Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH:26]1([N:29]([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=2)[CH2:28][CH2:27]1>>[CH:26]1([N:29]([CH3:37])[C:30]2[N:31]=[CH:32][C:33]([NH:36][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])=[N:13][C:12]=3[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:34][CH:35]=2)[CH2:28][CH2:27]1
Reactant: CN(c1ccc(N)cn1)C1CC1
Reactant: CCCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(-c2ccccc2Cl)oc1C(=O)Nc1ccc(N(C)C2CC2)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-cyclopropyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H23ClN4O2 (m/e) 410, obsd 411 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[C:18]([CH3:28])[C:17]2=[O:29])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[C:18]([CH3:28])[C:17]2=[O:29])[CH2:12][CH2:13]1
Reactant: COc1ccc2nc(C)c(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nc(C)c(=O)n(CCN3CCC(N)CC3)c2c1
Yield: 98.8 %

Procedure:
tert-Butyl{1-[2-(7-methoxy-3-methyl-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 160, 100 mg, 0.24 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 75 mg (99% yield) of the crude product as an oil.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[F:5][C:6]([F:17])([F:16])[O:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15].N1C=CC=CC=1>C(Cl)Cl>[O:15]=[C:11]1[N:10]([CH2:9][CH2:8][O:7][C:6]([F:17])([F:5])[F:16])[CH2:14][CH2:13][N:12]1[C:1]([Cl:4])=[O:2]
Reactant: O=C1NCCN1CCOC(F)(F)F
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1CCN(CCOC(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20 wt % in toluene, 0.497 mL, 0.945 mmol) in DCM (4 mL) was treated slowly with a solution of 1-(2-(trifluoromethoxy)ethyl)imidazolidin-2-one (0.156 g, 0.787 mmol) and pyridine (0.127 mL, 1.575 mmol) in DCM (4 mL), stirred for 1 h at 0° C., then concentrated to dryness to afford 2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carbonyl chloride (100% yield assumed). MS [quenched in MeOH] (ESI) m/z: 257.1 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([CH:27]=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](Cl)(=O)C.[Sn](Cl)(Cl)(Cl)Cl.O>ClCCl>[CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](=[O:28])[CH3:31])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)Cl
Reactant: O=Cc1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
10-(4-Cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbaldehyde of Step A (3.7 g) dissolved in dichloromethane (75 mL) was treated with acetyl chloride (1.9 g) and tin (IV) chloride in dichloromethane (12.5 mL, 1N). After stirring overnight at room temperature, water was added. The organic solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and filtered through a short column of Magnesol® to provide the desired title compound as a pale yellow amorphous solid (1.3 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:39]=[C:38]([Cl:40])[C:21]([O:22][CH:23]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[C:24]([O:26]CC)=[O:25])=[C:20]([Cl:41])[CH:19]=1>CN(C=O)C>[C:24]([CH:23]([C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[O:22][C:21]1[C:20]([Cl:41])=[CH:19][C:18]([CH2:17][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:13])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:39][C:38]=1[Cl:40])([OH:26])=[O:25]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CCOC(=O)C(Oc1c(Cl)cc(CBr)cc1Cl)c1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cc(Cl)c(OC(C(=O)O)c2ccc3c(c2)OCO3)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a solution of 0.034 g (0.20 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine in 0.5 mL anhydrous DMF was added 8.6 mg (0.22 mmol) of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. A solution of 0.100 g (0.22 mmol) of the product of Step B in 0.9 mL of DMF was added and the reaction was stirred an additional 1.5 hour at room temperature. The reaction mixture was partitioned between EtOAc and 5% aqueous NH4Cl, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.081 g (74%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[NH2:23][C:24]1[C:29]2[N:30]=[CH:31][N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[C:28]=2[C:27]([CH3:38])=[C:26]([CH3:39])[N:25]=1.C(N(CC)CC)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[NH2:23][C:24]1[C:29]2[N:30]=[CH:31][N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([CH:6]([O:5][CH2:4][CH2:3][N:2]([CH3:22])[CH3:1])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:8][CH:9]=3)[C:28]=2[C:27]([CH3:38])=[C:26]([CH3:39])[N:25]=1
