Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[CH3:22][N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)[CH3:23]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(CN(C)C)cc2)ccc1=O
Reactant: NNc1ccccc1F
Product: CN(C)Cc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-dimethylaminomethyl-phenyl)-1H-pyridazin-4-one (A-28) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=390.1 (M+H)+
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:12][C:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)=[O:14])[C:10]#[N:11])=[CH:4][CH:3]=1.[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[C:10]([C@@H:9]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1)=[O:14])[CH2:8][C:5]1[CH:6]=[N:7][C:2]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[OH:28])=[CH:3][CH:4]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1O
Product: N#C[C@H](Cc1ccc(-c2ccccc2O)nc1)NC(=O)[C@@H]1CCCCN1

Procedure:
Prepared by a process analogous to that described in Method 2 Example 2 using (S)-tert-butyl 2-((S)-2-(6-bromopyridin-3-yl)-1-cyanoethylcarbamoyl)piperidine-1-carboxylate and 2-hydroxyphenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>C(O)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:31]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(NN)cc1
Reactant: COc1ccc(C(=O)CC(=O)c2ccc(OC)cc2)cc1
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(-c3ccc(OC)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 1 (1.0 equiv.), 4-methoxyphenyl hydrazine (1.5 equiv.) conc. HCl aq. (catalytic amount) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCl, brine, dried, filtered and the solvent was concentrated in vacuo to give the product 1-[1,5-bis(4-methoxyphenyl)pyrazol-3-yl]-4-methoxybenzene.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]1[C:10]([NH2:12])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]1[CH2:10][NH2:12]
Reactant: NC(=O)C1Oc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1Oc2ccccc2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzo[1,3]dioxole-2-carboxylic acid amide (5.44 g, 32.9 mmol) was dissolved in tetrahydrofuran (THF, 100 mL). Lithium aluminum hydride (LAH, 1M in THF, 39.5 mL, 39.5 mmol) was added slowly to the solution at room temperature. The reaction was stirred at room temperature for 24 hours. Distilled water was added to destroy the excess LAH. Aqueous sodium hydroxide (3.0 M, 100 mL) was added and the solution was extracted with ethyl acetate (3×100 mL). The combined organic solution was washed with water and dried over MgSO4. The solvent was evaporated to yield C-benzo[1,3]dioxol-2-yl-methylamine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:20]([CH3:19])[CH3:30])=[CH:28][CH:27]=3)=[O:18])=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1
Product: CN(C)CCc1ccc(NC(=O)/C=C/c2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared analogously to Example 143 starting from (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylic acid (Z34b) and 4-(2-dimethylamino-ethyl)-phenylamine. The crude product was purified by column chromatography (silica gel, dichloromethane/EtOH/conc. aqueous ammonia 50:10:0.1).
Reaction SMILES: [O:1]=[C:2]([C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[N:9][CH:10]=1.[BH4-].[Na+].CO.C(Cl)(Cl)Cl>CO>[OH:1][CH:2]([C:19]1[N:20]=[C:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:22][C:23]=1[CH3:24])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[N:9][CH:10]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CC2SC(=O)NC2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1C(O)COc1ccc(CC2SC(=O)NC2=O)nc1

Procedure:
200 mg (0.47 mmol) of 5-((5-(2-oxo-2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy)-2-pyridyl)methyl)thiazolidin-2,4-dione (Compound No. I-2a-1) was dissolved in 5 ml of methanol dehydrated with molecular sieve. To this solution, was added 21.5 mg of sodium borohydride, and the resultant solution was stirred at room temperature for 1 day. The reaction was terminated with a saturated aqueous solution of ammonium chloride, and the reaction mixture was extracted with chloroform. The reaction product thus obtained was washed with brine, and was dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the solvent was distilled off under a reduced pressure to obtain a residue, and the residue thus obtained was subjected to silica gel column chromatography (eluent: 10%--methanol/chloroform) to obtain 203 mg (quantitative) of pale brown powder of the aimed product (Compound No. I-2a-3).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3[O:17][C:18](Br)=[CH:19][CH:20]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3[O:17][C:18]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)=[CH:19][CH:20]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1
Reactant: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(Br)o1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(-c2ccc(F)cc2)o1

