Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]=[CH:3][CH3:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([NH:22][CH:23]3[CH2:24][CH2:25][N:26]([CH2:4][CH:3]=[CH2:2])[CH2:27][CH2:28]3)=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)cc1
Reactant: CC=CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=CCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 22 %

Procedure:
A mixture of 1.2 parts of bromo-1-propene, 3.26 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 1.5 parts of sodium hydrogen carbonate and 40 parts of ethanol was stirred for 1 hour at reflux temperature. The reaction mixture was filtered over diatomaceous earth while hot and the filtrate was evaporated. The residue was taken up in water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.8 parts (22%) of 9-[(4-fluorophenyl)methyl]-N-[1-(2-propenyl)-4-piperidinyl)-9H-purin-8-amine; mp. 144.8° C. (compound 120).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[NH:20][N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:10]=1)=[O:8])[CH3:5].[H-].[Na+].Br.[CH3:39][N:40]([CH2:42][CH2:43]Br)[CH3:41]>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH2:43][CH2:42][N:40]([CH3:41])[CH3:39])[N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH3:5]
Reactant: CN(C)CCBr
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (80 mg, 0.16 mmol) was combined with DMF (8 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 19 mg, 0.47 mmol) was added and the reaction was stirred at 0° C. for 10 min. Dimethylaminoethyl bromide hydrobromide (54 mg, 0.23 mmol) was added and the reaction was stirred at 0° C. for 30 min, then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with 5 mL of brine and 10 mL of water, then extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine, then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford 50 mg (55%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a foaming solid. MS: (M+H)+=587.
Reaction SMILES: [Na].[C:2]1([S:8]([C:11]2[C:12]([CH2:28][CH3:29])=[N:13][N:14]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:18][C:17](Cl)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([OH:33])[CH2:31][OH:32]>>[C:2]1([S:8]([C:11]2[C:12]([CH2:28][CH3:29])=[N:13][N:14]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:18][C:17]([O:32][CH2:31][CH2:30][OH:33])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Reactant: OCCO
Agent: [Na]
Product: CCc1nn2c(N3CCN(C)CC3)cc(OCCO)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
0.274 g (12 mmol) of sodium was added to 40 ml of ethylene glycol and this solution was treated with 0.50 g (1.2 mmol) of 3-benzenesulphonyl-5-chloro-2-ethyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine and subsequently stirred at 80° for 1 hr. After cooling to RT the reaction solution was poured on to 70 ml of ice-water and extracted three times with 50 ml of AcOEt. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 9:1) of the residue and crystallization from EtOH yielded 0.24 g (44%) of 2-[3-benzenesulphonyl-2-ethyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidin-5-yl-oxy]-ethanol as colorless crystals, m.p. 153-154°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][OH:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]=[O:11]
Reactant: OCc1c(Cl)cc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (2,4,6-trichlorophenyl)-methanol (350 mg, 1.67 mmol) in CH2Cl2 (10 mL) was added Dess-Martin reagent (742 mg, 1.75 mmol). After the addition, the solution was stirred at ambient temperature for 2 h. The reaction was quenched with sat. NaHCO3 and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure to give 2,4,6-trichlorobenzaldehyde as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCCCCCC>CN(C)C(=O)C.O>[F:12][C:10]1[CH:11]=[C:2]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=[C:4]2[C:9]=1[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2
Reactant: Sc1ccccc1
Reactant: O=C1CCCc2cc(F)cc(F)c21
Solvent: O
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: O=C1CCCc2cc(Sc3ccccc3)cc(F)c21
Reaction time: 19 h
Yield: 78.8 %

