Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([O:12][CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A mixture of 2-[(tert-butoxycarbonyl)amino]pent-4-enoic acid (20.0 g), potassium carbonate (13.2 g) and N,N-dimethylformamide (100 mL) was stirred for 15 min. The mixture was cooled to 0° C., iodomethane (9.2 g) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the residue was washed with ethyl acetate. The filtrate was successively washed with 5% hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (21.0 g).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[H-].[Na+].Br[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]#[N:9])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: N#Cc1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 29.6 %

Procedure:
Combine anthranilonitrile (2.36 g, 20 mmol), sodium hydride (1.2 g (60% in oil), 30 mmol) and THF (50 mL), stir at ambient temperature for 30 minutes. Add 1-bromo4-chloro-2-nitro-benzene (7.1 g, 30 mmol) and stir at ambient temperature for 3 days. Pour the reaction mixture in ice-cold concentrated hydrochloric acid (200 mL) and filter the resulting solid. Purify by flash chromatography (dichloromethane) and recrystallize from hot ethyl acetate to give (1.62 g, 30%) of the title compound as orange needles: 1H NMR (CDCl3) δ 7.17 (d, 1H), 7.26 (t, 1H), 7.40–7.51 (m, 2H), 7.61 (t, 1H), 7.72 (d, 1H), 8.22 (d, 1H), 9.54 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[C:13]([Br:29])[N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Yield: 71.2 %

Procedure:
A mixture of 1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (147 mg, 0.39 mmol) and N-bromosuccinimide (76 mg, 0.43 mmol) in CH2Cl2 (1.5 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-15% EtOAc/hexanes+1% AcOH) to give 127 mg of the title compound as a yellow solid. MS: (−) m/z 455.21, 457.17 (M−1, 79/81Br).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([C:26]5[O:25][CH:29]=[CH:28][CH:27]=5)[CH2:35]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: c1coc(C2CNCCN2)c1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccco5)C4)c(F)cc3cc2c1=O
Yield: 66.7 %

Procedure:
(RS)-3-Ethoxycarbonyl-7,9-difluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.85 g) and (RS)-2-(2-furyl)piperazine (1 g). After concentration of the combined organic extracts under reduced pressure (20 kPa, approximately 40° C.), the residual solid is recrystallized in ethanol (100 cc). (RS)-3-Ethoxycarbonyl-7,9-difluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.72 g) is obtained in the form of a yellow solid, m.p. 208°-210° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-])=O)=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[NH2:20][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:9])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: [H][H]
Reactant: CN(Cc1ccc([N+](=O)[O-])c(C(=O)O)c1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(Cc1ccc(N)c(C(=O)O)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 80 mL of methanol, there were added 8.3 g of 5-(N-tert-butoxycarbonyl-N-methyl-aminomethyl)-2-nitrobenzoic acid prepared in the foregoing Step 2 and 500 mg of 10% Pd/C (wet product), then hydrogen gas was introduced into the resulting dispersion and the mixture was then stirred at room temperature. After 1.5 hours, additional 500 mg of 10% Pd/C was further added to the mixture and the latter was stirred over 7 hours in a hydrogen gas atmosphere. The catalyst was removed by the filtration through Celite and the Celite was washed with methanol. The filtrate was concentrated to dryness to thus give the title compound.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:37][C:36]([NH2:38])=[N:35][C:34]=1[CH3:39])(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:37][C:36]([NH:38][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:35][C:34]=1[CH3:39])(=[O:31])=[O:32]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NCCO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NCCO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-amide (example B.10) according to general procedure II. Yellow solid. MS (ISP) 575.1 [(M−H)−]; mp 134° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:15]>C(O)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COc1ccc(N(C(=O)CN)C(C)C)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: CCO
Solvent: O
Product: COc1ccc(N(C(=O)CNc2ccc(F)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
A mixture of 9.06 g of 2,5-difluoro-nitrobenzene (60 mmol) and 12.64 g of 2-amino-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, (60 mmol, 1.0 equiv) were combined in 225 mL of 2:1 ethanol/water and heated to reflux under nitrogen and stirred vigorously overnight (approx. 16 hrs.). The resulting slurry is cooled to ambient temperature, filtered and washed with 2:1 water/ethanol. The wet solid is dissolved in methylene chloride, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue is triturated with hexane, filtered and washed with hexane. The product is dried under high vacuum to provide 9.32 g of 2-(4-Fluoro-2-nitro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an orange solid: 1H NMR (300 MHz, CDCl3) δ7.89 (dd, 1H, J=3.1, 9.3), 7.12 (m, 3H), 6.99 (m, 2H), 6.35 (dd, 1H, J=4.8, 9.2), 5.03 (m, 1H), 3.89 (s, 3H), 3.57 (s, 2H), 1.09 (d, 6H, J=6.8); low resolution MS (ESI)m/e 362 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:18](=[O:20])[CH3:19])[CH:3]=1
Reactant: Cc1ccc(CO)cc1N
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(CO)ccc1C

