Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]1([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH:2]1([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Oc1ccc(C=NC2CCCCC2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=NC2CCCCC2)cc1
Reaction time: 15 h
Yield: 50.7 %

Procedure:
(a) To 70 ml of absolute ethanol is added 872 mg of sodium, and 7 g of 4-(N-cyclohexylformimidoyl)phenol is added to the solution. Subsequently, 7.4 g of ethyl 2-bromo-2-methylpropionate is further added. The mixture is refluxed under heating and with stirring for 15 hours. After distilling off the ethanol from the reaction mixture, water is added to the residue, and the solution is extracted three times with benzene. The extract is washed with water twice, with cooled dilute aqueous solution of sodium hydroxide three times and then with water twice. After drying the resulting solution over magnesium sulfate, the solvent is distilled off to give 5.54 g of ethyl 2-[4-(N-cyclohexylformimidoyl)phenoxy]-2-methylpropionate as an oil.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:20])[CH2:17][CH:18]=[CH2:19]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: C=CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: C=CCCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-but-3-enyloxy-3-(1H-indol-5-yl)-propionic acid methyl ester (preparation 9) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-2-but-3-enyloxy-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:12][CH2:13][CH2:14][OH:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][CH2:14][OH:15])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: OCCCBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCCCO
Yield: 39.6 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (3.1 g, 20 mmol), 3-bromo-propan-1-ol (4.1 mL, 24 mmol), K2CO3 (5.5 g, 4 mmol) and KI (0.5 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 200° C. for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (Yield: 1.7 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][C:23]([NH2:25])=[O:24].[F:26][C:27]([F:35])([F:34])[C:28](=O)[CH2:29][C:30](=O)[CH3:31].[OH-].[Na+]>OS(O)(=O)=O.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:30]([CH3:31])=[CH:29][C:28]([C:27]([F:35])([F:34])[F:26])=[N:25][C:23]1=[O:24]
Reactant: NC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nc(=O)n1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 80 °C

Procedure:
To [2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-urea (38 mg, 0.1 mmol) in 13% (v/v) H2SO4 in EtOH was added 1,1,1-trifluoro-2,4-pentanedione (15 μL, 0.15 mmol). The mixture was heated at 80° C. for 6 hrs, followed by neutralization with 6N NaOH solution. Purification by prep. LCMS yielded 1-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-6-methyl-4-trifluoromethyl-1H-pyrimidin-2-one 13-1. MS: 497.7 (M+H)+; tR=8.14 min (method 2).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([O:12]CC)=[O:11])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]>O1CCOCC1.Cl>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([OH:12])=[O:11])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(OC(C(=O)OCC)c2ccc(Cl)cc2)ccc(C(C)=O)c1O
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1c(OC(C(=O)O)c2ccc(Cl)cc2)ccc(C(C)=O)c1O
Yield: 32.3 %

