Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.COC(N1C2C(=C(NC(NC3C4C(=CC(C(C)(C)C)=CC=4)OCC3)=O)C=CC=2)C=N1)=O>O>[O:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]([NH:17][C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[CH:7]=[N:6][NH:5]3)=[O:16])[CH2:19][CH2:20]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4ccccc43)cccc21
Agent: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc21
Solvent: O
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCOc2ccccc21

Procedure:
The title compound was prepared according to the procedure as described in Example 1E, substituting the product of Example 16C for the product of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 13.00 (broad s, 1H), 8.58 (s, 1H), 8.03 (s, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.20 (m, 2H), 7.05 (d, J=6 Hz, 1H), 6.95-6.80 (m, 3H), 4.90 (m, 1H), 4.30-4.17 (m, 2H), 2.20-2.00 (m, 2H). MS (DCI) m/e 309 (M+H)+. Calcd. For C17H16N4O2.0.6; H2O: C, 63.98; H, 5.43; N, 17.56. Found: C, 63.85; H, 5.07; N, 17.62.
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)=[CH:15][O:16][C:11]=2[CH:10]=1)[CH3:7])=[O:5])C.O1CCOCC1.Cl>O>[OH:5][C:4]([CH:6]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)=[CH:15][O:16][C:11]=2[CH:10]=1)[CH3:7])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ccc2c(=O)c(-c3cccc(O)c3)coc2c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1ccc2c(=O)c(-c3cccc(O)c3)coc2c1)C(=O)O
Temperature: 0 °C
Yield: 90.5 %

Procedure:
A mixture of 3.0 g of 7-(1-ethoxycarbonylethyl)oxy-3-(3-hydroxyphenyl)-4H-1-benzopyran-4-one, 90 ml of dioxane, 120 ml of water and 15 ml of hydrochloric acid was refluxed for 2.5 hours, poured into ice water and extracted with ethyl acetate. The extract was washed with water and concentrated and the residue was recrystallized from ethyl acetate-dichloroethane to give 2.5 g of 7-(1-hydroxycarbonylethyl)oxy-3-(3- hydroxyphenyl)-4H-1-benzopyran-4-one as white crystals. m.p. 218°-219° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29](C)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[N:33]1(S(N2CCNCC2)(=O)=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(N1CCCCC1)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Yield: 87 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b), and 1-(piperidin-1-yl-sulfonyl)-piperazine to afford the desired product as a light-brown solid (87%). MS (ISP): 531.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[Mg]Br.[C:13]1(=[O:17])[CH2:16][CH2:15][CH2:14]1.Cl>C(OCC)C>[OH:17][C:13]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: O=C1CCC1
Agent: Cl
Solvent: CCOCC
Product: OC1(c2ccc3ccccc3c2)CCC1

Procedure:
To a mixture of 23.1 g. of 2-naphthyl magnesium bromide and 250 ml. of diethyl ether, 7 g. of cyclobutanone are slowly added. After the addition, the mixture is refluxed for one hour, cooled, acidified with aqueous hydrochloric acid and filtered. The product was isolated by methylene chloride extraction to furnish 2-(1'-hydroxycyclobutyl)-napthalene. The product is hydrogenated in 200 ml. of ethanol with a molar equivalent of hydrogen in the presence of 50 g. of Raney nickel; the reaction mixture is filtered after the hydrogenolysis and evaporated to furnish 2-cyclobutylnaphthalene.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:12]1[C:20]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:19][C:18]2[C:13]1=[N:14][C:15]([C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1)=[N:16][C:17]=2[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH:9]([CH3:11])[CH3:10].[CH3:40][N:41]1[CH2:45]CC[C:42]1=[O:46]>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:15]2[N:14]=[C:13]3[C:18]([N:19]=[C:20]([N:21]4[CH2:26][CH2:25][N:24]([C:42]([N:41]([CH3:45])[CH3:40])=[O:46])[CH2:23][CH2:22]4)[N:12]3[CH2:8][CH:9]([CH3:11])[CH3:10])=[C:17]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:16]=2)=[CH:34][N:35]=1
Reactant: CN1CCCC1=O
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(N2CCN(C(=O)N(C)C)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 24 h
Yield: 43 %

