Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.C(O[Si](OCC)(OCC)[C:24]1[CH:28]=[CH:27][O:26][CH:25]=1)C.N12CCN(CC1)CC2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[O:26]1[CH:27]=[CH:28][C:24]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[O:12])[N:10]=3)[CH:7]=2)=[CH:25]1
Reactant: O=C(Nc1ccccc1)c1cn2cc(Br)ccc2n1
Reactant: CCO[Si](OCC)(OCC)c1ccoc1
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1cn2cc(-c3ccoc3)ccc2n1

Procedure:
200 mg of 6-bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 1), 10 mL of dioxane, 400 μL of 3-(triethoxysilyl)furan, 42 mg of palladium acetate, 42 mg of 1,4-diazabicyclo(2.2.2)octane (DABCO) and 1.5 mL of a molar solution of tetrabutylammonium fluoride in tetrahydrofuran are placed in a microwave tube. The reaction mixture is heated for 3 hours in a microwave machine set at 120° C., 200 μL of 3-(triethoxysilyl)furan, 20 mg of palladium acetate and 20 mg of DABCO are then added and the mixture is heated for a further 1.5 hours in a microwave machine set at 150° C. and then cooled and filtered. The filtrate is concentrated to dryness under reduced pressure and the residue is chromatographed on a silica cartridge, eluting with dichloromethane. The fractions containing the pure expected product are combined and evaporated to dryness under reduced pressure. The solid is dissolved while hot in a mixture of dichloromethane and methanol. The hot solution is filtered and treated with diisopropyl ether. The precipitate formed is filtered off by suction and dried to give 25 mg of 6-(3-furyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO.O>CCCCCC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: Brc1ccc2c(c1)CNCC2
Yield: 59.6 %

Procedure:
A mixture of 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydoisoquinoline (G. E. Stokker, Tetrahedron Letters 1996, 37, 5453) (43.4g, 0.14 mol), potassium carbonate (104.3g, 0.75 mol), methanol (1 L) and water (150ml) was heated at reflux for 1 h, then cooled and evaporated in vacuo. Residue was partitioned between water (1 L) and dichloromethane (4×200 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil which was dissolved in hexane. The mixture was filtered and the filtrate evaporated in vacuo to give the title compound as an oil (17.7 g, 60%).
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[O:15]1[CH2:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1.O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:18]2[CH2:19][CH2:20][O:15][CH2:16][CH:17]=2)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1Br
Reactant: CC1(C)OB(C2=CCOCC2)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: O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Br
Temperature: 100 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a microwave vial containing a suspension of ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (300.0 mg, 0.8849 mmol, prepared as in MPI10-008P1M) and 3,6-dihydro-2 h-pyran-4-boronic acid pinacol ester (204 mg, 0.973 mmol) in 1,4-dioxane (8.98 mL, 115 mmol) and water (0.925 mL, 51.3 mmol) were added tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.0885 mmol) and cesium carbonate (865 mg, 2.65 mmol). The vial was sealed, degassed by bubbling argon through for 10 minutes, and then heated at 100° C. with stirring for 24 h. The reaction was then cooled to room temperature and partitioned between EtOAc and water. Layers were separated, and the aqueous layer was extracted 2× with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Residue was subjected to column chromatography as a solution in DCM (40 g column, gradient elution 0 to 25% EtOAc/hexanes) to afford ethyl 3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate as a white solid (183 mg, yield 63%). LCMS: (FA) ES+ 342, 344; 1H NMR (400 MHz, DMSO) δ 6.86-6.79 (m, 1H), 4.36-4.27 (m, 4H), 3.82 (dd, J=5.4, 5.4, 2H), 2.53 (ddd, J=2.1, 4.9, 10.0, 2H), 1.30 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1>CN(C)C(=O)C.C1COCC1>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1)[CH3:3])=[CH:13]2
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1cccnc1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (1) (50 mg, 0.17 mmol) in a mixture of N,N-dimethylacetamide (1 mL) and THF (3 mL), triethylamine (0.07 mL, 0.50 mmol) and nicotinoyl chloride hydrochloride (32 mg, 0.18 mmol) were added and the resulting mixture was stirred at RT for 30 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)nicotinamide (compound 51). ESI-MS m/z: 404.0 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[CH:5][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: COC(=O)c1ccc(C)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Yield: 140.4 %

Procedure:
4-Methyl-3-(trifluoromethyl)benzoic acid methyl ester (3.73 g, 18.3 mmol) in CCl4 (40 mL) with NBS (3.9 g, 22 mmol) and benzoylperoxide with 25% of water (0.55 g, 1.7 mmol) were stirred and heated to reflux for 6 h. Solvent was evaporated, a water solution of K2CO3 was added and product is extracted with EtOAc to obtain a pale yellow solid (7.64 g, 25.7 mmol). Yield=140% (crude).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Product: O=c1oc(=O)n(CC2CC2)c2ccccc12

Procedure:
Reagents: Isatoic anhydride (4.9 mmols, 0.8 g); Sodium hydride (5.9 mmols, 0.14 g); Cyclopropylmethyl bromide (5.9 mmols, 0.8 g). Yield: 0.53 g (50%), light brown solid, m.p.=122° C.-123° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:5]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ncnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(=O)C4)c3)ncnc21