Procedure:
A mixture of 5 g of Ethyl 2-(4-acetyl-2-n-propyl-3-hydroxyphenoxy)-2-(4-chlorophenyl)acetate in 100 ml of dioxane and 15 ml of concentrated hydrochloric acid was refluxed for 70 hours. The reaction mixture was then cooled and concentrated in vacuum to give 2.6 g of the crude solid. The crude product was crystallized from EtOAc/hexane to give 1.5 g of the pure product, melting point 163°-164°.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=O)[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][NH2:27]>CO>[CH3:1][C:2]1([CH3:18])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]/[C:6]/1=[N:27]\[O:26][CH3:25]
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CO/N=C1\CN(C(=O)OCc2ccccc2)CC1(C)C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of phenylmethyl 3,3-dimethyl-4-oxo-1-pyrrolidinecarboxylate (0.9135 g, 3.694 mmol) in MeOH (37 mL) was added sodium acetate (0.606 g, 7.387 mmol) and O-methylhydroxylamine hydrochloride (0.620 g, 7.397 mmol). The solution was stirred for 3 h, and then concentrated in vacuo. The residue was partitioned between DCM (100 mL), water (5 mL), and sat. aq. NaHCO3 (30 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide phenylmethyl (4Z)-3,3-dimethyl-4-[(methyloxy)imino]-1-pyrrolidinecarboxylate (0.9124 g, 89% yield) as a pale yellow oil. LCMS: (M+H)+: 277.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[N:11][C:10]=1[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([OH:30])[N:22]=1.[H][H]>[Pd].CO>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[N:11]=[C:12]([C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[NH:13][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:22][C:23]=1[OH:30]
Reactant: [H][H]
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)c1nc(-c2ccc(N)c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Temperature: 55 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
Methyl 2-[5-(2,4-difluorophenyl)-4-(6-hydroxy-5-nitro-2-pyridyl)-1H-imidazol-2-yl]-2-methyl-propanoate (90.0 g, 0.22 mol), wet 10% Pd/C (4.5 g), and methanol (1.77 L) are combined at 15-25° C. The reaction is stirred under 20-25 psig hydrogen atmosphere for 3-6 h. The reaction mixture is filtered over diatomaceous earth, and the filter aid is washed with methanol (227 mL). The filtrate is concentrated under reduced pressure below 40° C., and methyl tert-butyl ether (729.3 mL) is added. The MTBE is removed under reduced pressure below 40° C., and more methyl tert-butyl ether (729.3 mL) is added. The MTBE is removed under reduced pressure below 40° C. Methyl tert-butyl ether (182 mL) and methanol (46 mL) are added and the mixture heated to 50-60° C. for 1-2 h. The mixture is cooled to 10-15° C., and stirred for 2-4 h. The solids are collected by filtration and the filtercake washed with methyl tert-butyl ether (61 mL). The solids are dried under vacuum below 50° C. to furnish the title compound as a yellow solid (75.0 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][C:24]([NH:26][OH:27])=[NH:25])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:28](O)(=O)[CH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]([CH2:23][C:24]3[N:25]=[C:28]([CH3:29])[O:27][N:26]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)N2C(CC(=N)NO)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(Cc3noc(C)n3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, pale yellow oil, MS: m/e=416.3 (M+H+) was prepared in accordance with the general method of example 13 from (2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidine and acetic acid.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl>>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][N:19]([CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1CNCCC1(F)c1cccc(OCc2ccccc2)c1
Reactant: BrCCCC1CCCCC1
Agent: Cl
Product: CC1CN(CCCC2CCCCC2)CCC1(F)c1cccc(OCc2ccccc2)c1