Procedure:
The solution of 11.3 g of (3-amino-4-methylphenyl)methanol in 500 ml of chloroform is cooled to 0° C. with stirring and admixed with 13.4 ml of triethylamine. 6.03 ml of acetyl chloride are slowly added dropwise. Subsequently, the mixture is stirred at 0° C. over 2 hours. The reaction mixture is poured onto water (1 l) and extracted with dichloromethane (2×350 ml). The organic phases are washed with brine (350 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly brownish solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (1:2 dichloromethane-diethyl ether); Rt=2.14.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]=[C:25]=[S:26].CCOCC>C1COCC1>[CH3:23][NH:24][C:25]([NH:19][NH:18][C:16](=[S:17])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:26]
Reactant: CN=C=S
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC(=S)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 8 h

Procedure:
1.62 g (5 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydrazine carbothioamide are dissolved in 30 ml of THF, 0.44 g (6 mmol) of methyl isothiocyanate are added, and the reaction mixture is left to stand overnight at room temperature. Ether is added to complete precipitation and the precipitate formed is suction filtered, washed with ether and recrystallised from ethanol. The analytical values are summarized in Table I.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[NH2:26]/[C:27](/[CH3:35])=[CH:28]\[C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30]>C(O)C>[C:15]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:28]([C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30])=[C:27]([CH3:35])[NH:26][C:23]=1[CH3:24])(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)c1ccccc1
Reactant: CCCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccccc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
250 mg (0.75 mmol) of 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-1-phenylbutane-1,3-dione are dissolved with 143 mg (1.0 mmol) of n-propyl 3-aminocrotonate in 5 ml of ethanol and heated under reflux under argon for 24 h. The reaction solution is purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.O=[C:11]1[CH2:18][CH:17]2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:13]([CH2:14][CH2:15][CH2:16]2)[CH2:12]1>CCO>[Br:1][C:2]1[N:3]=[C:4]([NH:8][N:9]=[C:11]2[CH2:18][CH:17]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:13]([CH2:14][CH2:15][CH2:16]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CC(=O)C2
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCCC1CC(=NNc1cccc(Br)n1)C2
Yield: 99.9 %

Procedure:
2-Bromo-6-hydrazinylpyridine (393 mg, 2.09 mmol) and tert-butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (500 mg, 2.09 mmol) were heated at reflux in EtOH (5 mL) for 16 h and the mixture concentrated to provide the title compound (855 mg, 100%) as a yellow solid: ESI MS m/z 409 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:32])[CH:28]([CH3:31])[CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:32])[CH:28]([CH3:31])/[CH:29]=[CH:30]/[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C=CC(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(C)/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 59, Step 1, using 1-{4′-[4-(1-hydroxy-2-methyl-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:12](OC(Cl)(Cl)Cl)=[O:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:12]=[O:13]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N)c(F)c1
Solvent: Cc1ccccc1
Product: COc1ccc(N=C=O)c(F)c1

