Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(Br)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(Br)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-bromophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.56 g, 99%): 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.32-8.22 (m, 2H), 7.92 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.45-7.28 (m, 8H), 7.20 (d, J=8.0 Hz, 1H), 5.69 (s, 1H), 4.11-3.86 (m, 2H); ESIMS m/z 562 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCCC4)c3)n2)n1
Yield: 71.7 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.300 g, 0.613 mmol) by treatment with pyrrolidine (0.131 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.230 g, 71%) as a white solid. MS (ISP) 524.3 [(M+H)+]; mp 174° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:28][C:29](=O)[CH2:30][C:31]1[NH:35][CH:34]=[N:33][N:32]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]([CH3:25])[CH3:24])[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[NH:35][CH:34]=[N:33][N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Product: COc1ccc(N2CCN(C(=O)Cc3nnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Yield: 25 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-isopropoxy-4-methoxy-phenyl)-piperazine and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 5 days to afford the title compound as a yellow solid (94 mg, 25%). LC/MS (Method B) 3.12 min, [M+1]+ 450.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=O)[CH2:44][CH:45]1[CH2:48][CH:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:46]1)=[O:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:40][C:43]([CH2:44][CH:45]2[CH2:46][CH:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:48]2)=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To s solution of PPh3 (7.9 g, 30.0 mmol) in dry DCM (60 mL) was added I2 (7.8 g, 30.0 mmol). After I2 was dissolved completely, TEA (10.5 mL, 75.0 mmol) was added quickly at rt. The mixture was stirred for 15 mins. Tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutylcarbamate (4.9 g, 15.0 mmol) was added. The mixture was stirred at rt for 1 hr. The solvent was concentrated. EtOAc (300 mL) was added, and the solution was filtered to remove PPh3O. The filtrate was concentrated. The residue was purified by silica gel column chromatography (gradient elution 0-50% EtOAc/petroleum ether) to afford tert-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl-carbamate (6.2 g, 85%) as a white solid. ESI-MS (EI+, m/z): 484.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]4)[C:11]3=[O:24])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CN(C(O[N:33]1N=N[C:35]2C=CC=C[C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.C(N)C>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:15][CH2:16][N:17]([CH2:20][C:21]([NH:33][CH2:34][CH3:35])=[O:22])[CH2:18][CH2:19]4)[C:11]3=[O:24])=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)CN1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)CN1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
A mixture of mg 42.7 mg (0.13 mmol) [2-(4-Cyclopropyl-phenyl)-1-oxo-2,8-diaza-spiro[4.5]dec-8-yl]-acetic acid, 54.2 mg (0.195 mmol) TBTU, 26 mg (0.26 mmol) NEt3 and 8.7 mg (0.195 mmol) ethylamine in 2 mL DMF was stirred at room temperature for 16 h and evaporated to dryness. The residue was taken up in DMF and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 16.2 mg (35%) of the title compound. MS m/e: 356.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[CH2:7]([C:9]1[N:10]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20](OCCC)=[N:21][CH:22]=[C:23]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:27])=[O:26])[CH:24]=3)=[N:14][C:13]=12)[CH3:8]>CC(O)C>[CH2:7]([C:9]1[N:10]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20]([O:4][CH:2]([CH3:3])[CH3:1])=[N:21][CH:22]=[C:23]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:26])=[O:27])[CH:24]=3)=[N:14][C:13]=12)[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCCOc1ncc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Agent: [K+]
Solvent: CC(C)O
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(C)CC4)cnc3OC(C)C)[nH]c(=O)c2nn1Cc1ccccn1

Procedure:
Potassium t-butoxide (290 mg, 2.60 mmol) was added to a stirred solution of the title compound of Example 20 (239 mg, 0.43 mmol) in propan-2-ol (7 ml) under nitrogen and the reaction mixture heated under reflux for 48 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (20 ml) and ethyl acetate (20 ml).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[NH2:16][CH2:17][CH2:18][CH2:19][OH:20].[SH:21][CH2:22][C:23](O)=[O:24]>C1C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]2[N:16]([CH2:17][CH2:18][CH2:19][OH:20])[C:23](=[O:24])[CH2:22][S:21]2)[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: NCCCO
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: O=C(O)CS
Solvent: c1ccccc1
Product: CC(C)c1cc(C2SCC(=O)N2CCCO)cc(C(C)C)c1O
Yield: 24.1 %

