Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)[CH3:2].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOCC1(N(C(=O)CC)c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOCC1(N(C(=O)CC)c2ccccc2)CCNCC1

Procedure:
A mixture of 14.4 parts of N-[4-(ethoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenylpropanamide and 200 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water, cooled and basified with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated, yielding N-[4-(ethoxymethyl)-4-piperidinyl]-N-phenylpropanamide as an oily residue.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[C:10]1([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCCc1ccccc1
Yield: 98.6 %

Procedure:
Following the procedure described in Referential Example 3, but using 4-(S)-isopropyl-2-oxazolidinone (6.88 g) and 4-phenylbutyryl chloride (6.88 g), the desired compound (10.23 g) was obtained as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:13][CH2:14][CH2:15][OH:16].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([O:16][CH2:15][CH2:14][CH2:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[O:4][CH3:3])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(CCCO)c1OC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(CCCOCc2ccccc2)c1OC
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
2.50 g (62.5 mmol) NaH (60% in oil) were suspended under nitrogen in 70 ml dry THF and a solution of 7.1 g (36.2 mmol) 3-(2,3-dimethoxy-phenyl)-propan-1-ol (J. Org. Chem., 1987, 52, 1072) in 50 ml THF was added dropwise at 18° C. The resulting mixture was stirred for 30 minutes and then a solution of 6.81 g (39.8 mmol) benzylbromide in 30 ml THF was added dropwise and the mixture was stirred over night at 18° C. The reaction was quenched with 10 ml water and the organic solvent was evaporated under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate and the organic layer was washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by column chromatography on silica gel (ethyl acetate/n-hexane 1:40) to afford 8 g (77%) of the desired product as a colorless oil.
Reaction SMILES: CO.[C:3](Cl)(=O)C.[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[OH:17])[C:11]([OH:13])=[O:12].C(=O)([O-])O.[Na+]>O>[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[OH:17])[C:11]([O:13][CH3:3])=[O:12]
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)c(N)c1
Temperature: 25 °C

Procedure:
100 ml of methanol are introduced into a 500 ml three-necked flask and then, at 0° C., 9.75 ml of acetyl chloride are added dropwise. 5 g of 3-amino-4-hydroxybenzoic acid are subsequently added at 0° C. and then the reaction medium is stirred at ambient temperature for eighteen hours. A saturated solution of sodium hydrogencarbonate in water is subsequently added at 0° C. and the mixture is extracted three times with ethyl acetate. The organic phases are combined and then dried over magnesium sulfate and the solvent is evaporated under reduced pressure to result in 5.16 g of methyl 3-amino-4-hydroxybenzoate.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:32])=[C:9]([C:12](=[O:31])[C:13](=[O:30])[N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)[C:10]=1[CH3:11])=[O:5])C.O>C(O)C>[CH3:11][C:10]1[C:9]([C:12](=[O:31])[C:13](=[O:30])[N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=3)[CH2:18][CH2:19]2)=[C:8]([CH3:32])[NH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)c1C
Solvent: O
Solvent: CCO
Product: Cc1[nH]c(C(=O)O)c(C)c1C(=O)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85.5 %