Reactant: CN(C)CCOC(c1ccccc1)c1ccc(C(=O)Cl)cc1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2ncn(CCCCNC(=O)c3ccc(C(OCCN(C)C)c4ccccc4)cc3)c2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[[2-(Dimethylamino)ethoxy](phenyl)methyl]benzoyl chloride (1 equivalent) was added dropwise to a suspension of 4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butan-1-amine (0.22 g) in N,N-dimethylformamide (7 ml). At 1 hour, triethylamine (2 equivalents) was added followed by the addition at 2 hours of a small amount (approx. 10 mole %) of 4-dimethyaminopyridine. The reaction was maintained at room temperature overnight. The resulting mixture was poured into water and the pH was adjusted to 13. The aqueous fraction was extracted with chloroform (3×). The combined organic fractions were sequentially washed with water and brine; dried (magnesium sulfate); filtered; and concentrated to yield a yellow oil. The crude product was submitted to flash column chromatography [30 g silica gel, gradient elution:dichloromethane:methanol:triethylamine (100:0:0 to 97:2:1 to 92:7:1). A final HPLC purification using the method described above provided 83 mg of N-[4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide as a trifluoroacetate salt.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (2 gr, 6.22 mmol), (prepared as described for the starting material in Example 10), and 4-fluoro-5-hydroxy-2-methylindole (1.23 g, 7.46 mmol) in DMF (30 ml) containing potassium carbonate (1.28 g, 9.33 mmol) was stirred at 95° C. for 2 hours. After cooling, the volatiles were removed under vacuum and the residue was triturated with ether, filtered and dried under vacuum. The residue was purified by column chromatography eluting with methanol/methylene chloride (1/9) followed by methanol/methanol saturated with ammonia/methylene chloride (20/1/79 followed by 20/5/75). The fractions containing the expected product were combined and evaporated. The solid was triturated with methanol, filtered and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (1.95 g, 69%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>>[N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:19][CH:21]2[O:23][CH2:22]2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: ClCC1CO1
Reactant: Oc1ccccc1-n1cccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-n2cccc2)c(OCC2CO2)c1
Reaction time: 6 h

Procedure:
95.7 g of o-(pyrrol-1-yl)-phenol, 245 g of potassium carbonate and 167 g of epichlorohydrin are heated to the boil in a nitrogen atmosphere, whilst stirring. After 6 hours, the reaction mixture is cooled and filtered and the filtrate is evaporated in vacuo, ultimately at a bath temperature of 120° C. The oil which remains is dissolved in 300 ml of ether and the solution is extracted with 300 ml of 2 N sodium hydroxide solution and washed with 100 ml of water. The oil which remains after evaporating off the solvent is distilled in a high vacuum and gives 1-[o-(pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane of boiling point 103°-105° C/0.001 mm Hg.
Reaction SMILES: O=[C:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:4]2[CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:17]([NH:24][CH:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:4]2[CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC(NCc3ccccc3)CC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (9.57 g, 42.5 mmol) in DCM (170 mL) were added BnNH2 (4.56 g, 42.5 mmol) and AcOH (2.55 g, 42.5 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 0.5 h. Then NaBH(OAc)3 (18.00 g, 85.0 mmol) was added to the above mixture and the resulting mixture was stirred at rt for another 20 h, then quenched with saturated NaHCO3 solution (142 mL), and extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL×3), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a yellow solid (7.44 g, 55.3%).
