Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([O:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)COC(=O)NC1CCN(CC(O)COc2cccc3c2CCC(=O)N3)CC1
Solvent: c1ccncc1
Product: CC(=O)OC(COc1cccc2c1CCC(=O)N2)CN1CCC(NC(=O)OCC(C)C)CC1

Procedure:
3,4-Dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]carbostyril (3 g) was dissolved in pyridine (30 mL) and acetic anhydride (0.9 mL) was added dropwise with stirring. After the addition, the mixture was stirred at room temperature for 12 hours, and the pyridine was then evaporated under reduced pressure. The residue was dissolved in chloroform (100 mL) and the organic solution was washed twice with water (50 mL each) and dried over sodium sulfate. The solvent was then evaporated and the residue recrystallized from isopropyl ether to yield 1.5 g of the title compound, 3,4-dihydro-5-[2-acetyloxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]carbostyril, m.p. 120° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13](O)=[O:14])[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17].[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]1[CH2:38][CH2:39][N:40]([C:13]([CH:5]2[CH2:4][N:3]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:28])[F:27])(=[O:18])=[O:17])[C:2](=[O:1])[N:6]2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:14])[CH2:41][CH2:42]1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4C(F)(F)F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
Steps 4 and 5: In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid methyl ester was hydrolyzed using sodium hydroxide solution to give (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid. Finally, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 586.8 ([M+H]+)
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C@H:16]([CH2:26][O:27][CH3:28])[O:15][C:14]2=[O:29])=[O:12])=CC=1)([O-])=O.[ClH:30].Cl.[NH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=2[C:44]#[N:45])[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[ClH:30].[C:44]([C:43]1[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=1[CH:39]1[CH2:38][CH2:37][N:36]([CH2:35][CH2:34][CH2:33][NH:32][C:11]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C@H:16]([CH2:26][O:27][CH3:28])[O:15][C:14]2=[O:29])=[O:12])[CH2:41][CH2:40]1)#[N:45]
Reactant: COC[C@@H]1OC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H]1c1ccc(F)c(F)c1
Reactant: N#Cc1ccccc1C1CCN(CCCN)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1OC(=O)N(C(=O)NCCCN2CCC(c3ccccc3C#N)CC2)[C@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5-methoxymethyl-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (195 mg, 0.48 mmol) in dry tetrahydroftirin (3 mL) was added 2-[1-(3-aminopropyl)piperidin-4-yl]benzonitrile dihydrochloride (134 mg, 0.48 mmol) (see Example 3) followed by N,N-diisopropylethylamine (167 μL, 0.96 mmol). The reaction mixture was stirred at room temperature for 20 h when the reaction was diluted with ethyl acetate (50 mL), washed with 10% aqueous sodium carbonate solution (6×25 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (2% methanol in ethyl acetate) to afford an oil. The hydrochloride salt was prepared by standard procedures to provide (4S,5R)-4-(3,4-difluorophenyl)-5-methoxymethyl-2-oxo-oxazolidine-3-carboxylic acid {3-[4-(2-cyanophenyl)piperidin-1-yl]propyl}amide hydrochloride as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.Cl[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:10]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:5]2=[N:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Temperature: 90 °C
Yield: 75.1 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (378 mg, 1.272 mmol), (chloromethanetriyl)tribenzene (426 mg, 1.53 mmol) and triethylamine (193 mg, 1.91 mmol) in dry DMF (20 mL) was heated to 90° C. for 16 hours. Reaction mixture was extracted with ethyl acetate (100 mL), organic phase washed with water (3×10 mL) and brine (2×10 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with EtOAc: petroleum ether=1:15) to afford 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (515 mg, 75%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.29 (s, 1H), 8.01 (s, 1H), 7.29-7.26 (m, 10H), 7.13-7.11 (m, 5H), 1.51 (s, 9H). LCMS: (M+H)+=539.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[N:24][CH:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: Cc1cccnc1CN(CCCN)Cc1ncccc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(CCCNC(=O)c1ccc(O)nc1)Cc1ncccc1C
Yield: 13.8 %