Procedure:
To a solution of 0.100 g (0.221 mmol) 3,5-dimethyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-acetyl}-1H-pyrrole-2-carboxylic acid ethyl ester in 2 ml ethanol and 1 ml water 0.018 g (0.443 mmol) NaOH were added. The solution was stirred at 80° C. for 5 h. The solvent was evaporated and 1 N HCl was added to the residue. The precipitate was filtered off and dried to yield 80 mg (85%) of the title compound. MS 424.15 (M+H)+,
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[O:37]([C:44]1[CH:49]=[CH:48][C:47]([S:50][C:51]2([CH2:57][C:58](O)=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>C(Cl)Cl>[C:2]([O:6][NH:7][C:58](=[O:59])[CH2:57][C:51]1([S:50][C:47]2[CH:48]=[CH:49][C:44]([O:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:45][CH:46]=2)[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)ON
Reactant: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)ONC(=O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
O-(tert-Butyl)hydroxylamine hydrochloride (9.57 g), 4-methylmorpholine (15.64 ml), hydroxybenzotriazole (6.87 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.5 g) was added to a solution of 2-[4-(4-phenoxyphenylthio)-tetrahydropyran-4-yl]acetic acid (17.5 g) in methylene chloride (200 ml). After stirring for 3 hours at room temperature, 0.5 M hydrochloric acid (200 ml) was added to the mixture, and the mixture extracted with methylene chloride. The solvent was removed from the combined extracts under reduced pressure. Silica gel chromatography of the residue and elution with 35%-80% ethyl acetate/hexane gave N-tert-butoxy-2-[4-(4-phenoxyphenylthio)-tetrahydropyran-4-yl]-acetamide (15.3 g) as an oil, which can be used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Mg]Br)=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([F:28])[C:17](S(C2C=CC=CC=2)=O)=[N:18][CH:19]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([F:28])[C:17]([C:5]2[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=2[F:12])=[N:18][CH:19]=1
Reactant: COc1cc([Mg]Br)c(F)cc1Cl
Reactant: O=S(c1ccccc1)c1ncc(Cl)cc1F
Solvent: C1CCOC1
Product: COc1cc(-c2ncc(Cl)cc2F)c(F)cc1Cl
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A Grignard solution of 12.9 g (0.049 mol) of 4-chloro-2-fluoro-5-methoxyphenylmagnesium bromide in 60 ml of THF was added with stirring at 23-30° C. to a solution of 10 g (0.0392 mol) of 5-chloro-3-fluoro-2-phenylsulfinylpyridine in 150 ml of THF over a period of 10 min, and the mixture was stirred at 23° C. for another 4 h. The reaction mixture was concentrated under reduced pressure, taken up in methylene chloride and extracted in succession with 1 N hydrochloric acid, 1 N of aqueous sodium hydroxide solution and with water, and dried. The solution was filtered with suction through silica gel, concentrated, stirred with pentane, filtered off with suction and dried, affording 5.7 g (50.1% of theory) of the title compound of mp. 120-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[CH:44][C:45]([C:48]#[N:49])=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(C#N)cc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C#N)cc4)c3)c2cc1OC
Yield: 35.5 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-ylcarbamate (108 mg, 0.3 mmol), described in the previous step, to afford 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (60 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (s, 9H), 3.99 (s, 6H), 6.40 (s, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.34-7.40 (m, 2H), 7.52-7.55 (m, 2H), 7.79 (d, J=7.8 Hz, 2H), 7.99 (d, J=7.8 Hz, 2H), 8.55 (s, 1H), 8.62 (s, 1H), 9.24 (s, 1H); LC-MS (ESI) m/z 564 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
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: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCc1nc(-c2cc(-c3cccs3)cc(C(F)(F)F)c2)co1
Temperature: 100 °C
Yield: 31.7 %

Procedure:
A suspension of methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 44, 0.454 g, 1.20 mmol), thiophene-2-boronic acid (0.230 g, 1.80 mmol) and sodium carbonate (0.954 g, 9.00 mmol) in toluene (30.0 mL) was evacuated and purged with nitrogen. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (0.208 g, 0.180 mmol) and the resulting reaction mixture was heated at 100° C. for 7 h. After this time, the reaction mixture was cooled to room temperature, quenched with 1.0 M hydrochloric acid (20.0 mL), diluted with ethyl acetate and separated. The organic layer was washed with water and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 9:1) to provide methyl 3-(4-(3-(thiophen-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.145 g, 32%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH3:39])=[O:29])=[CH:25][CH:26]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CC(=O)O)cc3)C(=O)O2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc([C@H](C)N2CC[C@](CCCOCc3ccc(OC)cc3)(c3ccccc3)OC2=O)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetic acid (260 mg, 0.50 mmol) and K2CO3 in DMF (2 mL) was added CH3I (0.2 g, 1 mmol). The resulting mixture was stirred overnight. The solid was filtered, and the filtrate was concentrated to give the crude product, which was purification by TLC to afford methyl 2-(4-((S)-1-((R)-6-(3-(4-methoxybenzyloxy)propyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)acetate (100 mg, 37%). 1H NMR (CDCl3): δ=1.42 (d, 3H), 1.68 (m, 1H), 1.88 (m, 2H), 2.12 (m, 1H), 2.23 (m, 2H), 2.78 (m, 1H), 3.29 (m, 2H), 3.44 (s, 2H), 3.64 (s, 3H), 3.75 (s, 3H), 4.28 (s, 2H), 5.56 (q, 1H), 6.73 (m, 4H), 6.92 (m, 2H), 7.14 (m, 2H), 7.25 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[S:24])=[C:15]([CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[S:24])=[C:15]([CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(C3CCOC3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(C3CCOC3)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Yield: 68.4 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydrofuran-3-yl)thio-3-cephem-4-carboxylate (80 mg) (as obtained in Example 1) was dissolved in dimethylformamide (1.6 ml) and the solution was cooled to -20° C. The solution, after addition of iodomethyl pivalate (77 mg) thereto, was stirred at a temperature of -20° to -10° C. for 30 minutes (for the esterification reaciton), after which cold water (5 ml) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate, and the organic layer separated was washed with an aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to leave a yellow oil. The oily residue was purified by a column chromatography on a silica gel column (15 g) with elution using ethyl acetate as eluent to collect fractions containing the titled compound. Concentration of the fractions so collected under reduced pressure gave the titled compound (65 mg; 68%) as white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)#[N:31]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([C:30]#[N:31])=[CH:33][CH:34]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)c2ccc(C#N)cc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 97.8 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (810 mg, 2.35 mmol, described herein above) in CH2Cl2 (20 ml) was added triethyl-amine (0.42 ml, 3.05 mmol) and 4-cyano-benzoyl chloride (466 mg, 2.81 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 2:1) afforded 1.09 g (98%) of the title compound as a white foam. ES-MS m/e: 474.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[S:14]([CH2:24][N+:25]#[C-:26])([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[C-]#N.[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[C@H:4]1[O:5][CH:26]=[N:25][C@@H:24]1[S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2cc(C(F)(F)F)ccc2F)cc1