Procedure:
Triethylamine (64 μl) and 2-acetamide-4-dimethylcarbamoyl chloride (35 μl) were added to an N-methylpyrrolidone solution (1 ml) of 5-(9-isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-ylamine (100 mg) and the resulting mixture was stirred for 24 hours. The reaction mixture was partitioned with ethyl acetate and water, the insoluble solid was collected by filtration, and then the organic layer of the filtrate was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was combined with the solid separately collected by filtration followed by the addition of dimethyl sulfoxide (3 ml) and water (3 ml), the resulting mixture was stirred, and the insoluble matter was collected by filtration, washed with water, and dried to give the title compound (50 mg, 43%) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3([OH:28])[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[CH:13][C:12]=2[CH3:29])=[CH:9][C:8]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[C:34]([F:45])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO.O1CCCC1.[Cl-].[Na+].O>[C:1]([NH:4][C:5]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3([OH:28])[CH2:21][CH2:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25]3)=[CH:13][C:12]=2[CH3:29])=[CH:9][C:8]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[C:34]([F:45])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(NC(C)=O)c(-c3c(C)cc(OCC4(O)CCS(=O)(=O)CC4)cc3C)c2)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1-c1c(C)cc(OCC2(O)CCS(=O)(=O)CC2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of ethyl 3-{4-[({6-(acetylamino)-4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)amino]-2-fluorophenyl}propanoate (173 mg, 0.27 mmol) in a mixture of methanol (1 mL) and tetrahydrofuran (2 mL) was added 1 M aqueous sodium hydroxide solution (0.81 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1 M hydrochloric acid, and brine was added. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate/methanol=9/1) to give the title compound (103 mg, yield 62%) as a yellow amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:13][C:14]2[CH:15]=[C:16]([C:20]3([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:12])[CH2:10][CH3:11].[CH3:28]I>>[Cl:1][C:2]1[CH:3]=[C:4]([S:13][C:14]2[CH:15]=[C:16]([C:20]3([O:26][CH3:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[N:8]([CH3:28])[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)Nc1ccc(Sc2cccc(C3(OC)CCOCC3)c2)cc1Cl
Reactant: CI
Product: CCC(=O)N(C)c1ccc(Sc2cccc(C3(OC)CCOCC3)c2)cc1Cl
Yield: 67 %

Procedure:
Using a similar procedure to that described in Example 18, 4-[3-(3-chloro-4-propionamidophenylthio)phenyl]-4-methoxytetrahydropyran was reacted with methyl iodide to give 4-[3-(3-chloro-4-(N-methylpropionamido)phenylthio)phenyl]-4-methoxytetrahydropyran in 67% yield as a gum.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH:15]([F:22])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]>>[CH2:29]([C:31]1[N:32]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][C@H:16]([N:19]([CH3:20])[CH3:21])[C@H:15]([F:22])[CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: CN(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@H](N(C)C)[C@H](F)C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, racemic 1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-fluoro-N,N-dimethylpiperidin-4-amine and 2-ethylbenzimidazole were reacted. The enantiomers were separated by SFC to give 226. LCMS m/z: 522.3 (MH+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:57])([F:56])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:55])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:27]=3)[C@H:20]2[CH3:55])[CH:10]=[C:9]([C:8]([F:7])([F:57])[F:56])[CH:14]=1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CCOCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
Morpholine (207 μl, 2.369 mmol), methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (INTERMEDIATE 46, 350 mg, 0.474 mmol), and THF (2.4 mL) were stirred at 100° C. for 10 minutes in the microwave reactor, at which time LCMS shows complete conversion to target. The reaction was partitioned between water and ethyl acetate. The organic was then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude isolate was purified by silica gel chromatography, eluting with 25-100% ethyl acetate/hexanes to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ 8.20 (d, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.92 (d, 1H), 7.88 (s, 1H), 7.72 (s, 2H), 7.46 (d, 1H), 7.31 (d, 1H), 5.63 (d, 1H), 4.74 (d, 1H), 4.31 (m, 1H), 4.00 (m, s, 4H), 3.94 (s, 3H), 3.86 (m, 4H), 3.80 (m, 4H), 2.37 (s, 3H), 0.72 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.O.[NH2:10][NH2:11]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][NH2:11])=[N:6][CH:7]=1
Reactant: NN
Reactant: Clc1ccc(Br)cn1
Solvent: O
Product: NNc1ccc(Br)cn1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
A mixture of 5-bromo-2-chloropyridine (11.5 g, 60 mmol) and hydrazine hydrate (100 mL) was refluxed under Argon for 2 h. The mixture was cooled to room temperature, filtered and the solids were washed with water (50 mL×3), dried to give the title compound (8.30 g, 74.4% yield) as yellow solids. MS: m/z 188.0 [M+H+].
Reaction SMILES: C(#N)C.[CH3:4][O:5][C:6]([C:8]1[C@H:9]2[CH2:17][C@@H:16]3[O:18][C@:15]3([CH3:19])[C@@H:10]2[CH:11]([OH:14])[O:12][CH:13]=1)=[O:7].C(N(CC)CC)C.[CH3:27][N:28]=[C:29]=[O:30]>CCCCCC.C(OCC)(=O)C>[CH3:4][O:5][C:6]([C:8]1[C@H:9]2[CH2:17][C@@H:16]3[O:18][C@:15]3([CH3:19])[C@@H:10]2[C@H:11]([O:14][C:29](=[O:30])[NH:28][CH3:27])[O:12][CH:13]=1)=[O:7]
Reactant: CN=C=O
Reactant: COC(=O)C1=COC(O)[C@@H]2[C@@H]1C[C@@H]1O[C@@]12C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.7 %