Procedure:
In benzene (50 ml) were suspended 3,5-diisopropyl-4-hydroxybenzaldehyde (5.00 g) and 3-aminopropanol (1.82 g) in a nitrogen atmosphere. A Dean-Stark trap was fitted to the reactor, and the suspension was refluxed for 1.5 hours. After allowing the mixture to cool, α-mercaptoacetic acid (2.23 g) was added, then the mixture was further refluxed for 2 hours. After removal of benzene by evaporation, water (50 ml) was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 99:1) to afford 1.97 g (24%) of the title compound as a colorless oil. NMR (CDCl3, 60 MHz): 1.23 (12H, d, J=6.6 Hz), 1.0-1.8 (2H, m), 2.5-3.8 (7H, m), 3.73 (2H, brs), 5.50 (2H, brs), 6.92 (2H, s)
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([F:17])=[C:9]([CH:16]=1)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14].[H-].[Na+].[CH3:22][O:23][CH2:24]Br.O>CN(C)C=O>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([F:17])=[C:9]([CH:16]=1)[CH2:10][N:11]([CH2:22][O:23][CH3:24])[C:12](=[O:15])[O:13][CH3:14]
Reactant: COC(=O)NCc1cc(C#CC(C)(C)C)ccc1F
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(Cc1cc(C#CC(C)(C)C)ccc1F)C(=O)OC
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
0.20 g of methyl N-[5-(3,3-dimethyl-1-butynyl)-2-fluorobenzyl]carbamate was dissolved in N,N-dimethylformamide (5 ml). To this solution, 0.10 g of sodium hydride (60 wt %) was added at room temperature, followed by stirring for 30 minutes. Then, 0.14 g of bromomethyl methyl ether was added at room temperature, followed by stirring for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.13 g of methyl N-[5-(3,3-dimethyl-1-butynyl)-2-fluorobenzyl]-N-methoxymethylcarbamate as a colorless viscous liquid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[N:2]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(#N)C.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc2ccccc2cn1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc2ccccc2cn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Isoquinolin-3-amine (300 mg, 2.08 mmol) was dissolved in acetonitrile. To the reaction mixture was added pyridine (0.20 mL, 2.50 mmol) and phenyl chloroformate (0.27 mL, 2.18 mmol), respectively and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl isoquinolin-3-ylcarbamate (456 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.C(Cl)(=O)C([Cl:14])=O>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([Cl:14])=[O:10])[O:5][N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)on1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of 3-methoxyisoxazole-5-carboxylic acid (420 mg, 3 mmol) in THF (15 mL) and DMF (5 drop) was added dropwise oxalyl chloride (650 μL, 7 mmol) at 0° C. The mixture was then stirred at room temperature for 3 hours. The solution was concentrated in vacuo to yield the title compound as a light yellow oil (430 mg).
Reaction SMILES: C(O[C:4](=[O:13])[CH:5]=[C:6](OC)[C:7]([F:10])([F:9])[F:8])C.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].[OH-].[K+].OS(O)(=O)=O>CO.O>[CH3:19][O:18][C:14]([C:15]1[S:16][C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]=1[OH:13])=[O:17]
Reactant: COC(=O)CS
Reactant: CCOC(=O)C=C(OC)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1sc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A solution of 4,4,4-trifluoro-3-methoxy-but-2-enoic acid ethyl ester (9.6 g, 48.5 mmol) and methyl thioglycolate (4.3 mL, 48.5 mmol) in MeOH (75 mL) is cooled to 5° C. A solution of KOH (3.3 g, 58.2 mmol) in MeOH (75 mL) is then added over 30 min. The reaction mixture is stirred overnight at room temperature. The reaction mixture is then poured over a stirred mixture of ice (75 g), H2O (75 mL) and concentrated H2SO4 (4.5 mL). The mixture is extracted with EtOAc (2×250 mL). The combined extracts are washed with saturated NaHCO3. The washings are back-extracted with EtOAc. The combined organic layers are washed with brine, then dried (Na2SO4), filtered and concentrated to afford the title compound (10 g, 91%) as a brown oil which is used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:20][CH2:19]1)[CH2:11]2.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1>O.C1(C)C=CC=CC=1.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>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:20][CH2:19]2)[CH2:11]3)=[CH:30][N:31]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: O=C1c2ccc(Br)cc2CN1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1ncc(-c2ccc3c(c2)CN(C2CC2)C3=O)cn1
Temperature: 120 °C
Yield: 45.5 %