Procedure:
Using General Procedure G: To a solution of N1,N1-bis-(3-methyl-pyridin-2-ylmethyl)-propane-1,3-diamine (0.24 g, 0.84 mmol) in dry DMF (4 mL) was added 6-hydroxy-nicotinic acid (0.121 g, 0.87 mmol) followed by EDCI (0.182 g, 0.95 mmol), HOBT (0.128 g, 0.95 mmol), and DIPEA (0.25 mL, 1.44 mmol). Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 47 mg (14%) of the free base of the title compound as a colorless oil. Conversion to the HBr salt gave COMPOUND 232 (65 mg, 78%) as a white solid. 1H NMR (D2O) δ 1.74-1.84 (m, 2H), 2.47 (s, 6H), 2.64-2.69 (m, 2H), 3.24 (dd, 2H, 6.3 Hz), 4.31 (s, 4H), 6.62 (d, 1H, J=9.6 Hz), 7.80-7.84 (m, 3H), 7.95 (d, 1H, J=2.1 Hz), 8.32 (d, 2H, J=8.1 Hz), 8.58 (d, 2H, J=6.0 Hz); 13C NMR (D2O) δ 17.24, 25.16, 37.61, 51.91, 53.99, 115.32, 119.34, 126.02, 137.52, 137.87, 138.75, 140.81, 148.48, 150.88, 166.80; ES-MS m/z 406 (M+H). Anal. Calcd. for C23H27N5O2.3.2HBr.3.0H2O: C, 38.45; H, 5.08; N, 9.75; Br, 35.59. Found: C, 38.32; H, 4.94; N, 9.48; Br, 35.96.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CO>[Pd](Cl)Cl.C1(C)C=CC=CC=1>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[C:19]([C:20]#[N:21])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
2M Sodium carbonate solution (200 ml) was added to a stirred mixture of 4-methylphenylboronic acid (30 g), 2-bromobenzonitrile (36.4 g), palladium (II) chloride (0.4 g), methanol (200 ml) and toluene (200 ml) at 5° C. The temperature rose to approximately 20° C. and a solid precipitated. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture was allowed to cool and water (100 ml) was added, followed by diatomaceous earth (5 g). The mixture was stirred for 15 minutes, then filtered through diatomaceous earth. The organic phase of the filtrate was separated and washed with 2M sodium carbonate solution and then water. The organic phase was then filtered and the filtrate evaporated. The resultant solid was recrystallised from petroleum ether (b.p. 110°-120° C.) to give 4'-methylbiphenyl-2-carbonitrile (33 g) which was used without further purification.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17].CI>O1CCCC1.CCOCC>[CH3:1][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CI
Product: COCCc1ccccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 37.0 g of potassium t-butoxide in 400 ml dry tetrahydrofuran was cooled to 0° and a solution of 39.2 g of the product from Example 1 in 300 ml tetrahydrofuran was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. After cooling to 0°, 9.3 ml of methyl iodide was added dropwise and the mixture stirred for 15 minutes at 0°. The solution was diluted with ether, washed with water and dried (Na2SO4). Concentration gave a viscous brown oil which was used in the following example, without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[N:10](C)[CH3:11])[C:5]2[C:13]([I:35])=[N:14][N:15]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.Cl.[CH2:37](N)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO.CC(O)=O.ClCCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][CH3:37])[C:5]2[C:13]([I:35])=[N:14][N:15]([C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)/C=C/c1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CCNCCc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(E)-2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N-dimethylethenamine (1.0 g, 1.692 mmol) and ethanamine HCl (0.552 g, 6.77 mmol) were stirred in a 3:1:1 solution of DCE:AcOH:EtOH (5 ml) at 100° C. for 2 hrs. Solvent was removed by vacuum and the residue was taken in DCE (15 ml) and treated with sodium triacetoxyborohydride (0.9 g, 4.23 mmol), acetic acid (0.4 g, 6.7 mmol) and stirred at room temperature for 6 hours. The eaction mixture was partitioned between DCM and aqueous sodium bicarbonate and the organics was separated, washed with brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave 2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N-ethylethanamine. MS ESI calc'd. for C29H26ClIN4 [M+H]+ 593. found 593.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].Br[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)[OH:7])[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2cc(OC)cc(OC)c2)c1
Yield: 85.6 %