Procedure:
An acetonitrile solution containing 790 mg of a known (4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-1-hydroxy-7-methylcyclopenta[c]pyrane-4-carboxylic acid methylester was cooled with ice followed by addition of 0.54 ml of triethylamine and 0.23 ml of methylisocyanate and stirring for 15 hours at room temperature. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]pyrane-4-carboxylic acid methylester (610 mg, yield: 61.7%). The physicochemical properties of this compound are described in Table 1, Compound No. 3.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH2:13][CH:14]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:23][CH:22]=2)[C:15](OCC)=[O:16])[O:12][CH2:11][CH2:10][O:9]1.C(OCC)(=O)C.[OH-].[Na+]>CCOCC.O>[CH3:7][C:8]1([CH2:13][CH:14]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:25][CH:26]=2)[CH2:15][OH:16])[O:9][CH2:10][CH2:11][O:12]1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(CC2(C)OCCO2)C(=O)OCC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc(CC(CO)CC2(C)OCCO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a suspension of about 2.38 g of lithium aluminum hydride in about 40 ml of ether was added dropwise, over about 1/2 hour, a solution of about 20.5 g of 2-methyl-α-[[4-(tetradecyloxy)phenyl]methyl]-1,3-dioxolane-2-propanoic acid, ethyl ester in about 70 ml of ether at about 0° C. The mixture was stirred about 1/2 hour at room temperature, recooled to about 0° C. and about 10 ml of ethyl acetate, about one ml of water, about 2 ml of about 15% sodium hydroxide and about 3 ml of water were added dropwise. The mixture was filtered through celite, the solids were washed with ether and the ether removed from the combined solutions, which was then purified by HPLC, using the system hexane:ethyl acetate (about 3:7), giving a colorless oil which solidified on standing, giving about 15.28 g of the desired title compound, mp 28°-29° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[BH4-].[Na+].C([OH:35])C>>[CH2:29]([O:28][C:26]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9][C:8](=[O:35])[N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(CO)cc2)nc1
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of 1-[6-(4-formyl-phenoxy)-pyridin-3-yl]-pyrolidine-2,2-dicarboxylic acid diethyl ester (1.0 g, 2.3 mmol) in 30 mL of ethanol was added sodium borohydride (0.090 g, 2.3 mmol) at 0° C. After stirring for 3 hours, the mixture was concentrated in vacuo, diluted with ethyl acetate and water, and the aqueous layer was cautiously acidified with 1M hydrochloric acid, then neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, affording 0.80 g (80%) of 1-[6-(4-hydroxymethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup. 1H NMR (CDCl3, 400 MHz): 8.04 (d, 1H, J=2.4 Hz), 7.72 (dd, 1H, J=2.4, 8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 7.12 (d, 2H, J=8.4 Hz), 6.91 (d, 1H, J=8.8 Hz), 4.70 (s, 2H), 4.19 (q, 4H, J=7.6 Hz), 2.75 (m, 2H), 2.65 (m, 2H), 1.18 (t, 6H, J=7.2 Hz) ppm. MS (APCl, m/z): 429.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:12][OH:13].O.O.O.C([O-])(=O)C.[Na+].C(OCC)(=O)C>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[N:12][OH:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NO
Reactant: O=Cc1ccc2[nH]cnc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: ON=Cc1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1H-benzo[d]imidazole-5-carbaldehyde (0.57 mmol, 1 eq.) was dissolved in 5 mL methanol, hydroxylamine (0.68 mmol, 1.2 eq.) and sodium acetate trihydrate (0.68 mmol, 1.2 eq.) were added. The mixture was stirred for 1 hour at ambient temperature. 20 mL Ethyl acetate was added and the organic layer was washed with 20 mL of brine. The organic layer was dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure. The product was purified by means of flash-chromatography using silica gel and a ethyl acetate/MeOH-gradient.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][N:13]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32](Cl)=[N:31][CH:30]=2)[CH2:24][CH2:23]1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH3:12][N:13]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[N:31][CH:30]=2)[CH2:24][CH2:23]1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)nc2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 15.1 %

