Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28](Cl)=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:31][C:32]([F:47])([F:46])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:31][C:32]([F:46])([F:47])[C:33]1[CH:34]=[C:35]([C:28]2[O:27][C:22]3=[C:23]([NH2:26])[N:24]=[CH:25][C:20]([C:18]4[CH:17]=[N:16][N:15]([C@H:12]5[CH2:13][CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11]5)[CH:19]=4)=[C:21]3[CH:29]=2)[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cc34)cn2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chlorofuro[2,3-c]pyridin-7-amine (83 mg, 0.18 mmol), 3,5-bis(trifluoromethyl)benzeneboronic acid (71 mg, 0.28 mmol), (1,1′-bis-(diphenylphosphino)ferrocene)palladium dichloride (13.5 mg, 0.0186 mmol), and potassium carbonate (77 mg, 0.56 mmol) in 1,4-dioxane (1.0 mL) and water (0.30 mL) was degassed 3× with argon and heated in a microwave reactor at 100° C. for 1 h. The mixture was partitioned between EtOAc and brine and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried over sodium sulfate and concentrated. Purification of the residue by ISCO chromatography (0 to 5% 7 N NH3/MeOH:DCM) afforded 104 mg (90%) of the title compound as a foam. 1H NMR (400 MHz, CDCl3): δ 0.06-0.14 (m, 6H) 0.87-0.98 (m, 9H) 1.49-1.64 (m, 2H) 1.85-2.11 (m, 4H) 2.18-2.33 (m, 2H) 3.69-3.82 (m, 2H), 4.17-4.28 (m, 1H), 5.05 (br. s., 1H) 7.34 (s, 1H) 7.70 (s, 1H) 7.82 (s, 1H) 7.92 (s, 1H) 8.00 (s, 1H) 8.31 (s, 2H); MS (ESI): 624.34 [M+H]+; HPLC tR=2.00 min (TOF: nonpolar—3 min).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.CN.[CH3:35][N:36](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][NH:36][C:15]([CH2:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:18][C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][C:29]([F:31])([F:30])[F:32])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Temperature: 0 °C
Yield: 98 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid methylcarbamoylmethyl-amide (47 mg) was prepared by following General Procedure F using {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetic acid (47 mg), methylamine (0.2 ml, 1.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 480.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([N:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=[C:31]3[C:30]([F:29])([F:41])[F:40])[N:3]=2)[CH2:24][CH2:25]1
Reactant: FC(F)(F)c1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(C(F)(F)F)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure D, 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 was reacted with 2-(trifluoromethyl)-1H-benzo[d]imidazole to give 156. 1H NMR (400 MHz, DMSO) δ 8.20 (d, J=8.6 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.94 (d, J=8.6 Hz, 2H), 7.56 (t, J=7.5 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 4.56 (s, 4H), 4.04 (s, 1H), 3.86-3.79 (m, 4H), 3.75 (s, 2H), 2.93 (d, J=11.0 Hz, 2H), 2.00 (t, J=10.9 Hz, 2H), 1.67 (d, J=12.1 Hz, 2H), 1.38-1.12 (m, 3H), 1.04 (s, 6H). LCMS: 556.3
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@@H:4]([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl>COCCOC>[CH3:3][C@@H:4]([O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(-c2ccc(C3CCC(=O)CC3)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(-c2ccc([C@H]3CC[C@H](O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 0.14 g of sodium borohydride in 10 ml of 1,2-dimethoxyethane was treated at 0° C. with a solution of 4-(4'-[(R)-2-octyl]oxycarbonyl-4-biphenylyl)cyclohexanone in 10 ml of 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature for a further 30 minutes and then treated with 25% hydrochloric acid. The reaction mixture was extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with sodium hydrogen carbonate solution and several times with water and subsequently dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized twice from hexane and gave 0.8 g of trans-4-(4'-[(R)-2-octyl]oxycarbonyl 4-biphenylyl)cyclohexanol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:11]=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
3-(Methylsulfonyl)benzoic acid (540 mg, 2.70 mmol) was dissolved in tetrahydrofuran (40 mL), and the resulting solution was cooled to 0° C. Then, lithium aluminum hydride (102 mg, 2.70 mmol) was added thereto, and the temperature of the resulting mixture was raised to room temperature, and the mixture was stirred for 3 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 70:30 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (257 mg, yield: 51%).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[CH2:19][C:18]1=[O:26]>>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[C:19]2[C:20]3[C:25](=[N:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2cccnc2N1
Reactant: COc1ccc(C=O)cc1C1CCCCC1
Product: COc1ccc(C=C2C(=O)Nc3ncccc32)cc1C1CCCCC1

