Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=[CH2:6].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])C=O.O.FC(F)(F)C(O)=O>C1COCC1>[CH2:17]([O:16][C:12]([CH:1]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3][O:2]1)=[O:15])[CH3:18]
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: CCOC(=O)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CC(=O)C=CO1
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
ZnCl (0.63 g, 4.6 mmol) was dissolved in anhydrous THF (15 mL) and added to a solution of 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (7.94 g, 46.0 mmol) and ethyl glyoxalate (7.05 g, 69.0 mmol) in totuene (30 mL) at room temperature. After stirring for 30 minutes, water (30 mL) and TFA (trifluoracetic acid) (2 mL) were added and the mixture was stirred vigorously for 20 min. After concentration, the residue was partitioned between EtOAc (200 mL) and water (100 mL). The separated organic layer was washed with brine, dried over sodium sulfate, and concentrated to give 8.0 g (100%) of brown oil which was carried to the next step without further purification. 1H NMR (CDCl3) δ 1.30 (t, 3H), 2.85 (d, 2H), 4.26 (q 2H), 5.00 (t, 1H), 5.48 (d, 1H), 7.39 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:29][CH3:30])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=2)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:29][CH3:30])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCc1cc2cc(C(=O)OC)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCc1cc2cc(C(=O)O)ccc2[nH]1
Temperature: 50 °C

Procedure:
A 200 mL round bottom flask was charged with (S)-methyl 2-(3-(2-(tert-butoxycarbonylamino)butanamido)propyl)-1H-indole-5-carboxylate (1.67 g, 4.00 mmol), tetrahydrofuran (20 mL), and methanol (5.3 mL). 3N Sodium hydroxide (4.0 mL, 12.0 mmol) was added and the resulting mixture stirred and heated to 50° C. for 8 h. The resulting mixture was then cooled to room temperature and acidified with 1N hydrochloric acid. The resulting mixture was extracted two times with ethyl acetate (400 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield (S)-2-(3-(2-(tert-butoxycarbonylamino)butanamido)propyl)-1H-indole-5-carboxylic acid. 1H NMR (300 MHz, CD3OD) δ 8.20 (s, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.31 (s, 1H), 3.94-4.10 (m, 1H), 3.22-3.34 (m, 2H), 2.80-2.85 (m, 2H), 1.61-2.08 (m, 4H), 1.46 (s, 9H), and 0.93-1.03 (m, 3H); MS (ES+) 403 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[C:39]1[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=1>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:26][C:25]=1[C:39]1[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Temperature: 80 °C
Yield: 53.9 %

Procedure:
A stirred mixture of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (99.0 mg, 0.371 mmol), dried potassium phosphate (0.1581 g, 0.745 mmol) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (0.2402 g, 0.743 mmol) in anhydrous N,N-dimethylacetamide (2 ml) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (22.1 mg, 0.0191 mmol) was then added and the mixture was degassed with two more evacuation-refilling cycles before heating at 80° C. under nitrogen for 6.5 h. The mixture was diluted with ethyl acetate and filtered through glass fibre paper, washing the solid with more ethyl acetate. The filtrates were washed with brine (15 ml), and the aqueous layer was extracted further with ethyl acetate (25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 30% EtOAc/isohexane) to give 76.6 mg (54%) of the title compound: mp 168-174° C. (CH2Cl2-EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.43 (1H, t, J 9.0 Hz), 7.57 (1H, td, J 7.8, 1.2 Hz), 7.60 (1H, d, J 7.8 Hz), 7.73 (1H, td, J 7.8, 1.3 Hz), 7.85 (1H, dd, J 7.7, 1.1 Hz), 8.16-8.23 (2H, m), 8.62 (1H, s), 8.81 (1H, s); MS (ES+) m/z 384 [M+H]+. Anal. Found: C, 58.31; H, 2.28; N, 17.74%. Required for C19H9F4N5.0.5H2O: C, 58.17; H, 2.57; N, 17.85%.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12](C(O)=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.ClCCl.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29].[CH3:33][N:34]([CH:36]=[O:37])C>>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:36]([NH:34][CH2:33][C:2]3[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=3[CH:28]3[CH2:27][O:31][C:6]([CH3:7])([CH3:11])[O:29]3)=[O:37])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCc1ccccc1C1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 200 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 6 ml of dichloromethane, and one droplet of DMF was added 110 μl of oxalyl chloride under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and to the obtained residue were added 10 ml of THF, 300 μl of diisopropylethylamine, and a solution of 170 mg of 1-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)phenyl]methanamine in 5 ml of THF under ice-cooling, followed by stirring at room temperature for 24 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 278 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)benzyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:14]5[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Yield: 69.9 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (125 mg, 0.329 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (85 mg, 0.36 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (123 mg, 70%) as a white solid: ESI MS m/z 535 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[N:6]=[N:5]1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:7]2[N:6]=[N:5][N:4]([CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])[C:8]=2[CH:9]=[CH:10][C:11]=1[OH:13]
Reactant: CC(C)(C)Cn1nnc2cc(O)ccc21
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Temperature: 25 °C