Reaction SMILES: [H][H].[CH3:3][C:4]([NH:7][CH2:8][CH:9]([OH:19])[C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH2:16][OH:17])[CH:15]=1)([CH3:6])[CH3:5].[ClH:20].CCOCC>C(O)C.[Pd].C(OC)(C)(C)C>[CH3:6][C:4]([NH:7][CH2:8][C@H:9]([OH:19])[C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH2:16][OH:17])[CH:15]=1)([CH3:3])[CH3:5].[ClH:20]
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(CO)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)NC[C@H](O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of (R)-4-benzyl albuterol from Example-3 (6.6 g, 20 mmol) and 10% Pd/C (1.32 g) in 50 mL of ethanol (denatured with 5 vol % 2-propanol) is shaken on a Parr-hydrogenator under 50 psi of hydrogen at room temperature for 2-3 hours. The catalyst is removed by filtration and the filtrate is concentrated to give crude (R)-albuterol (compound IIIa). The crude albuterol (20 mmol) is dissolved in 20 mL of ethanol and treated with anhydrous HCl in ether (1.0M, 19 mL, 0.95 eq) at 0°-5° C. After 30 min at room temperature, 20 mL of methyl t-butyl ether (MTBE) is added to the mixture and the resulting mixture is stirred at room temperature for 30 min and at 0°-5° C. for 2 hours. The white solid (R)-albuterol hydrochloride (compound IIIb) is collected by filtration and recrystallized from 52 mL of ethanol and 26 mL of MTBE to give pure (R)-albuterol hydrochloride as a white powder (4.6 g, 83.5% yield, 99.6% ee, 99.3% purity).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>>[C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: O=C(O)CCCCC(=O)O
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(CCCCC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
A 3 L flask equipped with a stirrer, a thermometer, and a dehydration tube was charged with 438 g of adipic acid, 779 g of benzyl alcohol, and 5.7 g of paratoluenesulfonic acid monohydrate, and the components were reacted at 120° C. for 4 hours under a reduced pressure of from 6 to 10.7 kPa, while blowing nitrogen (500 mL/minute) into a space portion. The reaction mixture had an acid value of 1.2 (KOH mg/g). Eight grams of an adsorbent KYOWAAD 500SH (manufactured by Kyowa Kagaku Kogyo) was added to the reaction mixture, and the mixture was stirred at 80° C. and 2.7 kPa for 45 minutes. Thereafter, benzyl alcohol was distilled off at a liquid temperature of from 120° to 183° C. and a pressure of 0.27 kPa, and cooled to 80° C., and the residue was filtered under a reduced pressure, to provide dibenzyl adipate as a filtrate. The resulting dibenzyl adipate had an acid value of 0.16 (KOH mg/g), a saponification value of 512 (KOH mg/g), a hydroxyl value of 1 or less (KOH mg/g), and a hue APHA of 80.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15])=[O:4].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:15][C:7]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: Cc1c(NC(=O)CBr)cccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-N-(2-methyl-3-nitrophenyl)acetamide (0.5 g, 1.8 mmol) was dissolved in 15 ml of THF and to this was added morpholine (0.17 g, 2.0 mmol) and diisopropylethylamine (0.71 g, 5.5 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was then partitioned between EtOAc and H2O. The aqueous mixture was extracted with EtOAc, and the combined organic layers were washed with H2O, brine and then dried over MgSO4. Solvent evaporation afforded N-(2-methyl-3-nitrophenyl)-2-morpholinoacetamide as a yellow solid.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([C:27]1[N:35]=[C:22]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[CH:20][CH:21]=3)[CH2:13][N:8]([C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:9]2)[O:23][N:26]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(Cc1ccccc1)=NO
Product: CCc1ccc(C2CC(c3nc(Cc4ccccc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 50 mg (56% of theory)
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[N:38]=[CH:39][S:40][CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:38]=[CH:39][S:40][CH:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Brc1cscn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cscn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-thiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])[S:5][C:6]=1[Cl:7].[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1B(O)O.CCN(C(C)C)C(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:7][C:6]1[S:5][C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])=[CH:3][C:2]=1[C:27]1[CH:28]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=1[F:29]
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1O
Reactant: OB(O)c1cc(F)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(NS(=O)(=O)c2cc(-c3cc(F)ccc3F)c(Cl)s2)c1O
Reaction time: 8 h
Yield: 43.5 %

Procedure:
A mixture of 3-{[(4-bromo-5-chlorothiophen-2-yl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 22) (20.6 mg, 0.050 mmol), 2,5-difluorophenylboronic acid (8.7 mg, 0.055 mmol), DIPEA (35 μL, 0.200 mmol) and Pd(dppf)Cl2.CH2Cl2 (2 mg, 0.003 mmol) in aqueous dioxane (1 mL, 9:1 dioxane/water) was heated at 80° C. under nitrogen atmosphere over night. The reaction mixture was acidified by addition of TFA (50 μL). After being allowed to settle overnight the reaction mixture was filtered, diluted with MeOH and purified by reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, gradient: 0.1% TFA in water/MeCN over 6 minutes) to give 9.7 mg of the title compound (44%). 1H NMR (500 MHz, MeOH-d4) δ ppm 6.90 (t, J=7.94 Hz, 1 H) 7.14 (dddd, J=8.67, 5.60, 2.93, 0.46 Hz, 1 H) 7.16-7.21 (m, 1 H) 7.20-7.25 (tdd, J=8.96, 4.60, 0.46 Hz, 1 H) 7.34 (d, J=1.59 Hz, 1 H) 7.65 (dd, J=7.94, 1.65 Hz, 1 H) 7.74 (dd, J=7.94, 1.65 Hz, 1 H); MS (ESI+) m/z 446 [M+H]+.