Procedure:
3-Cyclohexyl-4-methoxybenzaldehyde was condensed with 7-aza-2-oxindole to give 0.25 g of 3-(3-Cyclohexyl-4-methoxybenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.IC.[CH3:30]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH3:30])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC)c12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.13 g), iodomethane (0.20 mL), N,N-dimethylformamide (1.0 mL) and potassium carbonate (0.14 g) were stirred at room temperature for 22 hours. The mixture was diluted with water and extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (1:19 to 19:1 by volume) gave title compound as a gum, 0.059 g.
Reaction SMILES: [CH:1]([N:3]1[C:8]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=O)=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2].[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[N:30]([CH3:31])[N:29]=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12>>[CH:1]([N:3]1[C:8]([C:9](=[N:13][O:14][CH3:15])[C:10]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]4[N:30]([CH3:31])[N:29]=[N:28][N:27]=4)[CH2:22][S:23][C@H:18]23)=[O:12])=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2]
Reactant: CON=C(C(=O)O)C1=CSCCN1C=O
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)C1=CSCCN1C=O

Procedure:
2-(4-Formyl-(2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 2.3 g.) was allowed to react with 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.3 g.) in a similar manner to that of Example 1 to give the captioned compound (2.5 g.), pale yellow powder, mp. 150° to 155° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[F:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(COc2cccnc2N)c(F)c1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1

Procedure:
A mixture of 2-amino-3-(2-fluoro-4-methoxylbenzyloxy)pyridine (1.00 g, 0.004 mol), 4chlorophenyl isothiocyanate (0.68 g, 0.0048 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield0.86g(51%),m.p.138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=[C:11]2[CH:10]([OH:26])[N:9]=1.[CH3:27]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=[C:11]2[CH:10]([O:26][CH3:27])[N:9]=1
Reactant: CO
Reactant: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(O)N=C2c1ccccc1Cl
Agent: O=S(=O)(O)O
Product: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(OC)N=C2c1ccccc1Cl

Procedure:
To a solution of 0.86 g. of 6-(2-chlorophenyl)-8-ethyl-4-hydroxy-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]-diazepine-2-carboxamide in 20 ml. of methanol is added one drop of concentrated sulfuric acid. The resulting mixture is refluxed for 5 minutes. After evaporation of the solvent a saturated sodium hydrogen carbonate solution is added to the residue, and the resulting precipitate is collected by filtration to give 6-(2-chlorophenyl)-8-ethyl-4-methoxy-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxamide as crystals melting at 200° to 201° C. This product is identical with the product obtained in Example 3 with respect to the melting point and infra red absorption spectrum thereof.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][CH:5]=1.Cl.[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[NH:23][CH2:22][C@@H:21]1[CH3:27])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[N:23]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][N:6]=2)[CH2:22][C@@H:21]1[CH3:27])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: COC(=O)c1ccc(F)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]2C)nc1

