Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C@H:5]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[C:14]([C:16]([CH3:18])=[CH2:17])=[CH:15][C:7]=2[CH2:6]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C@H:5]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:19][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[C:14]([CH:16]([CH3:18])[CH3:17])=[CH:15][C:7]=2[CH2:6]1
Reactant: [H][H]
Reactant: C=C(C)c1cc2c(c3cn[nH]c13)CN(CC(C)(C)C)C(=O)[C@H](CC(=O)OC)C2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1Cc2cc(C(C)C)c3[nH]ncc3c2CN(CC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
[(S)-9-(2,2-Dimethyl-propyl)-4-isopropenyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-acetic acid methyl ester (100 mg, 0.26 mmol) was dissolved in a mixture of ethyl acetate (5.0 mL) and methanol (5.0 mL). A catalytic amount of 10% palladium on carbon was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 1 hour. Mixture was filtered and the filtrate was concentrated to dryness. Title compound was obtained as brown residue in 90% yield. MS m/e (M+H)+=386.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Mn]([O-])(=O)(=O)=[O:10].[K+].[OH2:15]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccnc(F)c1

Procedure:
A stirred mixture of 30 grams of the above 2-fluoro-4-methylpyridine and potassium permanganate (100 g) in water (1.2 L) was heated at reflux. Additional potassium permanganate (50 g) was added after 1.5 hours and the stirred mixture was maintained at reflux for 15 hours. The reaction mixture was then steam distilled to remove unreacted starting material, the hot residual aqueous solution was filtered, and the filtrate was concentrated in vacuo to 450 mL. The solution was cooled on an ice-bath and acidified with concentrated HCl to pH 2.0. The resulting precipitate was collected and crystallized from water and gave 13.56 g of 2-fluoropyridine-4-carboxylic acid having a melting point of 220°-224° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:22]=1)[C:20]#[N:21]>O1CCCC1>[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:22]=1)[C:20](=[NH:21])[NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][N:11]=1
Reactant: Cc1ccc(N)nc1
Reactant: N#Cc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=N)c2cncc(Br)c2)nc1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M, 5.14 mL, 0.0081 mol) was added slowly at a temperature of −78° C. over a period of 5 min to a solution of 5-methylpyridin-2-amine (0.738 g, 0.0068 mol) in anhydrous tetrahydrofuran (40 mL). The reaction temperature was raised to −40° C. and the reaction mixture was stirred for 15 min. It was cooled to −78° C. and 5-bromonicotinonitrile (1.25 g, 0.0068 mol) in tetrahydrofuran (5 mL) was added. The reaction temperature was raised to RT and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was used directly on the next step. MS (M+1): 292.1.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:44]=[CH:43][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=5)[C:38]#[N:39])[O:32][C:33]=4[CH3:34])=[C:25]([O:45][CH3:46])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[N-:47]=[N+:48]=[N-:49].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:44]=[CH:43][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([C:38]6[NH:49][N:48]=[N:47][N:39]=6)[CH:40]=[CH:41][CH:42]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:45][CH3:46])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C#N)c4)oc3C)c(OC)c2)cs1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(-c5nnn[nH]5)c4)oc3C)c(OC)c2)cs1
Temperature: 120 °C
Reaction time: 6 h
Yield: 28.3 %

Procedure:
A mixture of 3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzonitrile (350 mg), sodium azide (55 mg), ammonium chloride (59 mg) and N,N-dimethylformamide (10 mL) was stirred at 120° C. for 6 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5-1:2-1:1, v/v) to give 5-{3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}-1H-tetrazole (106 mg, yield 28%) as colorless crystals. Recrystallization from ethyl acetate-diethyl ether gave colorless prism crystals. melting point: 144-147° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:45][N:46]2[CH:50]=[N:49][CH:48]=[N:47]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:43])[CH:40]([OH:42])[CH3:41])[C:35]5=[O:44])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.[Cl:51][CH2:52][C:53](Cl)=[O:54].N1C=CC=CC=1>C(Cl)Cl>[Cl:51][CH2:52][C:53]([O:42][CH:40]([CH3:41])[CH:39]([N:36]1[C:35](=[O:44])[N:34]([C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:45][N:46]6[CH:50]=[N:49][CH:48]=[N:47]6)[O:13]5)=[CH:17][CH:18]=4)[CH2:27][CH2:26]3)=[CH:33][CH:32]=2)[CH:38]=[N:37]1)[CH3:43])=[O:54]
Reactant: O=C(Cl)CCl
Reactant: CC(O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(OC(=O)CCl)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Temperature: 25 °C