Procedure:
The furyl bromide (84) (100 mg, 0.29 mmol) was coupled to 4-fluoro-phenylboronic acid (44 mg, 0.32 mmol) using Method E. The solvents were removed in vacuo as described, but the residue was dissolved in 2M NaOH (10 ml) and washed with EtOAc (2×10 ml). The aqueous layer was acidified to pH 1 with 2M HCl until a white precipitate formed and extracted with EtOAc (2×10 ml). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.[C:21](=[O:23])=[O:22]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:21]([OH:23])=[O:22])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: OCCc1csc(-c2ccc(Cl)cc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccc(Cl)cc2)nc1CCO
Temperature: -75 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Dissolve 2-[2-(4-chloro-phenyl)-thiazol-4-yl]-ethanol (107 g gross, 91 g net, 380 mmol) in THF (1210 mL) and cool to about −75° C. Evacuate the chilled solution under vacuum and fill with nitrogen three times. Slowly add n-BuLi (1.6 M in hexanes, 530 mL, 848 mmol) over approximately 4 h, keeping the temperature<−70° C. Slowly add the red-purple solution via cannula over 3.5 h to a flask containing −75° C. THF that has been saturated with CO2 gas (approximately 390 g) keeping the temperature<−60° C. Charge the resulting brown slurry with additional CO2 gas (approximately 355 g) and then allow the slurry to come to room temperature while stirring mechanically overnight. Quench the reaction with 1 N HCl (3000 mL), cool to 16° C., and collect the precipitate by filtration. Rinse the solid with hexanes (1400 mL) and dry under vacuum to give 81.3 g (75%) of the title compound. ES/MS m/z (35Cl) 284.0 [M+1]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=1[CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:10]([N+:25]([O-:27])=[O:26])=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=1[CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2]
Reactant: CCCc1c(NC(C)=O)ccc(C(C)=O)c1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc([N+](=O)[O-])c1NC(C)=O

Procedure:
1-(4-Acetylamino-2-hydroxy-3-propylphenyl)ethanone (58.75 g) was suspended in glacial acetic acid (750 ml), and this suspension was treated with a mixture of glacial acetic acid (250 ml), acetic anhydride (48 ml) and conc. nitric acid (10.2 ml) with vigorous stirring. After 18 hours the insoluble material was collected and dried in vacuo to afford the title compound 29.1 g. The structure was confirmed by NMR and mass spectrometry.
Reaction SMILES: Cl[CH:2]([C:7]1([C:16]([F:19])([F:18])[F:17])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[H][H]>C1COCC1.[Pd]>[F:6][C:3]([F:4])([F:5])[CH2:2][C:7]1([C:16]([F:17])([F:19])[F:18])[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[O:11]1
Reactant: [H][H]
Reactant: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1

Procedure:
306.5 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole of Example 2a were dissolved in 500 ml of THF and the solution was treated with 101 g of triethylamine and 30 g of palladium on charcoal (5% strength by weight). The mixture was then hydrogenated for 48 hours at 110° C. under 100 bar hydrogen. The mixture was subsequently filtered, the solvent was stripped off, and the residue was subjected to fractionation in vacuo. The yield was 126 g (46% of theory), and the boiling point was 60° C. at 10 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -59.0 and -84.6 ppm. 1H-NMR: 3.02 ppm.
Reaction SMILES: CO.[OH-].[Na+].[O:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([O:14]CC)=[O:13])[CH2:7][CH2:6]1>O>[O:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCOCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20 ml of methanol, 10 ml of water and 1 g of sodium hydroxide were added to 0.9 g of ethyl 4-tetrahydropyranylacetate and agitated at 80° C. for 1 hour. The solvent was removed by distillation, to which water was added. After washing with ethyl acetate, a hydrochloric acid aqueous solution was added to the resultant aqueous phase to an extent of pH of 3, followed by extraction with chloroform under salting-out conditions and drying with anhydrous magnesium sulfate. This was removed by filtration and the solvent was distilled off, thereby obtaining 0.87 g of a crude intended compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=1)(=[O:3])[CH3:2].CC1C=CC(S(O[CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: CC(=O)OCc1cc(O)cc(C)c1-c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Temperature: 90 °C
Reaction time: 21 h
Yield: 60.1 %

