Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.B(Br)(Br)Br.Cl[CH2:17]Cl>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]2[N:9]=[C:11]([CH3:17])[O:10][C:4]=2[CH:3]=1
Reactant: ClCCl
Reactant: COc1cc(Br)cc(C)c1N
Agent: BrB(Br)Br
Product: Cc1nc2c(C)cc(Br)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 g (2.31 mmol) 4-Bromo-2-methoxy-6-methyl-phenylamine in 5 mL dichloromethane is cooled with ice/ethanol and 0.24 mL (2.49 mmol) boron tribromide in 5 mL dichloromethane is added slowly. Stirring is continued for 30 under cooling and 2 h at rt. The mixture is poured onto ice, allowed to stand for 30 min and the aq. layer is extracted with dichloromethane. The aq. phase is treated with NaHCO3 until the mixture shows basic pH, followed by extraction with dichloromethane. The combined organic phases are dried and concentrated to yield the desired product which is used without further purification.
Reaction SMILES: [CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1)[CH3:2].C=O.[C:14](=O)([O-])[O-].[Na+].[Na+]>CO.O.[Pd]>[CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH3:14])[CH3:2]
Reactant: CCC1(C(=O)O)CCCCN1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC1(C(=O)O)CCCCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 2-ethylpiperidine-2-carboxylic acid (320 mg, 1.65 mmol) in MeOH (4.0 mL) and water (4.0 mL) was added paraformaldehyde (372 mg, 4.13 mmol) and Pd/C (10%) (88 mg, 0.83 mmol). One equivalent of sodium carbonate (175 mg, 1.65 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for overnight. LC/MS indicated complete conversion of starting material. The reaction mixture was filtered through diatomaceous earth. The filter cake was washed with MeOH (2×30 mL). The filtrate was concentrated in vacuo to give the crude product. The crude solid was suspended in methanol (50 mL) and the resulting suspension was filtered and the filtrate was concentrated to give 2-ethyl-1-methylpiperidine-2-carboxylic acid (202 mg, 71.4%) as a solid. LC/MS: 172 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 3.58 (td, J=12.80, 3.51 Hz, 1 H), 3.09-3.20 (m, 1H), 2.81 (s, 3H), 2.17-2.29 (m, 1H), 1.54-1.84 (m, 7H), 0.98 (t, J=7.40 Hz, 3H).
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[C:11]1([C:4](=[N:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=CC1=NCCC1)c1ccccc1
Reactant: CC(C)(C)N
Agent: F[B-](F)(F)F
Product: CC(C)(C)N=C(C=C1CCCN1)c1ccccc1

Procedure:
By heating the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate in 50 ml of tert.-butylamine in a closed tube at 105° for 18 hours and processing analogously to Example 1, there is obtained crude 2-[2-phenyl-2-(tert.-butylimino)-ethylidene]-pyrrolidine. The crude base is dissolved in ether, and 2.8 g of methanesulphonic acid is added, whereupon 2-[2-phenyl-2-(tert.-butylimino)-ethylidene]-pyrrolidine-(1:1)-methanesulphonate crystallises out. It melts at 208°-209° (decomposition) after recrystallisation from ethyl acetate.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16](=[O:19])[NH:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.[CH:22]1([C:25]2[CH:29]=[C:28]([CH2:30]O)[N:27]([CH3:32])[N:26]=2)[CH2:24][CH2:23]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:22]1([C:25]2[CH:29]=[C:28]([CH2:30][N:17]3[C:16](=[O:19])[N:14]4[CH:15]=[C:10]([C:7]5[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=5)[CH:11]=[CH:12][C:13]4=[N:18]3)[N:27]([CH3:32])[N:26]=2)[CH2:24][CH2:23]1
Reactant: Cn1nc(C2CC2)cc1CO
Reactant: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nc(C2CC2)cc1Cn1nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn2c1=O
Reaction time: 4 h