Procedure:
A mixture of intermediate 2a (0.01 mol) and chloroacetyl chloride (0.0115 mol) in CH2Cl2 (200 ml) was stirred at room temperature. Pyridine (0.02 mol) was added and the mixture was stirred for 2 hours, washed with water, dried, filtered and the solvent was evaporated. The residue was crystallized from MIK/DIPE. The precipitate was filtered off and dried, yielding 6.7 g (87%) [2S-[2α,4α[(R*,R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]-1-methylpropyl chloroacetate. (interm.3)
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:12][N:13]([CH2:15][C:16](=[CH2:19])[C:17]#[N:18])C>>[C:17]([CH:16]([CH2:15][NH:13][CH2:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:19][NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])#[N:18]
Reactant: C=C(C#N)CN(C)C
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCNCC(C#N)CNCCCCCCCCCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To stirred n-decylamine (47.2 g., 0.3 mole) at 20° C. is added dropwise 2-[(N,N-dimethylamino)methyl]-2-propenenitrile (11.0 g., 0.1 mole) over a 3 minute period. The reaction mixture, protected from moisture with an Ascarite drying tube, is stirred at room temperature an additional three hours. It is then heated at 80° C. for 48 hours. The mixture is fractionally distilled under reduced pressure to remove a small amount of unreacted, excess n-decylamine, 2-cyano-N-(n-decyl)-N',N'-dimethyl-1,3-propanediamine as byproduct, and finally the product, 2-cyano-N,N'-di(n-decyl)-1,3-propanediamine.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.Cl.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[CH2:42][CH2:43][CH2:44][NH2:45])=[CH:37][CH:36]=1.C(OCC)C>CN(C=O)C>[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([C:46]2[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=2)[CH2:42][CH2:43][CH2:44][NH:45][C:5]([C@@H:4]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH:2]([CH3:1])[CH3:23])=[O:7])=[CH:37][CH:36]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)N1CCN(c2ccccc2)CC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
(S)-4-Methyl-2-[(4-phenyl-piperazine-1-carbonyl)-amino]pentanoic acid (0.300 g, 0.940 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.490 mL, 2.81 mmol) and solid O-benzotriazol-1-yl-N,N,N,′,N′-tetramethyluronium hexafluorophosphate (0.356 g, 0.939 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.280 g, 0.940 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 35 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a solid. Recrystallization from ether afforded 0.18 g (34%) of the pure titled compound as a white solid; mp 138-141° C. APCI-MS m/z 563.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1.C(=O)([O-])O.[Na+]>ClCCl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: c1nc[nH]n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cn2cncn2)CC1
Temperature: -78 °C
Reaction time: 0.02 h
Yield: 35.5 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-piperidin-4-methanol (1.08 g, 5.0 mmol) and diisopropylethylamine (2.6 mL, 15 mmol) in dry dichloromethane (30 mL) was added anhydrous trifluoromethanesulfonic acid (1.0 mL, 6.0 mmol) at −78° C., and the mixture was stirred for 1 minute under iced cooling. The mixture was cooled to −78° C. To the reaction mixture were added 1H-1,2,4-triazole (1.04 g, 15 mmol) and THF (20 mL), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (50 g, ethyl acetate/ethanol=1/0 to 20/1), and recrystallization to give the titled compound as pale yellow crystals (473 mg, 36%).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])N1CCCCCC1=O.[CH3:13][C:14]1[CH2:15][S:16](=[O:36])[C@@H:17]2[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23](=[O:35])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21].NS(O)(=O)=O.[Br:42]N1C(=O)CCC1=O>ClCCl>[Br:42][CH2:13][C:14]1[CH2:15][S:16](=[O:36])[C@@H:17]2[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23](=[O:35])[N:18]2[C:19]=1[C:20]([O:22][Si:2]([CH3:12])([CH3:11])[CH3:1])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)N1CCCCCC1=O
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reaction time: 0.42 h
Yield: 51 %

Procedure:
255 mg of N-trimethylsilylcaprolactam (1.36 mmoles) were added to a refluxing suspension of 360 mg (1.03 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane and a clear, colorless solution was obtained within 2 minutes. Refluxing was continued for another 25 minutes and the solution was cooled in an ice-bath and diluted to 40 ml with dichloromethane 150 mg of amidosulfonic acid (1.53 mmoles) were added thereto and bromination was carried out in half an hour using 299 mg (1.68 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 51% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: F[C:2]1[N:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[S:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=2[CH:17]=1)=[O:5].Cl.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH2:32][NH2:33])=[C:26]2[CH:25]=[CH:24]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[O:16]=[C:13]1[NH:12][C:11]2[CH:17]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:18]=[CH:19][CH:20]=[N:21][C:2]=3[NH:33][CH2:32][C:31]3[CH:30]=[CH:29][N:28]=[C:27]4[NH:23][CH:24]=[CH:25][C:26]=34)[CH:8]=[CH:9][C:10]=2[S:15][CH2:14]1
Reactant: O=C1CSc2ccc(NC(=O)c3cccnc3F)cc2N1
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSc2ccc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)cc2N1
Temperature: 170 °C