Procedure:
A solution of potassium carbonate (0.10 g, 0.75 mmol) in water (0.7 mL) was added to a mixture of 5-bromo-2-cyclopropylisoindolin-1-one (0.095 g, 0.38 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.12 g, 0.56 mmol), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) in toluene (1.4 mL) and ethanol (0.7 mL). The resulting mixture was heated at 120° C. for 15 min. The reaction mixture was then quenched with saturated sodium bicarbonate (5 mL) and extracted with EtOAc. The organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with 10% methanol in dichloromethane to afford the desired product (0.046 g, 46%). LCMS: (M+H)=267.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1)#[N:29]>>[CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([O:16][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([C:28]#[N:29])=[CH:31][CH:32]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cccc(-c2nc(O)c3c(n2)CCN(Cc2ccccc2)C3)c1
Product: N#Cc1ccc(COc2nc(-c3cccc([N+](=O)[O-])c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 9) and 4-cyanobenzyl bromide according to Method A; LC retention time 2.53 min; MS: m/z (ESI) 478 (M+H).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2)=C.I([O-])(=O)(=O)=[O:13].[Na+].O1CCOCC1>O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH:1]([C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2)=[O:13]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1nc2ncccc2[nH]1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
A mixture of vinylimidazo[4,5-b]pyridine (1 eq.), osmium tetroxide (0.1 eq.), sodium periodate (3-4 eq.), 1,4-dioxane (30 ml/mmol), and water (25 ml/mmol) is stirred for 15-30 min at ambient temperature. The resulting slurry is diluted with even amounts of water and ethyl acetate. After filtration through Celite®, the organic phase is dried over sodium sulfate, concentrated in vacuo and purified via flash chromatography to yield the respective formylimidazo[4,5-b]pyridine.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.C(OCC)C.O>CN(C)C=O>[Br:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:21][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: Cc1cccc(C(Br)Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
0.57 g of potassium phthlimide was suspended in 20 ml of dimethylformamide, and 2.42 g of α,α-dibromo-m-xylene was added. The mixture was stirred overnight at room temperature, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane / ethyl acetate=10/1] to give 0.52 g of N-(3-bromomethylbenzyl)phthalimide as a white crystalline powder.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:16]2[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[N:30]=1)[CH3:11]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][S:2]([CH3:1])(=[O:5])=[O:3])[C:16]2[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[N:30]=1)[CH3:11]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CCCCNS(C)(=O)=O
Reaction time: 2.5 h
Yield: 142.1 %

Procedure:
Methane sulfonic anhydride (0.822 g, 4.72 mmol) was added over a period of 5 minutes to a solution of 4-[2-(ethoxymethyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butan-1-amine (1.5 g, 4.23 mmol) in a mixture of chloroform (35 mL) and triethylamine (0.77 mL). The reaction mixture was allowed to stir for 2.5 hours then it was washed with 1 N sodium hydroxide (10 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 2.6 g of crude N-[4-(2-ethoxymethyl-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH:42]1[CH2:46][CH2:45][CH2:44]C1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH:42]1[CH2:46][CH2:45][CH2:44]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (300 mg, 0.74 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclobutyl-amine (8e) (204 mg, 0.89 mmol) in dimethylformamide (5 mL) were added N,N-diisopropylethylamine (0.4 mL, 2.22 mmol) and HATU (423 mg, 1.11 mmol). After stirring at room temperature for 1 h, water (50 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclobutyl-amide (292) (420 mg, 91.94%) as a yellow sticky solid.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:12])[C:4]([CH:6]1CC[C:8](=O)[CH2:7]1)=[O:5].COCCN(S(F)(F)F)CCOC.F[C:27]([F:32])([F:31])[C:28](O)=O>C1(C)C=CC=CC=1.CCOCC>[F:31][C:27]1([F:32])[CH2:8][CH2:7][CH:6]([C:4]([N:3]([O:2][CH3:1])[CH3:12])=[O:5])[CH2:28]1
Reactant: CON(C)C(=O)C1CCC(=O)C1
Reactant: O=C(O)C(F)(F)F
Agent: COCCN(CCOC)S(F)(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C1CCC(F)(F)C1
Temperature: 40 °C

Procedure:
To a solution of N-methoxy-N-methyl-3-oxocyclopentanecarboxamide (2.43 g, 14.19 mmol) in 30 mL toluene under nitrogen was added deoxo-fluor® (7.05 mL, 38.3 mmol) followed by trifluoroacetic acid (0.219 mL, 2.84 mmol). The reaction was sealed and heated to 40° C. overnight. The reaction mixture was cooled, diluted with Et2O, cooled to 0° C. in an ice bath and quenched slowly with 75 mL 2N NaOH with rapid stirring. The aq. Layer was separated and extracted once with Et2O. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purified by silica gel chromatography (50% EA/hexanes) gave (rac)-3,3-difluoro-N-methoxy-N-methylcyclopentanecarboxamide as a light yellow oil. 1H NMR (400 MHz, CDCl3-d) δ ppm 3.71 (s, 3 H), 3.29-3.43 (m, 1 H), 3.21 (s, 3 H), 2.17-2.54 (m, 3 H), 1.93-2.15 (m, 3 H).