Procedure:
To a solution of 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (2-5) (3 mg, 0.015 mmol, 1.0 equiv.) in chloroform (500 μL), was added slowly pyridinium tribromide (4.67 mg, 0.015 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature. LCMS showed mostly the desired product. The reaction mixture was quenched with water, neutralized to pH=7, then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (1-6). LRMS m/z (M+H) 283.9 and 285.9 (intensity ratio ˜1:1) found, 284.0 and 286.0 required.
Reaction SMILES: CO[C:3]1[C:4](=O)[NH:5][CH:6]=[CH:7][CH:8]=1.COC1[C:13](=[O:31])[N:14](CC2C=CC(OC)=CC=2)CCC=1C(=O)CC.Cl.Cl.C1([NH:39]N)CCCC1>O1CCCC1>[N:39]1[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][C:4]=2[C:13](=[O:31])[N:14]=1
Reactant: NNC1CCCC1
Reactant: COc1ccc[nH]c1=O
Reactant: CCC(=O)C1=C(OC)C(=O)N(Cc2ccc(OC)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1N=Nc2cccnc21
Temperature: 88 °C

Procedure:
treating said 3-methoxy-pyridinone compound of Formula (7.0.0) with cyclopentylhydrazine dihydrochloride; wherein a reaction mixture is established with tetrahydrofuran (THF) solvent and heating of said reaction mixture to 88° C., for 12 hours, while said reaction mixture is being swept by nitrogen in order to remove methanol, THF, and HCl; whereby there is produced a pyrazolopyridinone compound N-protected by p-methoxybenzyl, of Formula (8.0.0):
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O>>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:19]([C:18]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH3:22])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1cccc2nonc12
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(C)Nc2n[nH]cc2C1c1cccc2nonc12

Procedure:
The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 25.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[N:8]3[C:9](=[N:14][C:15]([CH3:16])=[C:7]3[C:6]1=[O:17])[CH:10]=[CH:11][CH:12]=2.C(N(CC)CC)C.[F:25][C:26]([F:33])([F:32])[CH2:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:16][C:15]1[N:14]=[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[N:8]2[C:7]=1[C:6](=[O:17])[N:5]3[CH2:4][CH2:3][CH2:2][NH:1][S:28]([CH2:27][C:26]([F:33])([F:32])[F:25])(=[O:30])=[O:29]
Reactant: Cc1nc2cccc3n(CCCN)c(=O)c1n23
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 58.5 %

Procedure:
To a solution of 0.43 g (1.87 mmol) of 1-[3-(amino)propan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.39 ml (2.80 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 0.41 g (2.26 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 412 mg of the desired compound (58.6%, white powdery).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][N:29]2[C:34](=[O:35])[C:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)=[C:32]([CH2:51][CH2:52][CH3:53])[N:31]=[C:30]2[CH3:54])=[N:26][CH:27]=1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[OH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][N:29]2[C:34](=[O:35])[C:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[CH:39][CH:38]=3)=[C:32]([CH2:51][CH2:52][CH3:53])[N:31]=[C:30]2[CH3:54])=[N:26][CH:27]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(Cc2ccc(CO[Si](C)(C)C(C)(C)C)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(Cc2ccc(CO)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogen carbonate (1.56 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-[(1-{[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]methyl}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.7 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.27 g, 56%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]([F:14])([F:13])[C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[C:1](=[O:2])=[N:12][C:10]1[S:11][C:7]([C:6]([F:14])([F:13])[F:5])=[N:8][N:9]=1.[C:1](=[O:2])=[N:12][C:10]1[S:11][C:7]([C:6]([F:14])([F:13])[F:5])=[N:8][N:9]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C(F)(F)F)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C(F)(F)F)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-trifluoromethyl-2-amino-1,3,4-thiadiazole (45 grams) in ethyl acetate (300 ml) was added to the reaction vessel, and the resulting mixture was stirred for a period of about 16 hours, resulting in the formation of precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was filtered to recover 48 grams of a white solid. This solid was recrystallized from dimethyl formamide to yield the desired product 5-trifluoromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: F[B-](F)(F)F.CCCC[N+](CCCC)(CCCC)CCCC.[FH:23].[F-:24].[C:25]([CH:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)([O:27][CH2:28][CH3:29])=[O:26]>ClCCl>[C:25]([CH:30]1[CH2:35][CH2:34][C:33]([F:24])([F:23])[CH2:32][CH2:31]1)([O:27][CH2:28][CH3:29])=[O:26]
Reactant: [F-]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To an ice-cold suspension of diethylaminodifluorosulfinium tetrafluoroborate (458 mg, 2.0 mmol) and tetrabutylammonium hydrogen difluoride (463 mg, 2.0 mmol) in dichloromethane (3.0 mL) under nitrogen is added 4-carboethoxycyclohexanone (159 μl, 1.0 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 4 h. The reaction mixture is quenched at room temperature with a saturated aqueous ammonium chloride solution, stirred for 15 min, and the resulting mixture is extracted twice using dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated. The crude product is passed through a pad of silica gel using pentane to provide 1-carboethoxy-4,4-difluorocyclohexane (130 mg, 68%) as a clear oil.
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].[Cl:52][C:53]1[C:54]([CH2:60]Cl)=[N:55][C:56]([Cl:59])=[CH:57][CH:58]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:60][C:54]3[C:53]([Cl:52])=[CH:58][CH:57]=[C:56]([Cl:59])[N:55]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: ClCc1nc(Cl)ccc1Cl
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3nc(Cl)ccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 3,6-dichloro-2-(chloromethyl)pyridine and isolated as light yellow gum. MS (m/e): 422.3 (MH+).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.[CH3:50][O:51]CC(O)=O.CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:10]1[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:12][CH:13]=[CH:14][C:9]=1[CH:5]([NH:4][C:1](=[O:3])[CH2:2][O:51][CH3:50])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reaction time: 16 h
Yield: 74 %