Procedure:
1.16 g of 1,2,4-triazole and 1.16 g of potassium carbonate were added to a solution of 2.00 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-(6-chloronicotinoyl)piperidine in 10 ml of dimethyl sulfoxide. The container inside was purged with nitrogen and the container contents were stirred at 100° C. for 4 hours. The reaction mixture was cooled and water was added thereto. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluant: methylene chloride/methanol=150/1). The product was subjected to crystallization from diethyl ether and then to recrystallization from ethyl acetate-diethyl ether to obtain 0.33 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[6-(1,2,4-triazol-1-yl)nicotinoyl]piperidine as a white powder.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>CO.C(Cl)Cl>[C:16]1([S:15][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:1][NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=4)[CH:4]=3)[NH:8][C:7]=2[C:12]([NH2:14])=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1[nH]c2ccc(CNc3cccc(C(F)(F)F)c3)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 3-trifluoromethylaniline (80 mg, 0.50 mmol) as described in General Procedure X to afford Iac (36 mg, 48.3%) as an ivory colored solid, tlc Rf=0.5 (5% MeOH/CH2Cl2), m/z obs=442 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([NH:16][CH2:17][C:18](O)=[O:19])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>ClCCl>[O:19]=[C:18]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:17][NH:16][C:6](=[O:7])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: C1CCNC1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCC(=O)N1CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Pyrrolidine (248 uL, 3 mmol), N-CBZ-glycine (628 mg, 3 mmol), and HOAt (408 mg, 3 mmol) were dissolved in 10 mL of dichloromethane. NMM (0.66 mL, 6 mmol) was added, followed by EDC (575 mg, 3 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous NaHCO3 solution, and saturated aqueous NH4Cl solution, then dried (Na2SO4) and evaporated to yield phenylmethyl [2-oxo-2-(1-pyrrolidinyl)ethyl]carbamate as a beige solid (782 mg, 100%). LCMS: (M+H)+: 263.1.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([OH:12])=O)[N:8]=1)=[O:2].CN(C)C=O.P(Cl)(Cl)(Cl)=O.Cl.[NH2:32][CH:33]1[C:54](=[O:55])[N:35]2[C:36]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])=[C:37]([Cl:40])[CH2:38][S:39][C@H:34]12>C(OCC)(=O)C.CC(C)=O.O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([NH:32][CH:33]2[C:54](=[O:55])[N:35]3[C:36]([C:41]([O:43][CH2:44][C:45]4[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=4)=[O:42])=[C:37]([Cl:40])[CH2:38][S:39][C@H:34]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CCCCCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 90.2 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 3.24 g.), N,N-dimethylformamide (0.951 g.), and phosphoryl chloride (2.00 g.) in ethyl acetate (20 ml.), and a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (4 g.) in a mixture of acetone (20 ml.), water (20 ml.) and tetrahdrofuran (40 ml.) were treated in a similar manner to that of Example 21-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.78 g.).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[C:23]([Cl:30])[CH:22]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:31][C:32]#[N:33].[Na+]>>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:11][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:13][CH:14]=2)[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[C:23]([Cl:30])[CH:22]=2)=[N:33][C:32]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2ccccc2)c(C(=O)c2ccc(C(C)C)c(Cl)c2)c1
Agent: [Na+]
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)c(Cl)c1)nc(=O)n2Cc1ccccc1

Procedure:
The title compound is prepared from (2-benzylamino-5-prop-2-ynyloxy-phenyl)-(3-chloro-4-isopropylphenyl)-methanone (hydrochloric acid salt) by cyclisation with sodium cyanate analogously to the method described for the preparation of example 62.