Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH3:9].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>ClCCl>[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15]([C:36]([CH:33]2[CH2:35][CH2:34]2)=[O:37])[CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)C2CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
Triethylamine (0.37 mL, 2.7 mmol) was added to a stirred solution of 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 65) (300 mg, 0.87 mmol) in dichloromethane (10 mL) and the resulting mixture cooled to 0° C. Cyclopropanecarbonyl chloride (0.08 mL, 0.87 mmol) was added and the reaction mixture stirred at room temperature for 16 hours. The mixture was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was separated, washed brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 15% ethyl acetate in hexane to afford the title compound as a pale yellow solid (305 mg, 85%).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>C(O)(=O)C.O.[Rh]>[CH:1]1([C:7]23[CH2:14][CH2:13][N:10]([CH2:9][CH2:8]2)[CH2:11][CH2:12]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc(C23CCN(CC2)CC3)cc1
Agent: [Rh]
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: C1CCC(C23CCN(CC2)CC3)CC1
Reaction time: 120 h
Yield: 91.1 %

Procedure:
4-Phenylquinuclidine (5 g) (see J. Org. Chem., 22, 1484, (1957)) was dissolved in glacial acetic acid (25 ml), 5% w/w rhodium-on-alumina (2 g) was added and the mixture hydrogenated for 5 days at 345 kPa (50 psi). The mixture was filtered through a short column of Arbacel (trade mark) filter aid and the pad washed with methanol. The filtrate was collected and the solvent removed under reduced pressure to give a residue which was dissolved in water. The pH was adjusted to >10 by addition of 0.88 aqueous ammonia solution. The aqueous mixture was extracted with ethyl acetate (×3) and the organic layers combined, washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give 4-cyclohexylquinuclidine (4.7 g) as a pale pink solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:25][CH3:26])=[C:5]([C:11]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH3:2]>C1COCC1.O>[CH2:1]([C:3]1[C:4]([O:25][CH3:26])=[C:5]([C:11]([CH2:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(CC)c1OC
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(CS(=O)(=O)c2ccc(F)cc2)c(C(=O)O)c1OC
Yield: 19.9 %

Procedure:
Potassium trimethylsilanoate (0.257 g) was added to a solution of ethyl 3-ethyl-6-(4-fluorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 23, 0.076 g) in dry THF (10 ml). The resultant mixture was stirred at room temperature for 3 days. The mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified by careful addition of concentrated hydrochloric acid and then extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.1% formic acid with a gradient of 50-80% to give 3-ethyl-6-(4-fluorobenzenesulphonyl-methyl)-2-methoxybenzoic acid (0.014 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:19])[CH2:9][CH2:10][CH:11]2[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]2)=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:17][C:14]1([CH3:18])[CH2:13][O:12][CH:11]([CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])[O:16][CH2:15]1
Reactant: CC1(C)COC(CCC(O)c2ccc(F)cc2)OC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)COC(CCC(=O)c2ccc(F)cc2)OC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of α-(4-fluorophenyl)-5,5-dimethyl-1,3-dioxane-2-propanol (Step 3) (2.6 g, 10.7 mmol) in methylene chloride (100 ml), pyridinium chlorochromate (3.5 g, 16.05 mmol) was added. After stirring at room temperature for 3 hr, the reaction mixture was diluted with ether and filtered through a short silica gel column. The column was eluted with ether and the fractions containing 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one were combined and concentrated (2.2 g, 85%): mp (DSC) 65° C. Anal Calc'd. for C15H19FO3: C, 67.65; H, 7.19. Found: C, 67.21; H, 7.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(N)nc1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CCNc2ccc(C)cn2)cc1

Procedure:
Similarly prepared from 4-methoxyphenyl acetic acid and 2-amino-5-picoline.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.F[P-](F)(F)(F)(F)F.[PH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)=[O:8]
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of the (2,4-dichloro-phenoxyacetic acid (600 mg, 2.71 mmol) and 3-amino-phenol (592 mg, 5.43 mmol) in DMF (20.0 mL) were added benzotriazol-1-yl-N-oxy-trispyrrolidino)-phosphonium hexafluorophosphate (PyBOP) (2.8 g, 5.43 mmol), and N,N-diisopropylethylamine (DIPEA) (0.95 ml, 5.43 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:EtOAc:MeOH=10:3:1) gave 2-(2,4-Dichloro-phenoxy)-N-(3-hydroxy-phenyl)-acetamide as a white solid (837 mg, 99% yield)
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[S:4][C:3]=1[CH:16]1[O:20]CCO1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28]C>>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[S:4][C:3]=2[CH:16]=[O:20])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1
Product: Cc1c(-c2ccc(O)cc2)sc(C=O)c1-c1ccc(O)c(F)c1
Yield: 60.9 %