Procedure:
6-(4-(Trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50.0 mg, 0.169 mmol), (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)methanol (38.6 mg, 0.2535, 1.5 equiv.) and PPh3 (60.5 mg, 0.2535 mmol, 1.5 equiv.) were placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added THF (3 mL) and diethyl azodicarboxylate (40% in toluene, 110.5 mg, 0.2535 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred at the same temperature for 4 h. The reaction mixture was directly loaded onto prep-HPLC to give 2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as light yellow crystals. FTIR (ATR) 1710 cm−1 (CO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([OH:12])=O)[CH:4]=1.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>>[NH:15]1[C:14]([NH:13][C:10]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[N:6]=2)=[O:12])=[N:18][N:17]=[N:16]1
Reactant: Nc1nnn[nH]1
Reactant: COc1cc(C)nc(C(=O)O)c1
Product: COc1cc(C)nc(C(=O)Nc2nnn[nH]2)c1
Yield: 73.2 %

Procedure:
0.8 g of 4-methoxy-6-methyl-2-pyridinecarboxylic acid, 0.82 g of N,N'-carbonyldiimidazole and 0.45 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.82 g of N-(5-tetrazolyl)-4-methoxy-6-methyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[S:38][N:37]=1.O>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:39]3[S:38][N:37]=[C:36]([CH3:35])[CH:40]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ns1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (10 mg, 0.02 mmol), 3-methyl-5-(tributylstannyl)isothiazole (23.25 mg, 0.06 mmol) and tetrakis(triphenylphosphine)palladium(0) (23.07 mg, 0.02 mmol) in toluene (3 mL) was heated to 120° C. for 45 min under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. After removal of solvent, the resulting crude material was reconstituted in DMF and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (55-80% gradient, 0.035% TFA). The collected fractions were combined and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×50 mL), dried over anhydrous Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation to give the title compound. [M+H] calc'd for C26H34FN5O6S, 564; found, 564.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([O:23]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[S:45]1(=[O:52])(=[O:51])[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46]1>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([C:21]([NH:50][CH:47]2[CH2:48][CH2:49][S:45](=[O:52])(=[O:51])[CH2:46]2)=[O:23])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NC1CCS(=O)(=O)C1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NC2CCS(=O)(=O)C2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with tetrahydrothiophen-3-amine 1,1-dioxide (50.6 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (52 mg, 66% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]#[N:33]>CC(=O)CC>[NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:31][C:32]#[N:33])[CH:18]=2)[N:3]=1
Reactant: N#CCBr
Reactant: Cc1ccccc1C(=O)n1nc(Nc2cccc(O)c2)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccccc1C(=O)n1nc(Nc2cccc(OCC#N)c2)nc1N
Temperature: 75 °C
Reaction time: 20 h
Yield: 34.4 %

Procedure:
In particular, to a solution of 5-amino-3-[3-(hydroxy)phenylamino]-1-(2-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-6) (0.23 g, 0.75 mmol) in 2-butanone (3 mL) was added K2CO3 (0.11 g, 0.83 mmol) and BrCH2CN (0.10 g, 0.83 mmol). After stirring the mixture at 75° C. for 20 h, the 2-butanone was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed with water (50 mL), brine (30 mL), dried (Na2SO4) and concentrated to afford the crude product. Purification by flash chromatography (1:1 hexanes/EtOAc) gave 5-amino-3-[3-(cyanomethoxy)phenylamino]-1-(2-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-8) (0.09 g, 35%) as a white solid: Rf 0.29 (1:1 hexanes/ethyl acetate); mp (DSC) 204.5-207.9° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.43 (s, 1H), 7.84 (s, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.46-7.41 (m, 1H), 7.35-7.22 (m, 3H), 7.11 (t, J=8.1 Hz, 1H), 6.96-6.93 (m, 1H), 6.48 (dd, J=8.0, 2.2 Hz, 1H), 4.80 (s, 2H), 2.31 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 168.8, 158.5, 157.0, 156.9, 142.7, 135.5, 134.7, 130.5, 130.4, 129.8, 128.1, 125.5, 116.7, 111.2, 106.3, 103.3, 53.3, 19.5; IR (ATR) 3448, 3368, 2325, 1689 cm−1; APCI MS m/z 349 [C18H16N6O2+H]+; HPLC (Method A) 91.3% (AUC), tR=12.46 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=O.C(N(CC)CC)C.ClC(OC)=O>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:10][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:2]([OH:1])[CH:7]=1
Reactant: COc1cccc(C(=O)c2ccc(OC)cc2O)c1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(Cc2ccc(OC)cc2O)c1
Reaction time: 0.8 h
Yield: 97.6 %