Procedure:
A mixture of 6-fluoronicotinic acid methyl ester (1.0 g, 6.4 mmol), (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester HCl (1.6 g, 6.4 mmol), and potassium carbonate (1.78 g, 12.9 mmol) were stirred in DMSO (10 mL) at 120° C. for 2 h, cooled, diluted with ethyl acetate (50 mL), washed with water (2×10 mL), dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[C:38]1[C:42]([C:43](Cl)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[C:38]1[C:42]([C:43]([O:1][CH:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=3)[CH2:10][CH2:11]2)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)OC(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 1H), 7.47 (m, 2H), 7.44-7.39 (m, 3H), 7.25 (m, 2H), 7.09 (s, 1H), 7.03 (m, 2H), 6.95 (m, 1H), 6.83 (m, 1H), 5.75 (t, 1H, J=7.1 Hz), 3.03 (t, 2H, J=7.2 Hz), 2.93 (m, 2H), 2.78 (s, 3H), 2.48 (m, 3H), 2.25 (m, 2H), 1.48 (m, 3H), 1.77 (m, 2H), 1.54 (m, 2H), 1.25 (d, 6H, J=7.3 Hz); ESMS m/e: 647.7 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[OH:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:11][CH2:12]1
Reactant: OB(O)c1ccncc1
Reactant: OCC1CCNCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: OCC1CCN(c2ccncc2)CC1
Reaction time: 48 h
Yield: 70 %

Procedure:
The mixture of 4-pyridineboronic acid (0.97 g, 7.8 mmol), 4-piperidinemethanol (1.82 g, 15.8 mmol), Cu(OAc)2 (2.88 g, 15.8 mmol), DMAP (catalytic amount), pyridine (2.5 mL, 32 mmol), 4A activated molecular sieve in 50 mL dry DCM was stirred for over 2 days. It was diluted with DCM, filtered through celite. It was washed with brine and water, dried, filtered through a silica plug, evaporated in vacuuo to give 4-(4-hydroxylmethylpiperidin-1-yl)pyridine in 70% yield. ES-MS: (M+H)+193.
Reaction SMILES: [CH:1]1([C:6]2[N:10]3[C:11]([CH2:21][CH3:22])=[N:12][N:13]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:9]3=[N:8][C:7]=2[OH:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([N:26]1[C:30]([CH2:31]O)=[N:29][CH:28]=[N:27]1)[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([C:6]2[N:10]3[C:11]([CH2:21][CH3:22])=[N:12][N:13]=[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:9]3=[N:8][C:7]=2[O:23][CH2:31][C:30]2[N:26]([CH2:24][CH3:25])[N:27]=[CH:28][N:29]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCn1ncnc1CO
Reactant: CCc1nnc(-c2ccccc2)c2nc(O)c(C3CCCC3)n12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nnc(-c2ccccc2)c2nc(OCc3ncnn3CC)c(C3CCCC3)n12

Procedure:
To a solution of the product of Example 12 a) (150 mg, 0.48 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (93 mg, 0.73 mmol) in tetrahydrofuran (5 ml) at 0° C. was added triphenylphosphine (192 mg, 0.73 mmol) followed by diethyl azodicarboxylate (110 μl, 0.73 mmol) dropwise with stirring. After 2 hours the tetrahydrofuran was evaporated in vacuo and the residue dissolved in dichloromethane (50 ml) and washed with water (2×20 ml). The organic phase was separated, dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by prep. TLC (SiO2; 30% ethyl acetate in isohexane), and the product recrystallised from ether/isohexane to afford 35 mg (17%) as a white solid. δH (400 MHz; CDCl3) 1.43 (3H, t, J 7.2), 1.57 (3H, t, J 7.2), 1.71 (2H, m), 1.84 (2H, m), 2.02 (4H, m), 3.37 (2H, q, J 7.3), 3.66 (1H, quin, J 8.7), 4.30 (2H, q, J 7.2), 5.66 (2H, s), 7.53 (3H, m), 7.92 (1H, s), 8.54 (2H, m); m/z (ES+) 418 (M++H, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][N:8]1[C:7]2[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[CH:4]=[CH:5][C:6]=2[S:10][C:9]1=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2sc(=O)[nH]c2c1C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1ccc2sc(=O)n(C)c2c1C
Yield: 84.3 %