Procedure:
This material was prepared by the alkylation of 4-(3-benzyloxyphenyl)-4-fluoro-3-methylpiperidine hydrochloride with 1-bromo-3-cyclohexylpropane and subsequent salt formation with methanolic hydrogen chloride as described in Step 3 of Example 1 in 48% overall yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH3:25])[CH:7]=1)[CH3:2].Br[C:28]1[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)[C:16]=2[CH3:25])[CH:7]=1)[CH3:2]
Reactant: Cn1cc(Br)cn1
Reactant: CCOC(=O)Cc1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)Cc1ccc(OC)c(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methoxy-phenyl]-acetic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].O>C(O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:13]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:12][N:9]2[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)N1CCN(CC(c2ccc(F)cc2)N2CCN(C)CC2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(C(CN2CCNCC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
1.25 g of 1-Ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine was dissolved in 2 ml of ethanol, and 1.3 g of potassium hydroxide was added, followed by reflux with heating for an hour. The reaction solution was cooled to room temperature and, after addition of 2 ml of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure to give 1.0 g of a crude 1-[2-(4-fluorophenyl)-2-(4-methyl-piperazino)ethyl]piperazine.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:15][C:16]([O:18][C:19]1([CH3:29])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2)=[O:17]>C(OCC)C.CN(C)C=O>[CH3:29][C:19]1([O:18][C:16](=[O:17])[CH2:15][O:5][C:1](=[O:4])[CH2:2][OH:3])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2
Reactant: CC1(OC(=O)CCl)C2CC3CC(C2)CC1C3
Reactant: O=C(O)CO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(OC(=O)COC(=O)CO)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
37.6 g (494 mmol) of glycolic acid, 700 mL of DMF, 86.5 g (626 mmol) of potassium carbonate, and 28.3 g (170 mmol) of potassium iodide were charged into a 2 L three-necked flask equipped with a thermometer, a cooling pipe, and a stirrer, followed by stirring at room temperature for 30 minutes. Then, 300 mL of a dimethylformamide solution containing 100 g (412 mmol) of 2-methyl-2-adamantyl chloroacetate was gradually added thereto. The resultant was heated to 40° C., and was then stirred for 4 hours. Following completion of the reaction, 2,000 mL of diethyl ether was added to the reaction mixture, followed by filtration of the resulting mixture. The obtained solution was washed three times with 500 mL of distilled water, followed by crystallization using a mixed solution containing 300 mL of toluene and 200 mL of heptane, thereby obtaining 78 g of an objective compound in the form of a colorless solid (yield: 67%, GC purity: 99%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].[CH:21]([O:24][C:25]1[C:26](=O)[C:27](=[O:33])[C:28]=1[O:29]C(C)C)([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CO>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@H:3]([NH:2][C:26]2[C:27](=[O:33])[C:28](=[O:29])[C:25]=2[O:24][CH:21]([CH3:23])[CH3:22])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)Nc1c(OC(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A mixture of methyl (2S)-2-amino-3-(4-biphenylyl)-propanoate hydrochloride (415 mg, 1142 mmol),3,4-diisopropoxy-3-cyclobutene-1,2-dione (281 mg, 1.42 mmol), DIPEA (247 μl, 1.42 mmol) and MeOH (10 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2; DCM/MeOH, 98:2) to give the title compound (358 mg). δH (DMSO-d6, 390K) 8.50 (1H, d, J 8.0 Hz), 7.63-7.56 (4H, m), 7.47-7.42 (2H, m), 7.36-7.32 (3H, m), 5.24-5.18 (1H, m), 4.80-4.75 (1H, m), 3.74 (3H, s), 3.31 (1H, dd, J 14.2, 5.2 Hz), 3.13 (1H, dd, J, 14.2, 9.4 Hz), 1.38 (3H, d, J 6.0 Hz), 1.37 (3H, d, J 6.1 Hz); m/z (ES+, 70 V) 394 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([NH:20][CH3:21])[C:17]([N+:22]([O-])=O)=[CH:16][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][CH3:15])=[O:13])[CH:7]=1>CO.[Pd]>[NH2:22][C:17]1[CH:16]=[C:4]([C:3]([O:2][CH3:1])=[CH:19][C:18]=1[NH:20][CH3:21])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][CH3:15])=[O:13])[CH:7]=1
Reactant: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(Oc2cc(N)c(NC)cc2OC)ccn1

Procedure:
A solution of {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. In methanol was hydrogenated with 10% Pd/C. The catalyst was filtered off and the solvent was concentrated to yield {4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+: 302.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[C:3]1=[N:9]O.C(=O)([O-])[O-:12].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[NH:9][C:3]1=[O:12]
Reactant: C[C@H]1CCC[C@H](C)C1=NO
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C[C@H]1CCC[C@H](C)C(=O)N1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Into 20 ml of xylene were added 1.3 g of trans-2,6-dimethylcyclohexanone oxime and 6 g of polyphosphoric acid, the mixture was stirred for 10 hours at 100%. The reaction mixture was cooled to near room temperature, poured into ice-water. Sodium carbonate was added to the mixture, and the mixture was extracted with ethyl acetate three times. The organic layers was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.2 g of trans-3,7-dimethylhexahydro-1H-azepine-2-one.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: NNc1cccc(F)c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(F)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-fluorophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that resulting solid was the named product (m.p. 55° C.-56.1° C.).
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:42])[CH2:10][CH2:11][CH2:12][C@H:13]([OH:41])/[CH:14]=[CH:15]/[C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C@@H:18]([Cl:28])[C@@H:17]1[CH2:29][CH2:30][CH2:31][C:32]1[S:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[Cl:28][C@H:18]1[C@H:17]([CH2:29][CH2:30][CH2:31][C:32]2[S:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=2)[C@@H:16](/[CH:15]=[CH:14]/[C@@H:13]([OH:41])[CH2:12][CH2:11][CH2:10][C@H:9]([OH:8])[CH3:42])[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19]1
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Yield: 79.3 %