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1995, (30), 5335. To a solution of (2-hydroxy-4-methoxyphenyl)(3-methoxyphenyl)methanone (5.2 g) in tetrahydrofuran (100 ml) were sequentially added triethylamine (3.0 g) and methyl chloroformate (2.2 g) on an ice bath, the solution was stirred for 48 minutes, and then the reaction mixture was filtered. To a solution of sodium borohydride (3.0 g) in water (50 ml) was added dropwise the above-mentioned filtrate on an ice bath, and the solution was stirred for 1 hour and 10 minutes. The reaction solution was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (4.8 g).
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH2:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])(=O)=O.[F:19][C:20]([F:29])([F:28])[CH2:21][CH2:22][CH:23]([C:26]#[N:27])[C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:16][C:10]([F:15])([C:11]([F:12])([F:13])[F:14])[CH2:9][CH2:8][CH2:7][C:23]([CH2:22][CH2:21][C:20]([F:19])([F:28])[F:29])([C:24]#[N:25])[C:26]#[N:27]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: O=S(=O)(OCCCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CCCC(F)(F)C(F)(F)F)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.4 %

Procedure:
To 10 ml of ethylene glycol dimethyl ether, 6.2 g of 4,4,5,5,5-pentafluoropentyl trifluoromethanesulfonate, 1.6 g of 2-(3,3,3-trifluoropropyl)malononitrile and 1.4 g of potassium carbonate were added and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of 2-(4,4,5,5,5-pentafluoropentyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (89)).
Reaction SMILES: [CH2:1]([N:5](C(OC(C)(C)C)=O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][CH:3]=[CH2:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 95.8 %

Procedure:
To a solution of 186 (708 mg, 2.61 mmol) in DCM (20 mL) was added trifluoroacetic acid (593 mg, 5.20 mmol) and the mixture was allowed to stir for 5 min before being quenched with 2M NaOH (25 mL) and extracted with DCM (3×20 mL). The combined organic fractions were dried, and concentrated to yield the title compound (429 mg, 2.50 mmol, 96%) as a light brown oil, which had spectral data in agreement with that reported.104 1H NMR (CDCl3, 300 MHz): δ 5.75 (m, 1H, H3); 5.08 (m, 2H, H4); 4.59 (bs, 1H, NH); 3.20 (dd, J=6.3, 12.6 Hz, 2H, H1); 2.24 (dd, J=6.9, 12.6 Hz, 2H, H2); 1.44 (s, 9H, (CH3)3). Mass Spectrum (ES, +ve) m/z 116 (100%) [MH+] less 56 (Boc rearrangement].
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH3:14])[N+:20]([O-:22])=[O:21]
Reactant: CCCC(Oc1ccccc1)C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: CCCC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 54.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.69 g of 2-phenoxyvaleric acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.55 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:14](=O)(OC)OC.C([O-])([O-])=O.[K+].[K+].N#N>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]([CH3:14])[C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)OC
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cccc(C(C)C#N)c1
Temperature: 180 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
The reaction for the selective methylation is carried out placing into a 250 ml (φi =45 mm) stainless steel autoclave a mixture of (3-methoxycarbonylphenyl)acetonitrile (10 g, 96% purity), dimethyl carbonate (86 ml) and K2CO3 (12 g), in the 1:18:2 molar ratio. Air is replaced by a N2 stream; then the mixture is heated at a temperature of 180° C., with stirring. During the reaction, which is completed within 6 hours, the pressure raises from 7 bars, reached at the working temperature, to about 12 bars after 5 hours of isothermal heating. After cooling K2CO3 is filtered off, DMC is recovered and the residue is distilled (b.p. 0.078=109°-110° C.) to obtain 8.3 g of 2-(3-methoxycarbonyl-phenyl)propionitrile which is 99,5% pure (78% yield) (>99% selectivity in monomethylation).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:40])[O:36][CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:40])[O:36][CH:37]([CH3:38])[CH3:39])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4Cl)CCCCC3)CC2)c1