Procedure:
To a solution of [4-hydroxy-3′-(hydroxymethyl)-6-methylbiphenyl-2-yl]methyl acetate (1.02 g, 3.56 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (1.25 g, 4.27 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.640 g, 4.32 mmol), and the mixture was stirred at 90° C. for 21 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0) to give the title compound (0.87 g, yield 60%) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=O)[CH3:3].[C:7]12[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12]C(=O)O[C:8]2=[O:9]>N1C=CC=CC=1>[CH3:3][C@H:2]1[NH:1][C:8](=[O:9])[C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][C:4]1=[O:6]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: C[C@@H](N)C(=O)O
Solvent: c1ccncc1
Product: C[C@H]1NC(=O)c2ccccc2NC1=O
Yield: 20.7 %

Procedure:
Following the procedure of Example 5, D-alanine (73.6 mmol) and isatoic anhydride (61.3 mmol) were allowed to reflux in pyridine (50 mL) to give (3R)-3-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (12.7 mmol) as a light brown solid.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
A solution of KOH (0.19 g, 3.43 mmol) in ethanol (5 mL) was added to a solution of 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-malonic acid diethyl ester (1.20 g, 3.27 mmol) in ethanol (5 mL) and methylene chloride (5 mL) at 0° C. The mixture was stirred for 18 h at room temperature. The mixture was concentrated under reduced pressure and water was added to the residue. The aqueous layer was washed with diethyl ether, acidified to pH 4 by 1M HCl, and extracted with methylene chloride. The organic layer was washed with water, brine and dried. After filtration and evaporation in vacuo, the crude product was purified by flash chromatography (CH3OH/CH2Cl2, 1:20) to yield 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-malonic acid monoethyl ester (0.90 g, 81%).
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:31]=[CH:30][C:19]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:18]([F:32])[CH:17]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[CH3:35]B1OB(C)OB(C)O1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:32][C:18]1[CH:17]=[C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([CH3:35])=[CH:3][C:4]=2[O:33][CH3:34])[CH:31]=[CH:30][C:19]=1[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27]
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Yield: 58.4 %

Procedure:
Following General Procedure I, tert-butyl 4-(6-bromo-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)-2-fluorophenethylcarbamate (300 mg, 0.55 mmol) was reacted with trimethylboroxine (207 mg, 1.65 mmol) and Pd(pph3)4 (63 mg, 0.05 mmol) to afford the desired product (155 mg, 58%) as a brown solid. ESI MS m/z 483 [C26H27FN2O4S+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:25])[NH:18][C@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH3:24][C@@H:19]([NH:18][C:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH2:8])=[CH:15][CH:14]=1)=[O:25])[C:20]([F:23])([F:21])[F:22]
Reactant: C[C@@H](NC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](NC(=O)Cc1ccc(CN)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Dissolve (R)—N-(tert-butoxycarbonyl)-4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzylamine (155 mg, 0.43 mmol) in DCM (8 mL). Add 4M hydrogen chloride in dioxane (0.85 mL) and stir at room temperature overnight. Concentrate in vacuo and partition the hydrochloride salt between saturated aqueous NaHCO3 and EtOAc. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound (105 mg, 91%). MS (ES+) m/z: 261 (M+H)+.
Reaction SMILES: Cl.OO.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][CH:13]=[O:14].[O-:15]Cl=O.[Na+]>O.CC#N.[O-]Cl=O.[Na+]>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]([OH:15])=[O:14]
Reactant: [O-][Cl+][O-]
Reactant: O=CC#Cc1ccccc1F
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C#Cc1ccccc1F
Yield: 86 %

