentrated under reduced pressure to afford 2.10 g (63.6%) of 3-(chloromethyl)pyridine hydrochloride as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4](N)[CH:3]=1.[I:22]CI.C(ON=O)(C)(C)C>CCOC(C)=O>[I:22][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=1
Reactant: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Reactant: ICI
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Product: Cc1cc(I)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
A suspension of Example A9 (0.62 g, 2.2 mmol), KI (3.7 g, 22.3 mmol), and diiodomethane (5 mL, 62 mmol) was treated with t-butylnitrite (1.4 mL, 11.7 mmol) and stirred at RT for 12 h. The mixture was treated with EtOAc, washed successively with satd. NaHCO3 (3×), 10% Na2S2O3 (2×), and brine (2×) and the combined aqueous washes were back-extracted with EtOAc (2×). The combined organics were dried over MgSO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/DCM) to afford 2-iodo-4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.51 g, 59%). MS (ESI) m/z: 393.0 (M+H+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.O[C:21]1[C:29]2N=N[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.C1CCC(N=C=NC2CCCCC2)CC1.OC1C=CC(C2S[S:55][C:54](=S)C=2)=CC=1>CN(C)C=O.C(OCC)(=O)C>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][C:8]([O:10][C:22]1[CH:23]=[CH:24][C:25]([N:26]=[C:54]=[S:55])=[CH:29][CH:21]=1)=[O:9]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc(N=C=S)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To the solution of 1 (diclofenac, 1717 mg, 5.8 mmol) in 60 mL of dimethylformamide, hydroxybenzotriazole (862 mg, 6.38 mmol) and DCC (1316 mg, 6.38 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxyphenylisothiocyanate (2; 965 mg, 6.38 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate and the precipitate was removed. The solvent was evaporated and the crude product was loaded on a silica gel open column and eluted with chloroform/n-hexane 9:1, from which 4-isothiocyanatophenyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate (3) was obtained (580 mg, 23% yield).