Procedure:
Example 147 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: ESMS m/e: 558.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:12]([N:15]2[CH2:21][CH:20]3[CH2:22][CH2:23][CH:17]([CH2:18][CH2:19]3)[CH2:16]2)(=[O:14])=[O:13])[CH:3]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.[H-].[Na+]>CN(C=O)C>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([S:12]([N:15]3[CH2:21][CH:20]4[CH2:22][CH2:23][CH:17]([CH2:18][CH2:19]4)[CH2:16]3)(=[O:14])=[O:13])[CH:3]=2)[CH:26]=1
Reactant: ClCc1cccnc1
Reactant: O=S(=O)(c1cc(O)c2ccccc2c1)N1CC2CCC(CC2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc(OCc2cccnc2)c2ccccc2c1)N1CC2CCC(CC2)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
The product from Example 52 (147 mg, 0.44 mmol), 3-picolylchloride hydrochloride (73 mg, 0.44 mmol and a crystal of KI were combined in DMF (30 ml). Sodium hydride (44 mg, 1.1 mmol, a 60% dispersion in oil) was added and the mixture was stirred at 90° C. for 15 hr. At this time the solvent was evaporated under reduced pressure and the residue was partitioned between 1N aq KOH and CHCl3. The CHCl3 phase was dried (Na2SO4) and concentrated and the residue was purified by flash chromatography using 5% acetone in CHCl3. The pure product was obtained as a tan foam (124 mg, 66% yield): 1H NMR (CDCl3) δ 1.53-1.76 (8H, m, 4×CH2), 2.06 (2H, s, 2×CH), 3.21 (4H, d, J=4.19 Hz, 2×CH2), 5.34 (2H, s, CH2Ar), 7.12 (1H, s, ArH), 7.37 (1H, m, ArH), 7.64 (2H, m, ArH), 7.82-7.98 (3H, m, ArH), 8.35 (1H, m, ArH), 8.62 (1H, m, ArH), 8.80 (1H, m, ArH).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9]>>[C:7]([O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C1=COCCC1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OC1CCCCO1

Procedure:
Dihydropyrane was added to methacrylic acid by the use of an acid catalyst to obtain tetrahydropyranyl methacrylate (Compound (III-G)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([NH:19]C(=O)C)=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc2cc(OCc3ccccc3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C

Procedure:
A solution of N-(6-benzyloxy-naphthalen-1-yl)-acetamide (5.0 grams, 17 mmol) and potassium hydroxide (2.88 grams, 51 mmol) in EtOH (35 mL)/H2O (25 mL) was heated at 93° C. for 17 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with saturated aqueous NaCl (25 mL) and extracted with EtOAc (5×100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 30% ethyl acetate/hexanes. 1H NMR (250 MHz, CDCl3): d 7.78 (d, 1 H), 7.50 (s, 1 H), 7.38 (m, 3 H), 7.20 (m, 4 H), 6.67 (d, 1 H), 5.18 (s, 2 H).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:38]3[CH:37]=[N:36][C:35]([O:34][CH3:33])=[N:40][CH:39]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: COc1ncc(B(O)O)cn1
Product: CCCCCCc1cccc(-c2nc(-c3cnc(OC)nc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 2-methoxy-pyrimidin-5-yl-boronic acid to give the title compound as yellow oil. MS: 531.5 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: O=c1cc(COC2CCCCO2)occ1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1cc(COC2CCCCO2)occ1OCCCCBr
Temperature: 80 °C
Yield: 71 %

Procedure:
The compound was prepared according to example 11 using 5-hydroxy-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one (1.00 g, 4.42 mmol), Cs2CO3 (1.58 g, 4.86 mmol) and 1,4-dibromobutane (2.00 mL, 16.7 mmol). The sealed tube was heated at 80° C. for 2 h 30. A white solid 2 was obtained (1.14 g, 71% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](I)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:36][CH3:37])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: CCI
Reactant: COc1cc2c(cc1O)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1
Product: CCOc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl iodide