Procedure:
A mixture of NaH2PO4 (37 g, 0.3 mol, 0.3 equiv) in water (330 mL) buffered to pH 2 with conc. HCl and H2O2 (30%, 112 mL, 1.1 mol, 1.1 equiv) was added to a solution of 3-(2-fluorophenyl)prop-2-ynal (151 g, 1.02 mol) in CH3CN (830 mL). The resulting mixture was cooled in an ice bath and was treated slowly with a solution of NaClO2 (102 g, 1.1 mol, 1.1 equiv) in water (1.1 L), keeping the temperature below 10° C. After 30 min a solution of NaClO2 (5.8 g, 64 mmol, 0.06 equiv) in water (50 mL) was added. After another 30 min the layers were separated and the aqueous layer was washed with EtOAc (3×500 mL). The organic layers were combined and back-extracted with a saturated NaHCO3 solution (3×500 mL). The aqueous layers were combined, acidified to pH 1 with conc. HCl and extracted with EtOAc (3×500 mL). The combined organic layers were washed with a saturated NaCl solution (1 L), dried (Na2SO4) and concentrated under reduced pressure to give 3-(2-fluorophenyl)prop-2-ynoic acid (144 g, 86%) as a yellow solid: TLC (1% AcOH/CH2Cl2) Rf 0.34; 1H NMR (CDCl3+d4-MeOH) δ 6.98-7.08 (m, 2H), 7.29-7.48 (m, 2H), 12.77 (br s, 1H); 13C NMR (CDCl3+d4-MeOH) δ 78.3, 85.7 (d, JC−F=2.5 Hz, 1C), 108.3 (d, JC−F=15.8 Hz, 1C), 115.4 (d, JC−F=20.7 Hz, 1C), 124.0, 132.1 (d, JC−F=7.3 Hz, 1C), 134.1 (d, JC−F=9.8 Hz, 1C), 135.2, 154.8, 163.1 (d, JC−F=256.1 Hz, 1C).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:16]#[C:17][Si](C)(C)C)=[O:5])[CH3:2].[OH:22]S(O)(=O)=O.CC(C)=O>O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:16](=[O:22])[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C#C[Si](C)(C)C
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C(C)=O
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-1,5-dimethyl-6-oxo-2-trimethylsilanylethynyl-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent), HgSO4 (1.00 equivalent) and H2SO4 (2.00 equivalents) in ˜6:1 acetone:water is refluxed for 3 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with a mixture or THF and ethyl acetate and washed with water and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure. The desired product is obtained by flash column chromatography as necessary.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>CC#N>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:20])=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ccc(Cl)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cc(Br)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To 6-chloro-3,3-dimethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl-ester (0.500 g, 2.75 mmol) in MeCN (3.78 mL) was added N-bromosuccinimide (0.492 g, 2.76 mmol) at room temperature. The reaction was stirred for 1 h at room temperature and concentrated. Chromatography (silica gel, gradient elution, 0-40%, EtOAc in petrol 40-60) gave the title compound (356 mg), 1H NMR (Me-d3-OD): 7.80 (1H, s), 7.43 (1H, s), 3.73 (2H, s), 1.66-1.51 (9H, m), 1.32 (6H, s).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH:9]([NH2:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:18][CH:9]([C:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC1CCN(C(=O)C(N)CCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CCN(C(=O)C(CCc2ccccc2)NS(=O)(=O)c2ccccc2Cl)CC1
Reaction time: 16 h

Procedure:
A mixture of 29 mg (0.11 mmol) of 1-(4-methylpiperidin-1-yl)-1-oxo-4-phenylbutan-2-amine, 2-chlorobenzenesulfonyl chloride, and 0.19 mL (0.11 mmol) of iPr2NEt in 4 mL of CH2Cl2 is stirred for 16 h, concentrated, and purified by preparative HPLC to provide Example 1
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:19][NH:20][C:21]([NH:23][CH3:24])=[O:22].C(O)C>Cl.O>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]2[N:23]([CH3:24])[C:21](=[O:22])[N:20]([CH3:19])[C:14](=[O:16])[CH:13]=2)[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: CNC(=O)NC
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1OC
Temperature: 120 °C
Yield: 69.4 %

Procedure:
To a mixture of ethyl veratroylacetate (10 g) and N,N'-dimethylurea (3.84 g) were added conc. hydrochloric acid (1 drop) and ethanol (1 ml). The mixture was heated at 120° C. for 3.5 hours under reduced pressure. To the residue was added another conc. hydrochloric acid (2 drops) and the mixture was heated again at 120° C. for 4 hours under reduced pressure. To the reaction mixture was added water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with a mixture of isopropyl ether and ethyl acetate to give 6-(3,4-dimethoxyphenyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (7.60 g).