Procedure:
3,5-Dimethoxybenzaldehyde (0.84 g, 5.03 mmol), 1-bromo-3,5-dimethoxybenzene (1.20 g, 5.53 mmol), and n-butyl lithium (2.20 ml, 5.53 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 60% EtOAc in hexane in about 40 min.) to give Bis-(3,5-dimethoxy-phenyl)-methanol as an off-white solid (1.31 g, 86%): 1HNMR (CDCl3) 6.55 (d, J=2 Hz, 4H, Ar), 6.36 (t, J=2 Hz, 2H, Ar), 5.67 (d, J=3 Hz, 1H, CHOH), 3.77 (s, 12H, 4OCH3), 2.24 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.CC1(C)C(C)(C)OB([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])O1.[C:34](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>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.O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]([CH3:34])[S:29]([CH3:32])(=[O:31])=[O:30])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2
Reactant: O=C([O-])[O-]
Reactant: CSc1ncc2c(Cl)cc(I)n2n1
Reactant: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CSc1ncc2c(Cl)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
5-Chloro-7-iodo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.252 g, 0.774 mmol), N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (0.333 g, 1.12 mmol) and Tetrakis(triphenylphosphine)palladium(0) (72 mg, 0.062 mmol) were placed in a vial, followed by N,N-Dimethylformamide (8.0 mL) and 2.00 M of Sodium carbonate in Water (2.00 mL, 4.00 mmol). The sample was partially evacuated, placed under nitrogen and then heated in a 80° C. block for 20 h. Dimethyl sulfate (0.100 mL, 1.06 mmol) was then added to the mixture and heating continued for 7 h. The mixture was then added to water (50 mL) with stirring, portionwise. The resultant ppt was collected, washed with water and dried on the Buchner to afford N-[2-(5-Chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide.
Reaction SMILES: [F-:1].[K+].[C:3]([C:25]([F:27])=[O:26])([C:6]([C:9]([C:12]([C:15]([C:18]([C:21]([F:24])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4].S(OC)(O[CH3:32])(=O)=O>CN(C)C=O>[C:25]([O:26][CH3:32])([C:3]([C:6]([C:9]([C:12]([C:15]([C:18]([C:21]([F:22])([F:23])[F:24])([F:19])[F:20])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4])([F:27])[F:1]
Reactant: COS(=O)(=O)OC
Reactant: [F-]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 8967.9 %

Procedure:
The title compound was prepared essentially as in Example 3 using anhydrous potassium fluoride (6.62 g, 0.011 mole), anhydrous dimethyl formamide (800 g), C7F15COF (456.7 g, 1.09 mole), and dimethyl sulfate (14.4 g, 0.011 mole). The resulting mixture was worked up essentially as in Example 3 to give 444 g of the title compound (99.7% purity, b.=142-144° C.). The product identity was confirmed by IR, GCMS, and 1H and 19F NMR.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.B([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH:35]([NH:39][C:40](=[O:50])[C:41]2[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=2[CH3:49])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=1)(O)O.CCN(CC)CC>ClCCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH:35]([NH:39][C:40](=[O:50])[C:41]3[C:42]([CH3:49])=[CH:43][C:44]([CH3:48])=[CH:45][C:46]=3[CH3:47])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C)c(C(=O)NC(Cc2ccc(B(O)O)cc2)C(=O)O)c(C)c1
Reactant: c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(N3CCC(CNc4nc5ccccc5[nH]4)CC3)cc2)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
95 mg (0.207 mmol, calculated as bistrifluoroacetate salt) of crude piperidine derivative (19), 113 mg (0.621 mmol) Cu(OAc)2, 147 mg (0.415 mmol) boronic acid (6) and 1.72 ml (12.42 mmol) NEt3 were mixed in 10 ml DCE and stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol and subsequently submitted to reversed phase HPLC purification using a water/acetonitrile gradient containing 0.1% TFA. The required fractions were collected and lyophilized to yield (20) as white solid.
Reaction SMILES: F[C:2]1[C:20]([CH:21]=O)=[CH:19][C:5]2[C:6]([N:9]3[C@@H:13](COC)[C@@H:12](C)[O:11][C:10]3=[O:18])=[N:7][O:8][C:4]=2[C:3]=1[F:23].[NH:24]1[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]1=[O:32].[C:33]([OH:36])(=O)[CH3:34]>O>[F:23][C:3]1[C:4]2[O:8][N:7]=[C:6]([N:9]3[CH2:13][CH2:12][O:11][C:10]3=[O:18])[C:5]=2[CH:19]=[C:20]2[C:2]=1[N:9]1[CH2:10][C@@H:33]([CH3:34])[O:36][C@@H:5]([CH3:4])[C@@H:6]1[C:28]1([C:27](=[O:31])[NH:26][C:25](=[O:32])[NH:24][C:29]1=[O:30])[CH2:21]2
Reactant: CC(=O)O
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: COC[C@H]1[C@@H](C)OC(=O)N1c1noc2c(F)c(F)c(C=O)cc12
Solvent: O
Product: C[C@@H]1CN2c3c(cc4c(N5CCOC5=O)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 110 °C
Yield: 61.7 %