Procedure:
A solution of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one (1.58 kg) in N,N-dimethylacetamide (4.65 liters) was treated with triethylamine (877 g) and thiophenol (954.9 g) at 20° C. and the reaction mixture was stirred for 19 hours. The reaction mixture was treated with heptane (2.38 liters.), followed by water (9.5 liters) and the precipitate was isolated by filtration and the resulting slurry washed with twice with heptane (790 ml each time), three times with water (1.0 liters each time) and five times with cyclohexane (1.0 liters, each time). The slurry was dried to give 8-fluoro-6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one (1.86 kg, 79% yield) with a purity of 96.2% by HPLC, together with 3.6% yield of the isomer 6-fluoro-8-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one: MP=111.7-112.7° C.; MS (M+1)=273; H1 NMR (300 MHz): δ (DMSO): 1.96 (2H, p, J=6.4 Hz), 2.53 (2H, t, J=6.03 Hz), 2.84 (2H, t, J=6.03 Hz), 6.69 (1H, dd, J=1.51, 12.06 Hz), 6.91 (1H, d, J=1.13 Hz), 7.5-7.61 (5H, m, Phenyl).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][C@:5]1([CH3:33])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][O:26]COC)[C:19]=3[S:18](=[O:31])(=[O:30])[N:17]=2)[C:6]1=[O:32].Cl>O1CCOCC1>[CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][C@:5]1([CH3:33])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][OH:26])[C:19]=3[S:18](=[O:31])(=[O:30])[N:17]=2)[C:6]1=[O:32]
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)(C)C)C1=O)N2
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
A solution of Example 184 (2.84 g, 5.5 mmol) in 20 mL of dioxane was cooled to 0° C., treated with 60 mL of 4N HCl in dioxane, allowed to warm to room temp, stirred for 2 hrs, and concentrated in vacuo to afford the title compound (2.96 g, 100% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (m, 1H), 0.72 (s, 9H), 0.82 (m, 1H), 1.56 (s, 3H), 2.03 (m, 1H), 2.22 (m, 1H), 4.61 (s, 2H), 7.26 (s, 1H), 7.52 (m, 1H), 7.74 (d, J=4.0 Hz, 2H), 8.13 (d, J=7.7 Hz, 1H), 14.07 (s, 1H); MS (APCI+) m/z 475 (M+H)+.
Reaction SMILES: C1[NH:3]C1.C(N(CC)CC)C.[F:11][C:12]([F:31])([F:30])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:21](OCC(F)(F)F)=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(OCC)C>[F:11][C:12]([F:31])([F:30])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:3])=[O:18]
Reactant: C1CN1
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1OCC(F)(F)F
Temperature: 25 °C

Procedure:
Ethyleneimine (2.9 g., 0.068 mole), triethylamine (6.8 g., 0.068 mole) and diethyl ether (250 ml.) are cooled to 0° C. and stirred while adding 2,5-di-(2,2,2-trifluoroethoxy)benzoyl chloride (22.8 g., 0.068 mole). The mixture is allowed to warm to room temperature and filtered. The filtrate is treated with 6.6 N isopropanol-hydrochloric acid mixture and filtered and the solvent evaporated in vacuo to give N-(2-chloroethyl)-2,5-di-(2,2,2-trifluoroethoxy-benzamide, m.p. 87°-88.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16]Cl)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:14]=3)[CH2:23][CH2:22]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2cccc(CN3CCCN(Cc4cccc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
3-(3,4,5-Trimethoxyphenyl)benzyl chloride (184 mg) and homopiperazine (52 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[O:19]1[CH2:24][CH2:23]OCC1>[Ni]>[CH2:12]([NH:11][C:4]1[N:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[N:8]=[CH:17][C:18]([C:13]1[CH:12]=[CH:23][C:24]([OH:19])=[CH:15][CH:14]=1)=[N:1]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(NCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: C1COCCO1
Agent: [Ni]
Product: Oc1ccc(-c2cnc3ccc(NCc4ccccc4)nc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
2-Amino-6-benzylamino-3-nitropyridine (25 g, 0.10 mol) was hydrogenated under 5.5 bar of H2 in the presence of 10 g of Raney-Ni in 400 mL of dioxane at 60 C. After 2 hours the reaction mixture was cooled to room temperature, filtrated and 4-hydroxy phenylglyoxal was added and stirred for 2 hours under an argon atmosphere. The suspension was then diluted with water, the solid was collected by filtration, washed with water, recrystallized from 2-propanol, and dried at 50 C. in vacuo to give 6-benzylamino-3-(4-hydroxyphenyl)-5-azaquinoxaline (8 g, 24.4%, m.p. 271-273 C.).
Reaction SMILES: [CH3:1][N:2]([CH2:26][C:27](=[O:33])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][C:24]#[N:25])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[OH:34][Li].O.OO>CO>[CH3:1][N:2]([CH2:26][C:27](=[O:33])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:3]1[CH2:4][CH2:5][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][C:24]([NH2:25])=[O:34])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:7][CH2:8]1
Reactant: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCC#N)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: O
Solvent: CO
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A 25-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of 3-[(3S)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (80 mg, 0.17 mmol, 1.00 equiv) in methanol (5 mL) and cooled to 0° C. Then LiOH.H2O (22 mg, 0.52 mmol, 3.00 equiv) and H2O2 (30%, 0.3 mL) were added at 0° C. and the resulting solution was stirred for 2 h at the same temperature. The reaction was quenched by the addition of saturated aqueous Na2SO3 and extracted DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 16 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 3-[(3S)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (82.5 mg) as a white solid. MS (ES): m/z 486 [M+H]+; 1H NMR (400 MHz, CD3OD): δ 8.47 (1H, s), 5.32-5.22 (1H, m), 3.58 (2H, t), 3.45 (2H, t), 3.35 (2H, s), 3.20-3.09 (1H, m), 3.03-2.95 (1H, m), 2.73-2.65 (2H, m), 2.37 (3H, s), 2.33-2.19 (5H, m), 2.03-1.88 (6H, m), 1.66 (2H, m), 1.69-1.52 (4H, m).
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:13]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:13][C:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCc2ccccc21
Temperature: -20 °C