Procedure:
To a stirred solution of Example 13 Part A compound (222 mg, 0.45 mmol) under argon at room temperature in CH2Cl2 (1.5 mL) was added triethylamine (85 μL, 0.6 mmol), HOAt (69 mg, 0.5 mmol) and methoxyacetic acid (46 mg, 0.5 mmol) was added EDAC (96 mg, 0.5 mmol). After 16 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 153 mg (74% yield). LC/MS gave the correct molecular ion [(M+H)+=518] for the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:29][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2c(C)cccc2n1C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2c(CBr)cccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of methyl 1-tert-butoxycarbonyl-4-methylindole-2-carboxylate (0.13 g, 0.48 mmol), NBS (0.087 g, 0.48 mmol), and AIBN (4 mg, 0.024 mmol) in carbon tetrachloride (1.9 mL) was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and filtered and washed with carbon tetrachloride. The filtrate was evaporated to give a yellow oil that was purified by silica gel chromatography (EtOAc:hexane=8:92) to give 0.12 g (72% yield) of the title compound as a pale yellow solid:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[CH2:10][C:11]#[N:12])[CH:5]=[C:6]([F:8])[CH:7]=1.CSC.B.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:13]
Reactant: N#CCC(O)c1cc(F)cc(Br)c1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: NCCC(O)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(3-bromo-5-fluorophenyl)-3-hydroxypropanenitrile (2.50 g, 8.65 mmol) in THF (16.0 mL) was added borane methyl sulfide (1.20 g, 15.7 mmol). The mixture was heated to reflux for 2 h. After cooling to room temperature, saturated aqueous NaHCO3 (10 mL) was added and the mixture was stirred for 1 h. The THF was removed under reduced pressure and the remaining aqueous portion was extracted with ethyl acetate (2×60 ml). The extract was dried (Na2SO4) and concentrated to give 3-amino-1-(3-bromo-5-fluorophenyl)propan-1-ol that was used in following reaction without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]([NH:11][NH2:12])=[O:10].[Cl:13][C:14]1[CH:31]=[CH:30][C:17]2[O:18][C:19]3[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=3[CH2:21][N:22]([C:23](Cl)=[O:24])[C:16]=2[CH:15]=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]([NH:11][NH:12][C:23]([N:22]1[CH2:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=2[O:18][C:17]2[CH:30]=[CH:31][C:14]([Cl:13])=[CH:15][C:16]1=2)=[O:24])=[O:10]
Reactant: NNC(=O)COCc1cccs1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(COCc1cccs1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(2-thienylmethoxy)acetyl]hydrazide (21) was prepared in the manner described in Example 6 from 1 mmol of 2-(2-thienyl-methoxy)acetic acid, hydrazide (20), prepared as described above in Example 20, and 1.0 mmol of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carbonyl chloride (2), prepared as described above in Example 2, to yield 0.28 g (64%) of product. Analysis calculated for C21H18N3O4SCl (M.W. 443.91): C, 56.82; H, 4.09; N, 9.47. Found: C, 56.55; H, 4.08; N, 9.28.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH2:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>C(O)(=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][N:32]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[CH2:6][N:5]2[C:4](=[O:14])[C:3]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]3[C:1]2=[O:19])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(CCN)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(CCn2c(C)ccc2CN2C(=O)c3ccccc3C2=O)cc1OC

Procedure:
13.0 g (0.05 mol) of 6-phthalimido-2,5-hexanedione and 9.1 g (0.05 mol) of 2-(3,4-dimethoxyphenyl)-ethylamine are stirred in 250 ml of acetic acid at 80° C. for 7 hours. After working up as in Example 1, 7.3 g of product are obtained.