Procedure:
In a manner analogous to Preparation 1, 2-fluoro-5-(trifluoromethyl)benzaldehyde (0.26 g 1.47 mmol), tosylmethylisocyanide (0.27 g, 1.40 mmol) and NaCN (6.9 mg, 0.14 mmol) gave the desired compound as a tan solid. 1H NMR (300 MHz, CDCl3) δ2.48 (s, 3H), 5.10-5.14 (dd, 1H), 6.12-6.16 (dd, 1H), 7.16-7.20 d, 2H), 7.40-7.44 (dd, 2H), 7.52-7.56 (d, 1H), 7.66-7.70 (d, 1H), 7.88-7.92 (dd,2H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@H:21]2[CH2:26][C@@H:25]([C:27]#[N:28])[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:40]([Si](C)(C)C)=[N+:41]=[N-:42].C([Sn](CCCC)=O)CCC>>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@H:21]2[CH2:26][C@@H:25]([C:27]3[N:40]=[N:41][NH:42][N:28]=3)[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C#N)CN(C(=O)OC(C)(C)C)C1
Agent: CCCC[Sn](=O)CCCC
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](c2nn[nH]n2)CN(C(=O)OC(C)(C)C)C1
Yield: 58.3 %

Procedure:
To tert-butyl (3S*,5R*)-3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-cyanopiperidine-1-carboxylate (120 mg) were added azido(trimethyl)silane (55 mg) and dibutyl(oxo)stannane (5 mg), and the mixture was stirred with heating to reflux for 1 day. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object compound (75.5 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:10][OH:11])[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[S:5]2.[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][O:11][CH2:10][C:9]1[N:8]2[C:4]([S:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=32)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc2sc3ccccc3n2c1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1c(C)nc2sc3ccccc3n12
Temperature: 25 °C
Yield: 60.8 %

Procedure:
In 30 ml of dry dimethylformamide was suspended 2.18 g of 2-methylimidazo[2,1-b]benzothiazole-3-methanol and, 0.50 g of 60% sodium hydride was added to the suspension followed by stirring at room temperature for minutes. After 1.74 g of methyl iodide was added thereto, the mixture was stirred for one hour. Then ice water was added to the reaction mixture followed by extracting with ethyl acetate. After the ethyl acetate was removed, 1.41 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[C:23]1([NH:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:32][CH2:31][CH2:30][NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCNc1ccccc1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccc2)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and N-phenylethylenediamine in DME. ES-MS m/e (%): 320 (M+H+, 100).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:26][CH3:27]>CN(C=O)C>[CH2:26]([N:10]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]([C:1]#[N:2])=[C:11]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:27]
Reactant: N#CCc1ccccc1NC(=O)c1cccnc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(-c2cccnc2)c(C#N)c2ccccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of N-(2-cyanomethyl-phenyl)-nicotinamide (Example 83a, 400 mg, 1.69 mmol) in DMF (17 mL) is added Cs2CO3 (1.1 g, 3.37 mmol). The reaction is heated to 80° C., at which time a solution of iodoethane (0.14 mL, 1.75 mmol) in DMF (5 mL) is added over 75 min. The temperature is then increased to 100° C. After stirring for an additional 2 h, the reaction is cooled to room temperature and quenched with saturated aqueous NH4Cl, and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 3:10 to 1:0) to furnish 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 1.40 (t, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 2H), 7.32-7.45 (m, 2H), 7.47-7.51 (m, 1H), 7.54 (dd, J=7.8, 5.6 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.91-7.98 (m, 1H), 8.78-8.85 (m, 2H). HRMS (ESI) m/z 248.1190 [(M+H)+ Calcd for C16H14N3: 248.1188].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16](O)[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([SH:31])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Solvent: Cc1ccccc1C
Product: SC1CCn2c(CCc3ccccc3)nc3cccc1c32
Yield: 30.9 %

Procedure:
A portion (5.55 g) of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-ol obtained in Example 4 was suspended in xylene (700 mL); following the addition of a Lawesson reagent (4.04 g), the suspension was heated under reflux for 30 min under an argon atmosphere. After standing to cool, the supernatant was concentrated under vacuum and the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate) to yield the titled compound as colorless crystals (0.91 g).