Procedure:
A solution of indane-1-carboxylic acid (4.1 g, 25.3 mmol) in THF (30 ml) was added in portions to a solution of lithium diisopropylamide in THF (2M, 27.8 ml, 55.6 mmol) with stirring at −20° C. The solution was then stirred at 35° C. for 1 hour, then cooled again to −20° C. and a solution of methyl iodide (2.05 ml, 32.89 mmol) in THF (10 ml) was added. The light yellow solution was warmed at 35° C. for 4 hours before extracting between HCl (2M) and EtOAc to yield the crude product (4.5 g) as a brown oil. This mixture was chromatographed on HPLC with EtOAc/hexane to yield 1-methyl-1-indanecarboxylic acid (1 g) and recovered starting material (700 mg)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].O[N:39]1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:39])=[O:31])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 65 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammonium salt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (09.13 g, 65.0%) as crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[N:15]1[C@H:14]([CH3:13])[CH2:18][O:17][C:16]1=[O:19])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[C@@H]1COC(=O)N1
Reactant: COC(=O)c1ccc(Br)c(F)c1
Product: COC(=O)c1ccc(N2C(=O)OC[C@H]2C)c(F)c1
Yield: 92 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using methyl 4-bromo-3-fluorobenzoate (1.2 g) and (R)-4-methyloxazolidin-2-one (607 mg) described in Preparation Example 25, the title compound (1.2 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[NH:6][C:7](=O)[C:8]=1[CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[CH3:2].P(Cl)(Cl)([Cl:26])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:26][C:7]1[C:8]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:3]([CH2:1][CH3:2])[N:4]=[C:5]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:6]=1
Reactant: CCCC(C(=O)OC)c1c(CC)nc(N2CCCCC2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1CC

Procedure:
To a suspension of methyl 2-(4-ethyl-6-oxo-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoate (2.53 g; 7.86 mmol) in dry toluene (15 mL) under nitrogen atmosphere were 5carefully added phosphorus oxychloride (7.30 mL; 79 mmol) and dimethylaniline (0.794 mL; 6.29 mmol) and the reaction mixture was heated under reflux for 3 h. The volatiles were removed under reduced pressure (while the reaction mixture was still at elevated temperature), the residue was cooled in an ice-bath and quenched by adding crushed ice and a saturated solution of sodium hydrogen carbonate until neutralization. The aqueous layer was extracted with ethyl acetate, the organics were collected, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.352 g (8.6%, over 3 last steps) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[N:8][N:9]([C:12]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:13]=2[CH3:21])[C:10]=1[NH2:11])=[O:5])[CH3:2].CCN=C=N[CH2:28][CH2:29][CH2:30][N:31](C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[N:8][N:9]([C:12]2[CH:17]=[C:16]([C:18](=[O:20])[NH:31][CH:30]3[CH2:28][CH2:29]3)[CH:15]=[CH:14][C:13]=2[CH3:21])[C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1c(C)nn(-c2cc(C(=O)O)ccc2C)c1N
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C)nn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Reaction time: 8 h
Yield: 17.3 %