Procedure:
To an oven-dry microwave tube was added 2-fluoro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-nicotinamide (150 mg, 0.5 mmol), C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine hydrochloride salt (220 mg, 1.0 mmol), DIEA (1 mL), and t-BuOH (2 mL). The resulting mixture was sealed off and underwent microwave heating at 170° C. for 20 min. Solvent was removed in vacuo. The crude solid was purified by chromatography on silica gel. Elution with DCM:MeOH mixture (97:3) gave final compound. MS (ES+): 430.6 (M+H). Calc'd. for C22H18N6O2S—430.49.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[S:3](OC1C(C)(C)[C@H]2[C@](C)(CC=1)[C@@H]1[C@](C)([C@@]3(C)[C@H](CC1)[C@H]1[C@H](C(C)=C)CC[C@]1(NCCN1CCS(=O)(=O)CC1)CC3)CC2)(=[O:5])=[O:4].[C:49]([NH:52][C:53]1([C:60]([O:62][CH3:63])=[O:61])[CH2:58][CH2:57][C:56](=[O:59])[CH2:55][CH2:54]1)(=[O:51])[CH3:50]>>[C:49]([NH:52][C:53]1([C:60]([O:62][CH3:63])=[O:61])[CH2:54][CH2:55][C:56]([O:59][S:3]([C:2]([F:48])([F:47])[F:1])(=[O:5])=[O:4])=[CH:57][CH2:58]1)(=[O:51])[CH3:50].[C:49]([NH:52][C:53]1([C:60]([O-:62])=[O:61])[CH2:54][CH2:55][C:56](=[O:59])[CH2:57][CH2:58]1)(=[O:51])[CH3:50]
Reactant: COC(=O)C1(NC(C)=O)CCC(=O)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: CC(=O)NC1(C(=O)[O-])CCC(=O)CC1
Product: COC(=O)C1(NC(C)=O)CC=C(OS(=O)(=O)C(F)(F)F)CC1

Procedure:
The title compound was prepared following the procedure described on step 6 of method 2 for the preparation of intermediate 1, using methyl 1-acetamido-4-oxocyclohexanecarboxylate, as the reactant. 1-acetamido-4-oxocyclohexanecarboxylate was prepared following the procedures described in Journal of Chem. Soc., Perkin Trans. I, 1999, pp. 3375-3379. (84.0% yield), MS: m/e 346.1 (M+H)+, 2.213 min (method ?). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.24 (s, 1H), 5.69 (td, J=3.3, 1.4 Hz, 1H), 3.82-3.58 (m, 3H), 2.87-2.67 (m, 1H), 2.61-2.44 (m, 2H), 2.42-2.33 (m, 2H), 2.19-2.07 (m, 1H), 2.01-1.94 (m, 3H). 19F NMR (376 MHz, CHLOROFORM-d) δ −74.02 (s, 3F).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]>C(O)C.C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2cncc(NC(=O)OC)c2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1ccc(C2CNCC(NC(=O)OC)C2)cc1

Procedure:
A solution of 1.0 g (3.7 mmol) of methyl [5-(4-ethylphenyl)pyridin-3-yl]carbamate in 100 ml of ethanol and 100 ml of acetic acid was reacted according to General Method 5A. The solution was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/methanol 4:1). Yield: 171 mg (16% of theory)
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]4=[O:30])=[CH:20][CH:19]=3)=[N:11][N:12]([CH3:17])[C:13]=2[C:14](O)=O)=CC=1.[NH2:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[NH2:42])[C:37]#[N:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:8][C:9]1[C:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C:25]3=[O:30])=[CH:20][CH:19]=2)=[N:11][N:12]([CH3:17])[C:13]=1[C:14]1[NH:42][C:41]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=2[N:33]=1
Reactant: COc1ccc(COc2c(-c3ccc(N4CCCCC4=O)cc3)nn(C)c2C(=O)O)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(N3CCCCC3=O)cc2)c(O)c1-c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-methoxybenzyloxy)-1-methyl-3-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazole-5-carboxylic acid T-22 (180 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL) were added 3,4-diaminobenzonitrile (66 mg, 0.5 mmol), HATU (204 mg, 0.54 mmol) and diisopropylethylamine (0.22 mL, 1.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate. Solvent was evaporated under reduced pressure. The residue was purified by flash chromatography. To the purified fraction (155 mg, 0.28 mmol) was added acetic acid (4 mL). The reaction mixture was heated in a microwave reactor at 150° C. for 55 minutes. Solvent was evaporated under reduced pressure. To the residue was added trifluoroacetic acid (4 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 30 minutes. Solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography to afford the desired 2-(4-hydroxy-1-methyl-3-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile T-23 (110 mg, 0.27 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.[C-]#N.[Na+].C[N:16]([CH2:18][C:19]1C2C(=NC=C(F)C=2)NC=1C)C>O>[C:18]([CH2:19][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][C:9]=1[CH3:11])#[N:16]
Reactant: Cc1[nH]c2ncc(F)cc2c1CN(C)C
Reactant: Cc1cc2cc(F)cnc2[nH]1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c2ncc(F)cc2c1CC#N
Temperature: 0 °C
Yield: 67 %