Procedure:
Starting from 2-[3-bromo-5-(4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (1.1 g, 3.0 mmol, made in Example 1, Step 1) and substituting 3-fluoro-4-methoxyphenylboronic acid (0.56 g, 3.3 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.60 g, 97%, m.p. 223-26° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[Br:30]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([Br:30])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCOC)c1
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(OCOC)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-(4-methoxybenzoyl)phenylacetate (490 mg, 1.2 mmol) obtained in Example 134, Step 2 was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (220 mg, 1.2 mmol) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/1) to obtain methyl 3,5-bis(methoxymethoxy)-2-bromo-6-(4-methoxybenzoyl)phenylacetate (520 mg, 89%).
Reaction SMILES: [IH:1].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(O)C>C(OCC)C>[IH:1].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1ccc(F)cc1
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: N=C(NCc1ccc(F)cc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 3.75 g. of p-fluorobenzylamine in 25 ml. of absolute ethanol is heated under reflux for 24 hours and then evaporated under reduced pressure, giving a mixture of gum and crystals. This mixture is dissolved in 50 ml. of absolute ethanol and diluted with 175 ml. of diethyl ether. The colorless plates which form are removed by filtration and discarded. The filtrate is diluted with petroleum ether (b.p. 30°-60° C), causing colorless needles to separate. These needles are removed by filtration and recrystallized from a mixture of ethanol-diethyl ether-petroleum ether (b.p. 30°-60° C), giving the desired product as colorless crystals, m.p. 162.5°-164° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:23]([O-])=O)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[NH2:23][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([NH2:1])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(OC)cc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(Oc2ccc(OC)cc2)c(N)c1
Yield: 31.8 %

Procedure:
To a Parr shaker bottle containing a suspension of methyl 3,5-di-nitro-4-(4-methoxyphenoxy)-benzoate (20.2 g; 77.5 mmol) in glacial acetic acid (80 mL) was added 10% palladium on charcoal (0.7 g). The bottle was shaken under an atmosphere of hydrogen (3 atm) until no more hydrogen was consumed. The catalyst was filtered off and the resulting solution concentrated to approximately 10 mL. The residue was dissolved in acetone (50 mL) and heated on a steam bath while water (100 mL) was added in portions. Upon cooling, medium brown needles formed which were collected by suction filtration and dried to give 7.1 g (86%) of methyl 3,5-diamino-4-(4-methoxyphenoxy)benzoate. 300 MHz 1H NMR (CDCl3) d 3.73 (s, 3H, OCH3), 3.80 (bs, 4H, ArNH2) 3.86 (s, 3H, OCH3), 6.84 (m, 4H, ArH), 6.91 (s, 2H, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH2:34][CH2:35][NH2:36].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:36][CH2:35][CH2:34][NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(Cc3ccccc3)c12
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(Cc3ccccc3)c12
Temperature: 0 °C
Yield: 53.8 %

Procedure:
A solution of 5-amino-1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.11 mmol), N-2-pyridyl-1,2-ethanediamine (305 mg, 2.22 mmol) and triethylamine (0.310 mL, 2.22 mmol) in DMSO (4 mL) was stirred at 100° C. After 4 h the reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol, and dried to yield 5-amino-1-benzyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (285 mg, 54%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH3:6].[Mg].[CH3:8][S:9][CH2:10][CH2:11][CH:12]=[O:13].[Cl-].[NH4+]>C1COCC1.CCOCC>[CH3:8][S:9][CH2:10][CH2:11][CH:12]([OH:13])[CH2:2][CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCCC=O
Reactant: CSCCCCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSCCCC(O)CCSC
Temperature: 50 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1-Chloro-3-methylthiopropane (3.73 g, 30 mmole) in dry THF (50 mL) was added to stirred magnesium turnings (0.72 g, 30 mmole) under argon. Once the addition was complete, the mixture was heated to 50° C. for 3 hours. The mixture was then allowed to cool to room temperature and 3-methylthiopropanal (3.12 g, 30 mmole) was added. The reaction was stirred at room temperature for 1 hour. 2M ammonium chloride solution (50 mL) was added, followed by ether (50 mL). The organics were separated, dried, filtered, and evaporated to give a pale yellow oil that was purified by chromatography in 40-60 petroleum ether/ether (4/5) to give 5 (2.1 g, 36%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:10]1.[NH:24]1[CH:28]=[CH:27][CH:26]=[N:25]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[F:1][C:2]1[CH:7]=[C:6]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(C(=O)N(C)OC)c1=O
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (1.73 g, 4 mmol), pyrazole (0.408 g, 6 mmol), Cu2O (0.057 g, 0.4 mmol), salicylaldoxime (0.219 g, 1.6 mmol), and Cs2CO3 (2.60 g, 8 mmol) in CH3CN (8 mL) was refluxed for 6 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title, compound (0.370 g, 25% yield) as a white solid: mp 187-189° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.40 (3H, s), 3.72 (3H, s), 3.93 (3H, s), 6.55 (1H, dd, J=1.5, 2.3 Hz), 7.60 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.71-7.77 (3H, m), 7.84 (1H, d, J=2.3 Hz), 7.98 (1H, d, J=2.6 Hz). Anal. Calcd for C17H16FN5O4: C, 54.69; H, 4.32; N, 18.76. Found: C, 54.58; H, 4.40; N, 18.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([F:29])[F:28])[CH:21]=1>>[F:28][CH:27]([F:29])[O:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][N:15]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH:13]([CH3:17])[C:14]1=[O:16]
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Reactant: FC(F)Oc1cccc(CBr)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with commercially available 1-(bromomethyl)-3-(difluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.84 min.; [M+H]+: 392.16 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]([CH2:45][NH2:46])[CH:42]=[CH:43][CH:44]=2)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:46][CH2:45][C:41]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:44]=[CH:43][CH:42]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cccc(CN)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN)c4)cc23)CC1
Temperature: 160 °C
Yield: 8.5 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30.0 mg, 0.072 mmol), Cs2CO3 (95 mg, 0.290 mmol) and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (82 mg, 0.350 mmol) in dioxane/H2O (2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (7.5 mg, 0.0072 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by reverse phase HPLC method A (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (2.7 mg, 8.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]=[CH:12][C:13](=[O:15])[CH3:14].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>CCOCC>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[C:3]=1[CH:11]=[CH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)C=CC1=C(C)C(O)CCC1(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)C=CC1=C(C)C(=O)CCC1(C)C
Temperature: 5 °C
Yield: 734.3 %