Procedure:
To a solution of 5-amino-1-(5-carboxy-2-methyl-phenyl)-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (150 mg, 0.49 mmol, 1.0 eq), EDCI (190 mg, 0.98 mmol, 2.0 eq), HOBt (134 mg, 0.98 mmol, 2.0 eq), and diisopropylethyl amine (362 μL, 0.98 mmol, 2.0 eq) in DMF (5 mL) which had been stirred at RT for 15 min was added cyclopropylamine (68 μL, 0.98 mmol, 2.0 eq). After stirring overnight, the solution was diluted with EtOAc and water and the organic layer was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography on silica gel (gradient elution, 3/2 EtOAc/hexanes then 100% EtOAc) to provide the product as a white solid (29 mg, 17%). HPLC (4 minute 10-95 gradient) tR 1.97 min; MS m/z 343 [M+H]+; 1H NMR (CD3OD), δ 7.87 (d, J=7.1 Hz, 1H), 7.76 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 4.29 (q, J=7.0 Hz, 2H), 2.84 (m, 1H), 2.34 (s, 3H), 2.18 (s, 3H), 1.36 (t, J=7.0 Hz, 3H), 0.79 (d, J=5.5 Hz, 2H), 0.62 (s, 2H) ppm; 13C NMR (CD3OD), δ 168.1, 164.4, 151.3, 149.8, 140.1, 135.2, 132.6, 130.7, 127.9, 126.3, 92.0, 58.6, 22.1, 15.7, 12.9, 12.6, 4.6 ppm.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[CH:27][O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[CH:27][O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-oxazole-4-carboxylic acid (2-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-yl)-amide (120 mg, 0.24 mmol) in dry THF (2.1 mL) was treated at 0° C. with TBAF (0.48 mL of a 1M solution in THF, 0.48 mmol). The reaction mixture was stirred at 0° C. for 45 min. The mixture was then diluted with EA (10 mL), washed with NaHCO3 (10 mL) followed by brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as a white foam. TLC:rf (19:1 CH2Cl2-MeOH)=0.19. LC-MS-conditions 02: tR=0.88 min; [M+H]+=381.23.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[I:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:17]=1[NH2:18].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([CH2:11][C:12]([NH:18][C:17]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=3[I:15])=[O:14])=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COc1cccc(I)c1N
Reactant: O=C(O)CC1=CCC2(CC1)OCCO2
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(I)c1NC(=O)CC1=CCC2(CC1)OCCO2
Yield: 89.6 %

Procedure:
A solution of (1,4-dioxaspiro[4.5]dec-7-en-8-yl) acetic acid (567 mg; 2.86 mmol; 1 eq) (7) and 2-iodo-6-methoxyaniline (1 g; 2.86 mmol; 1 eq) in anhydrous dichloromethane (30 mL) is admixed with 2-chloro-1-methylpyridinium iodide (1.46 g; 5.73 mmol; 2 eq) and triethylamine (3.98 mL; 28.65 mmol; 10 eq). The reaction mixture is heated at reflux for 20 hours. After cooling and acidification with iN HCl solution to pH=5–6, the mixture is extracted with dichloro-methane. The organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 4/6) gives 1.10 g of 2-(1,4-di-oxaspiro[4.5]dec-7-en-8-yl)-N-(2′-iodo-6′-methoxy-phenyl)acetamide (16) in the form of a yellow foam (yield: 90%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH3:15])#[N:2].Br[CH2:17][CH2:18]CC>>[CH2:14]([O:13][C:4]1[CH:5]=[C:6]([S:9]([Cl:12])(=[O:11])=[O:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[CH2:15][CH2:17][CH3:18]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: CCCCBr
Product: CCCCOc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing bromoethane with 1-bromobutane.