Procedure:
A solution of 11.38 g (51 mmol) of methyl 4-methylbenzo-thiazol-2-one-5-carboxylate in 400 ml of acetone was admixed with 14.18 g of potassium carbonate. 5.1 ml (54 mmol) of dimethyl sulfate were then added dropwise with stirring, and the mixture was stirred at 23° C. for 78 hours. The precipitated solid was filtered off and the solvent was removed under reduced pressure. Recrystallization from ether gave, in a yield of 84%, 10.15 g (43 mmol) of methyl 3,4-dimethylbenzothiazol-2-one-5-carboxylate of m.p. 97° C.-100° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:13]([O-])=O.[Na+]>CC(O)=O.O>[F:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:9]=[N:13][NH:7]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=N[O-]
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc2cn[nH]c2cc1F
Temperature: 25 °C
Reaction time: 28 h
Yield: 42.4 %

Procedure:
The product of Step (b) (1.22 g, 7.17 mmol, 1.0 equiv) was dissolved In AcOH (62 mL). NaNO2 (0.495 g, 7.17 mmol, 1.0 equiv) was dissolved in H2O (1.5 mL) and added all at once via pipet. The reaction was warmed to room temperature and stirred for 28 hours. The reaction mixture was concentrated en vacuo to provide an orange solid, which was dried azeotropically several times with hexanes. The residue was purified by flash chromatography (linear gradient 20→60% EtOAc/hexanes) to afford 550 mg (43%) of the title compound. MS (ES+) m/e 182 [M+H].
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:28])[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:16]1)([CH3:10])([CH3:9])[CH3:8].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:7]([O:11][C:12](=[O:28])[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:26]=2)[CH2:16]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: Brc1ccccc1
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(Oc3ccccc3)cc2)C1
Temperature: 140 °C
Yield: 116.2 %

Procedure:
To a mixture of Cs2CO3 (70 mg; 0.21 mmol), 3-[2-(4-Hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (33.8 mg, 0.11 mmol) and bromobenzene (12.6 μL, 0.12 mmol) was added 0.5 mL of a freshly prepared catalyst stock solution (see below) in a 2-5 mL Biotage® microwave vial. The vial was briefly flushed with N2 and sealed to maintain a semi-inert atmosphere. The resulting mixture was heated for 22 h, at 140° C. After cooling to room temperature, water (5 mL) was added and the mixture was extracted with EtOAc (1×7.5 mL, 2×5 mL). The combined organic layers were concentrated in vacuo, and the residue was purified by preparative TLC (SiO2, CH2Cl2/MeOH 99:1) to afford 3-[2-(4-phenoxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (49 mg). The catalyst stock solution was prepared as follows: To a suspension of copper(I)iodide (73 mg, 0.16 mmol) in anhydrous toluene (9 mL) was added 1-butylimidazole (127 μL; 120 mg; 0.41 mmol). The solution was purged with N2 for 15 min. and vigorously agitated until all the CuI had fully dissolved.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>CN(C=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:6][CH2:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:23]
Reactant: CCOC(=O)NCCc1ccc(C)o1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CCc1ccc(C)o1)C(=O)OCC
Yield: 95.8 %

Procedure:
Ethyl[2-(5-methylfuran-2-yl)ethyl]carbamate (0.60 g) prepared in the step 3 was dissolved in 6 mL of DMF, 0.15 g of 60% sodium hydride was slowly added thereto with stirring and ice-cooling and the mixture was stirred at room temperature for 1 hour more. Ethyl bromoacetate (0.40 g) was slowly dropped into the reaction solution under cooling with ice and the mixture was made back to room temperature followed by stirring overnight. The reaction solution was poured over 20 mL of water followed by extracting with diethyl ether. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.65 g of the objective compound as pale yellow liquid.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>C(O)(=O)C>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc[nH]n1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Solvent: CC(=O)O
Product: CC(C)(C)C1=CC(=Nc2cc[nH]n2)C=C(C(C)(C)C)C1=O
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A mixture of 5.3 g of 2,6-di-tert-butyl-1,4-benzoquinone, 2.1 g of 3-aminopyrazole and 16 drops of acetic acid was heated with stirring at 110° C for 15 minutes. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (eluent: diethyl ether-chloroform=1:20), giving 5.5 g of 2,6-di-tert-butyl-4-(3-pyrazolylimino)-2,5-cyclohexadien-1-one (Compound 34a) as a pale red solid.