Procedure:
Intermediate 6 (800 mg, 1.95 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (250 mg, 1.95 mmol) in a mixture of acetic acid (8 mL) and water (2 mL) was heated at 110° C. for 3.5 hours. The solvent was removed and the reaction mixture was purified using Super Critical Fluid Chromatography (Chiralpak IA column with 40% isopropanol and 60% CO2 mobile phase) to give the title compound (571 mg, 61.7% yield) as a solid as the first eluting compound. 1H NMR (300 MHz, DMSO-d6) δ 0.9 (d, 3H) 1.1 (d, 3H) 2.8-3.2 (m, 2H) 7.7 (s, 1H) 11.4 (s, 1H) 11.8 (s, 1H). MS (ES) MH+: 474 for C21H20FN5O7.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([NH:28]C(=O)C)[CH:20]=[C:21]([N:23]5[CH:27]=[CH:26][CH:25]=[CH:24]5)[CH:22]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)[CH3:4]>C(O)C.C(OCC)(=O)C>[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([CH:20]=[C:21]([N:23]5[CH:27]=[CH:26][CH:25]=[CH:24]5)[CH:22]=4)[NH2:28])[CH:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)[CH3:4]
Reactant: CCn1cc(-c2ccc3c(c2)ncn3-c2cc(NC(C)=O)cc(-n3cccc3)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-n3cccc3)c2)cn1
Yield: 78 %

Procedure:
A mixture of 20% NaOH (5 ml) and the compound of Example 171 (0.9 g, 2.12 mmol) in 25 ml of ethanol was heated at 90° C. for 2 h. The mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with water (50 ml) and brine (25 ml). The solvent was distilled off and the residue was purified by column chromatography over silica gel to afford the compound in 78% yield (0.7 g).
Reaction SMILES: [O:1]([CH2:9][CH:10]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][C:13]#N)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C[OH:29].Cl>C1(C)C=CC=CC=1.CCOCC>[O:1]([CH2:9][CH:10]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][CH:13]=[O:29])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CO
Reactant: CCCC(CCC#N)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCC(CCC=O)CO[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 3.25 h
Yield: 81.4 %

Procedure:
To a solution of 12.15 g (47.6 mmol) of 4-(t-butyldimethylsiloxymethyl)heptanenitrile in 120 mL of toluene at -70° C., under argon, was added 35.3 mL (53.0 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene. After stirring at -70° C. for 3.25 hr, 36.5 mL of methanol was added and the mixture was poured into a mixture of ca. 200 mL of ether, ca. 100 g of ice and 214 mL of 3N hydrogen chloride solution. The aquenous layer was separated and extracted with 3×200 mL of ether. The combined organic layers were washed with 120 mL of saturated sodium bicarbonate solution and 120 mL of saturated brine (a gelatinous precipitate, which resulted on washing with saturated brine, was removed by filtration through celite prior to separation of the aqueous layer), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel to give 10.01 g (81.4%) of crude 4-(t-butyldimethylsiloxymethyl)heptanal; TLC (SiO2, 1:9 ethyl acetate:hexane) Rf 0.55 (PMA); IR (chloroform): μmax 1719 (aldehyde C=O) cm-1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([O:27]CC)=[O:26])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([OH:27])=[O:26])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][C:13]=1[S:21][CH3:22]
Reactant: CCOC(=O)Cn1c(=O)n(-c2ccc(C(C)C)cc2SC)c2nc(C)nc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(=O)O)c2c(Cl)nc(C)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
In a mixed solvent of 3 ml of methanol and 1 ml of water, 0.83 g of ethyl 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetate was dissolved, and subsequently, 80 mg of sodium hydroxide was added thereto. The reaction mixture was stirred for 30 minutes at room temperature. Water was poured into the reaction mixture. The reaction mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=8:1) to yield 0.47 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetic acid as an oil.