Procedure:
To a solution of 13.75 g (0.0967 mole) of 2-fluoro-4-methoxyaniline in 120 mL of toluene was slowly added over a period of 30 minutes a solution of 19.13 g (0.0967 mole) of trichloromethyl chloroformate in 30 mL of toluene. During the addition the temperature rose to 35° C. The reaction mixture was stirred without external heating for 30 minutes and then heated at reflux for approximately 17 hours. At the end of this time all of the solvent was removed by distillation, leaving 2-fluoro-4-methoxyphenyl isocyanate as a purple liquid, which was used immediately in Step B.
Reaction SMILES: [CH2:1]([C:3]1([OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH3:10])[CH3:2].C([Li])CCC.CCCCCC.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>CCOCC>[C:23]([O:11][C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH3:10])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: CCC1(O)CCCCC1OC
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C(C)C(=O)OC1(CC)CCCCC1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-ethyl-2-methoxycyclohexanol from the previous step (10 g, 0.063 mole) in 50 ml ether was placed in a three neck flask equipped with a water condenser, addition funnel and a nitrogen inlet. This solution was cooled in an ice/water bath and n-butyllithium, 1.6 molar in hexane (45 ml, 0.072 mole) was added dropwise. The contents were allowed to warm to room temperature and stirred for 30 minutes. The mixture was cooled again in ice/water bath and methacryloyl chloride (7.31 g, 0.070 mole) in 25 ml ether was added dropwise and heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature and quenched with 125 ml of deionized water. The organic phase was separated and the water phase was extracted with 50 ml ether. The combined ether solutions were washed with 100 ml brine and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator and the crude product was chromatographed on a neutral alumina column using hexane as elutant. The product was a clear liquid (9.79 g) which was characterized by NMR and IR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[F:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])=[CH:28][C:27]=3[F:39])=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)c(F)c1
Product: CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1F)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.29 mmol, 1.0 eq.) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 91 mg (0.43 mmol, 1.5 eq.) of tert-butyl 4-amino-3-fluorobenzoate were reacted according to General Method 5C. The crude product was purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 35%-50% mixtures). Yield: 126 mg (81% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[OH:16]>>[Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:16])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1ccc(-c2ncccc2Cl)cc1
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
{circle around (2)} 100 g (0.49 mol) of 3-chloro-2-para-tolylpyridine was dissolved in 0.5 L of methanol in a reactor. A solution of 537 g (0.98 mol) of ceric ammonium nitrate in 1 L of methanol was added dropwise, and the mixture was refluxed for 4˜6 hours. The reaction solution was cooled to 25° C. and concentrated under reduced pressure. A 10% sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 60% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1>CC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:12]([CH:16]=1)[C:13]([O:15][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[O:14]
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1cccc(F)c1)c1cc(Br)ccc1OCc1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Solid potassium carbonate (2.76 g, 20 mmol) was added to a stirred solution of 5-bromo-2-hydroxybenzoic acid (1 g, 4.61 mmol) in acetone (20 ml) at 20° C. The reaction mixture was stirred at 20° C. for 10 min, and then 1-(bromomethyl)-3-fluorobenzene (1.92 g, 10.14 mmol) was added dropwise. The reaction mixture was stirred at 71° C. for 18 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated to give a colourless oil. The crude product was added to a silica gel column and was eluted with hexane/ethyl acetate (100:5 then 20:1) to yield the title compound as a white solid. 1.65 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[Mg].Cl[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCCCC1Cl
Reactant: COc1cccc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Product: COc1cccc(C2CCCCC2=O)c1

Procedure:
A mixture of 261.8 g of 3-methoxybromobenzene in 500 ml of ether is added dropwise to a 34.0 g sample of magnesium in 600 ml of ether. To the reaction mixture is added a suitable catalyst and the mixture is heated vigorously to initiate the reaction. The prepared Grignard Reagent is cooled in an ice bath while 185.6 g of 2-chlorocyclohexanone in 500 ml of ether is introduced. The ether is removed and xylene added and the xylene solution is refluxed for 1 hour. The solution is poured over ice and dilute hydrochloric acid, the organic layer separated, the aqueous layer extracted with benzene, the organic layer and benzene extracts are combined and washed with dilute sodium hydroxide solution, dried, filtered, and the solvent removed leaving a red oil. The oil is vacuum distilled to give a clear pink liquid of 2-(3-methoxyphenyl)cyclohexanone.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[CH3:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(C)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Temperature: 85 °C
Yield: 37 %

Procedure:
0.1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2,5-dimethylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.04 g of the title compound. Yield 37% ES MS (+) m/z 371.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[F:14][C:15]1[CH:28]=[CH:27][C:18]2[S:19][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([CH3:22])[C:17]=2[CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:23]([C:20]2[S:19][C:18]3[CH:27]=[CH:28][C:15]([F:14])=[CH:16][C:17]=3[C:21]=2[CH3:22])(=[O:25])=[O:24])=[C:4]([O:9][C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2OC(F)(F)F)sc2ccc(F)cc12
Yield: 24.8 %

Procedure:
This compound was prepared in analogy to Example 1, starting from 4-bromo-2-(trifluoromethoxy)aniline (CAS: 175278-09-8, 2.82 g) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (0.265 g) in pyridine (2.0 ml) for 18 h to obtain the desired compound (0.12 g) as a colorless foam. MS (ISP): 501.0, 503.0 (M+NH4)+
Reaction SMILES: C([O:3][C:4](=[O:19])/[C:5](/[C:13]1S[C:15]([Br:18])=[CH:16][CH:17]=1)=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Na+].[CH3:22]O>O1CCOCC1>[Br:18][C:15]1[CH2:22][C:13](/[C:5](=[CH:6]/[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)/[C:4]([OH:3])=[O:19])=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(Br)s1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)/C(=C\C1CCCCC1)C1=CC=C(Br)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve (Z)-2-(5-bromo-thiophen-2-yl)-3-cyclohexyl-acrylic acid ethyl ester (116 g, 0.338 mol) in MeOH (600 mL) and dioxane (600 mL), add sodium hydroxide (730 mL, 1.0 M, 0.730 mol) and stir 16 h at ambient temperature. Concentrate the reaction mixture, acidify the aqueous residue with concentrated hydrochloric acid (75 mL) and extract with ethylacetate. Wash with saturated sodium chloride, dry over sodium sulfate and remove solvent under vacuum to get 124 g crude product. MS (m/e): 315.0/317.0 (M+H).