Procedure:
To a solution, pre-cooled to 0° C., of 140 g (0.068 mol) of 4-(2,6,6-trimethyl-3-hydroxy-cyclohex-1-en-1-yl)-but-3-en-2-one in 500 ml of ether are added dropwise over a period of 10 minutes 700 ml of an aqueous solution, cooled to 0° C., of 202.6 g of sodium dichromate dihydrate and 186 g of concentrated sulphuric acid with intensive cooling and good stirring so that a temperature of 5° C. is not exceeded. The mixture is then stirred for a further 5 minutes at 5° C., treated with 500 ml of ether, the ether phase is washed three times with water, three times with soda solution and again three times with water, dried over sodium sulphate and concentrated. Distillation of the resulting 125 g of crude product over a 10 cm Widmer column gave 103 g of more than 94% pure 4-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)-but- 3-en-2-one of boiling point 109°-110° C./0.05 mm Hg; melting point 50°-51° C.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[NH2:5]/[C:6](=[N:20]\[OH:21])/[C@@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH:9]1[CH2:11][CH2:10]1>CN(C=O)C>[CH:9]1([CH2:8][C@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])[C:6]2[N:5]=[C:1]([CH3:2])[O:21][N:20]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)/C(N)=N/O
Reactant: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1nc([C@H](CC2CC2)NC(=O)OC(C)(C)C)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a solution of acetic acid (0.224 g, 4 mmol) in DMF (5 mL) was added N,N′-carbonyldiimidazole (0.6 g, 4 mmol) and the mixture was stirred for 0.5 h at room temperature. (S,Z)-tert-butyl 1-amino-3-cyclopropyl-1-(hydroxyimino)propan-2-ylcarbamate (0.84 g, 3 mmol) was added and the mixture was heated to 120° C. and stirred for 4 h. After evaporation of solvents, the residue was purified by column chromatography (silica gel, 20 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.5 g; 54%) as yellow solid; MS (EI): m/e 290.1 [M+Na]+.
Reaction SMILES: [C:1]([N:9]=[C:10]1[NH:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][NH2:31])[N:25]=[CH:24]1>C(#N)C.C(O)C>[C:1]([NH:9][C:10]([NH:14][CH2:13][CH:12]([OH:11])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:31][CH2:30][CH2:29][CH2:28][C:26]1[N:25]=[CH:24][NH:23][CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCc1c[nH]cn1
Reactant: O=C(N=C1NCC(COc2ccccc2)O1)c1ccccc1
Solvent: CC#N
Solvent: CCO
Product: O=C(NC(=NCCCc1c[nH]cn1)NCC(O)COc1ccccc1)c1ccccc1
Yield: 38 %

Procedure:
1.48 g (5 mmol) of 2-benzoylimino-5-phenoxymethyloxazolidine and 0.69 g (5.5 mmol) of 3-(imidazole-4-yl)-propylamine are heated together under reflux in a mixture of 40 ml of acetonitrile and 10 ml of ethanol for 8 hours. The reaction mixture is concentrated by evaporation under vacuum and the product is isolated and purified by preparative layer chromatography (silica gel 60 PF254 containing gypsum: solvent; chloroform/methanol 98:2, ammoniacal atmosphere). Crystallisation from acetonitrile results in 0.8 g (38%) of colourless crystals, melting point 129° C.