Procedure:
A solution of silyl ether 9 (325 mg, 0.51 mmol) in 1 mL of THF was stirred at 30° C. with 2 mL of 1.0M TBAF/THF in a vial for 7.5 h. TLC indicated starting material was mostly desilylated and the reaction was concentrated in vacuo. The residual crude products were taken up in 50 mL of ethyl acetate and washed sequentially with saturated aqueous ammonium chloride (50 mL), brine (50 mL), and dried over 10 g of anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residual products were purified by preparative layer chromatography on 2×2 mm thick silica gel plates eluted in EtOAc (Rf=0.5). Extraction of the major band yielded 214 mg (80%) of pure diol 10 as an oil; 1H NMR (CDCl3): 1.18 (d, J=6 Hz, 3H), 1.38-1.68 (m, 11H), 1.66-2.37 (m, 9H), 2.84 (t, J=7.2 Hz, 2H), 3.47 (m, 1H), 3.79 (m, 1H), 3.86 (s, 3H), 3.98 (p, J=7.5 Hz, 1H), 4.09 (m, 2H), 4.63 (dt, J=3, 27 Hz, 2H), 5.58 (m, 2H), 6.78 (dd, J=0.6, 3.6 Hz, 1H), 7.62 (d, J=3.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[C:18]([N+:20]([O-])=O)[CH:19]=2)[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH4+].[OH-].CO>CCOC(C)=O>[NH2:20][C:18]1[CH:17]=[C:10]([CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[CH:19]=1)[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)COc1cc(-c2ccnc(C)c2)cc([N+](=O)[O-])c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)COc1cc(N)cc(-c2ccnc(C)c2)c1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To a rt solution of 65.D (476 mg, 1.58 mmol) in EtOAc (9 mL) was added SnCl2-2H2O (1.88 g, 7.93 mmol). The reaction solution was refluxed for 2.0 hr, cooled to rt, and treated with concentrated NH4OH (2.5 mL). To the resulting mixture was added MeOH (10 mL) followed by celite. Solid was filtered off and washed with MeOH, the liquid layers was collected and concentrated. Purification of the residue by flash chromatography on silica gel using 0-20% MeOH/CH2Cl2 for elution gave title product 65.E as colorless syrup (282 mg, 65%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH:20]1([C:23]2[C:24]([O:31][CH:32]([F:34])[F:33])=[N:25][CH:26]=[C:27]([CH:30]=2)[CH:28]=O)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:30]=[C:27]([CH2:28][N:1]3[CH:2]([C:10]4[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=4[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]3=[O:8])[CH:26]=[N:25][C:24]=2[O:31][CH:32]([F:34])[F:33])[CH2:21][CH2:22]1
Reactant: O=Cc1cnc(OC(F)F)c(C2CC2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc(OC(F)F)c(C2CC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 5-cyclopropyl-6-(difluoromethoxy)nicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 432.88 g/mol.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12]O.[CH2:14]([NH2:21])[CH2:15][S:16]S(O)(=O)=O>>[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12][S:16][CH2:15][CH2:14][NH2:21]
Reactant: Cc1nc[nH]c1CO
Reactant: NCCSS(=O)(=O)O
Agent: O=S(=O)(O)O
Product: Cc1nc[nH]c1CSCCN
Yield: 97.2 %

Procedure:
4.8 g of 4-methyl-5-hydroxymethylimidazole sulfate is reacted with 5.2 g of 2-aminoethanethiolsulfuric acid according to the procedure described in Example 1 (i), yielding 3.8 g of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole as an oily product (yield: 73.3%).