Reaction SMILES: [CH2:1](O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:23][CH2:24][C:25]1([CH3:44])[O:29][N:28]=[C:27]([S:30][CH2:31][C:32]2[C:33]([C:40]([F:43])([F:42])[F:41])=[N:34][N:35]([CH2:38][CH3:39])[C:36]=2[OH:37])[CH2:26]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C.O>[Cl:23][CH2:24][C:25]1([CH3:44])[O:29][N:28]=[C:27]([S:30][CH2:31][C:32]2[C:33]([C:40]([F:43])([F:42])[F:41])=[N:34][N:35]([CH2:38][CH3:39])[C:36]=2[O:37][CH2:1][CH3:2])[CH2:26]1
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1O
Reactant: CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(CSC2=NOC(C)(CCl)C2)c(C(F)(F)F)nn1CC
Reaction time: 1 h
Yield: 86.4 %

Procedure:
0.3 g (5.4 mmoles) of ethanol and 1.4 g (5.4 mmoles) of triphenylphosphine were added, at room temperature, into a solution of 1.6 g (4.5 mmoles) of 5-chloromethyl-3-(1-ethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazoline dissolved in 20 ml of tetrahydrofuran. Thereto was added, with ice-cooling, 1.1 g (5.4 mmoles) of diisopropyl azodicarboxylate. The mixture was stirred for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.5 g (yield: 86.8%) of 5-chloromethyl-3-(5-ethoxy-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[C:15](=[O:21])[NH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22]([O:26][C:27](=[O:30])[CH2:28]Br)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27](=[O:30])[CH2:28][N:16]1[C:17]([CH3:20])=[CH:18][CH:19]=[C:14]([NH:13][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[C:15]1=[O:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Sodium hydride (5.3 g, 0.22 mol) was added to a stirred slurry of 3-benzyloxycarbonylamino-6-methyl-2-pyridinone (16-2; 53.2 g, 0.20 mol) in THF at 0° C. t-Butylbromoacetate (45 ml, 0.27 mol) was added to the resulting solution and a precipitate rapidly forms. The reaction was warmed to rt over 1 h and after 2 h the solvent was evaporated in vacuo and the residue was partitioned between 1:1 water/brine (200 ml) and 6:1 THF/methylene chloride (700 ml). The organic layer was dried (Na2SO4) and evaporated in vacuo to a solid which was triturated with hexane to give the title compound 16-3 as a crystalline solid:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.N.C[N:25]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:16])[NH2:25]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(=O)O)C1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A stirred solution of 2-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]benzoic acid a1-3 (5.5 g, 19 mmol, 1 eq) in dichloromethane (150 ml) is saturated, at 0° C., with gaseous ammonia NH3 for 1 hour. BOP reagent (8.82 g, 19.9 mmol, 1.05 eq) is added portionwise to this solution. The reaction mixture is warmed to room temperature and stirred overnight. The reaction mixture is filtered off and the solid washed with dichloromethane (100 ml). The organic layer is evaporated under vacuum and the residue obtained is purified by chromatography over silicagel (eluent: CH2Cl2/MeOH 98.5/1.5) to give 5.4 g of tert-butyl 3-(2-carbamoylphenyl)pyrrolidine-1-carboxylate a1-4.