Procedure:
Mannich reagent (0.8 ml, prepared according to Liebigs (1971) Ann. Chem., 743, 95-111) was added under stirring to pre-cooled (-78° C.) 5-fluoro-2-methylpyrrolo[2,3-b]pyridine (0.33 g, 2.2 mmol) under argon. The flask containing the reaction mixture was then placed in an ice bath and stirring was continued to give a white suspension. The ice lumps melted within 2 h and the resulting water bath was allowed attain room temperature. After 24 h almost all suspension had dissolved. The reaction mixture was cooled in an ice bath, diluted with deinionized water (8 ml) and extracted with diethyl ether (2×5 ml) to remove some remaining starting material and a by-product (propably the corresponding Mannich dimer). Sodium cyanide (1.08 g, 0.022 mol) was added to the water phase, assumed to contain 3-(dimethylaminomethyl)-5-fluoro-2-methylpyrrolo[2,3 -b]pyridine, and the resulting solution was refluxed for 2 h to afford a suspension which was isolated by filtration. Purification by flash chromatography (SiO 2 /CH2Cl2 :MeOH 19:1) gave 0.28 g (67%, two steps) of 3-(cyanomethyl)-5-fluoro-2-methylpyrrolo[2,3-b]pyridine.
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.C[O:39][CH2:40][C:41](O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:40]([O:22][CH:13]1[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/[C:12]/1=[CH:11]\[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:39])[CH3:41]
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Reactant: COCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of Compound 20b (37 mg, 0.13 mmol), DCC (26.7 mg, 0.13 mmol), and DMAP (31.6 mg, 0.26 mmol) in dry CH2Cl2 (20 mL) cooled in an ice-water bath was added methoxyacetic acid (17.5 mg, 0.19 mmol) followed by stirring at room temperature for 2 hours. The reaction mixture was filtered through a short plug of Celite with rinsing by EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 30.1 mg (65 percent) of Compound 30b: pale yellow oil; Rf=0.38 (20 percent EtOAc in hexane); IR (neat) 2932, 2239,2229, 1756, 1182, 1126 cm−1; 1H NMR (300 MHz, CDCl3) δ8.32 (d, J=7.29 Hz, 1H), 8.14-8.00 (m, 1H), 7.92-7.81 (m, 2H), 7.58-7.44 (m, 3H), 7.50 (s, 1H), 6.33 (t, J=1.05 Hz, 1H), 4.15 and 4.13 (AB q, J=16.50 Hz, 2H), 3.48 (s, 3H), 2.55-2.20 (m, 4H), 2.00-1.60 (m, 4H); 13C NMR (75 MHz, CDCl3) δ170.4, 134.2, 133.4, 132.8, 132.2, 129.8, 129.3, 127.1, 127.0, 126.5, 125.9, 124.1, 123.3, 103.5, 94.4, 80.8, 79.0, 70.6, 70.2, 60.1, 28.2, 28.1, 22.5, 21.4; MS (+CI) m/z (relative intensity) 359 (M+H+, 4), 269 (100); HRMS (+EI) calcd for C24H22O3 (M+) 358.1569, found 358.1574.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[C:19](Cl)[CH:18]=[C:17](Cl)[CH:16]=2)=[C:6]1[C:23]([O-:25])=[O:24].[C:33]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)#[N:34].FC(F)(F)OC1C=CC(CBr)=CC=1>>[Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([C:33]#[N:34])=[CH:36][CH:37]=3)=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]1[C:23]([OH:25])=[O:24]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C([O-])c1c(-c2cc(Cl)cc(Cl)c2)c2cc(O)ccc2n1Cc1cc2c(cc1Cl)OCO2
Agent: FC(F)(F)Oc1ccc(CBr)cc1
Product: N#Cc1ccc(COc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2cc3c(cc2Cl)OCO3)cc1

Procedure:
Following the procedure of Example 26(c)-26(d), except substituting ethyl 1-(2-chloro-4,5-methylenedioxyphenylmethyl)-5-hydroxy-3-phenylindole-2-carboxylate for 1-(2-chloro-4,5-methylenedioxybenzyl)-3-(3,5-dichlorophenyl)-5-hydroxyindole-2-carboxylate and 4-cyanobenzyl bromide for 4-trifluoromethoxybenzyl bromide in step (c), the title compound was prepared as a white solid (41% overall). MS (MH-): 535.0