Procedure:
To a solution of {3-hydroxy-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (9.3 g, 22 mmol, as a mixture of diastereomers from Step 6) in methylene chloride (300 mL) at 0° C. was added Dess-Martin periodinane (10.0 g, 24 mmol). After a reaction time of 2 hours, the mixture was poured into 1N NaOH and extracted with three portions of DCM. The combined extracts were washed with further 1N NaOH, dried over sodium sulfate, decanted and the solvent removed in vacuo. Flash chromatography, eluting with a gradient from 0-10% MeOH in DCM afforded product as a yellow foam. Theoretical yield assumed for use in Step 8. 1H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 7.42 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.11-4.00 (m, 2H), 3.74-3.61 (m, 2H), 3.59-3.50 (m, 2H), 3.31 (s, 2H), 0.96-0.88 (m, 2H), −0.06 (s, 9H); LCMS (M+H)+: 423.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:31].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:7]=3[C:8]([NH2:31])=[N:9][C:10]=2[CH:11]=1
Reactant: CC(C)Cn1cnc2cnc3cc(Br)ccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CC#N
Product: CC(C)Cn1cnc2c(N)nc3cc(Br)ccc3c21

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (18.7 g, 58.4 mmol). 3-Chloroperoxybenzoic acid (22.1 g of 50% pure material, 129 mmol) was added in five portions during the oxidation step, and the amination with ammonium hydroxide (146 mL) and p-toluenesulfonyl chloride (16.6 g, 87.6 mmol) proceeded overnight. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration, washed with a small amount of acetonitrile, and recrystallized from acetonitrile to provide 4 g of 7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white needeles, mp 218–220° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](O)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.CCCCCC.S(Cl)([Cl:28])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([Cl:28])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5.0 g of 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid in 5.0 ml of thionyl chloride is heated on a steam bath under Argon for 1 hour and hexane added. The resulting solid is collected and dried to give 5.36 g of the desired product as a colorless oil. M+ =280 as methyl ester.
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[CH2:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[C:11]=1[NH:17]C(=O)OC(C)(C)C)[CH3:9].CCOCC>C(#N)C>[NH2:17][C:11]1[C:12]([F:16])=[N:13][CH:14]=[CH:15][C:10]=1[CH2:8][CH3:9]
Reactant: CCc1ccnc(F)c1NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCc1ccnc(F)c1N
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (2.2 g, (0.18 mmol) and sodium iodide (2.7 g, 0.18 mmol) were added to a solution of 3.6 g (0.15 mmol) of t-butyl N-(4-ethyl-2-fluoro-3-pyridyl)carbamate in 50 mL of dry acetonitrile with stirring at ambient temperature. After 2 hours the mixture was poured into ether and the resulting solution was washed with dilute aqueous sodium bisulfite, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain an oil. This oil was purified by column chromatography to obtain 1.6 g (76 percent of theory) of the title compound as a gold oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[F:45][C:46]([F:55])([F:54])[C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:53][C:50]3[CH:49]=[CH:48][C:47]([C:46]([F:54])([F:45])[F:55])=[CH:52][N:51]=3)[C:3]=2[N:10]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Nc2ncnc3sc(Cc4c(Cl)cccc4Cl)nc23)nc1
Temperature: 90 °C

Procedure:
To a mixture of 7-chloro-2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidine (120 mg, 0.36 mmol), 2-(dicyclohexylphosphino)biphenyl (25 mg, 0.07 mmol), palladium acetate (8.0 mg, 0.04 mmol), and 5-trifluoromethyl-pyridin-2-ylamine (88 mg, 0.54 mmol) in toluene (3 mL) was added NaOtBu (49 mg, 0.51 mmol) at rt. The mixture was heated to 90° C. for 18 h under N2. The reaction mixture was cooled and filtered through a pad of diatomaceous earth, eluting with EtOAc (30 mL). The filtrate was concentrated and the crude residue was purified using preparative reverse-phase HPLC to afford the title compound a colorless solid (95 mg, 58%). MS (ESI): mass calcd. for C18H10Cl2F3N5S, 455.0; m/z found, 456.0 [M+H]+. 1H NMR ((CD3)250): 9.76 (s, 1H), 8.73-8.71 (m, 2H), 8.50 (d, J=8.8 Hz, 1H), 8.23 (dd, J=8.9, 2.4 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 7.45 (dd, J=8.5, 7.7 Hz, 1H), 4.83 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cn1)cc(-c1cc(NC(=O)c3ccccc3)ccc1C)c(=O)n2C
Temperature: 65 °C

Procedure:
N-(3-(7-chloro-1,2-dihydro-1-methyl-2-oxo-1,6-naphthyridin-3-yl)-4-methylphenyl)benzamide A6 (70 mg, 0.17 mmol) is treated with sodium methoxide (0.8 mL of a 0.5 M solution in methanol) and heated to 65° C. for 3 h. The reaction is cooled to rt and partitioned with EtOAc and aqueous ammonium chloride. The organic layer is washed with brine, dried over magnesium sulfate, filtered and solvent removed. Crude product is dissolved in DMF (1 mL) and purified by preparative LCMS to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>CCCCCCC.CCOC(C)=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2cc(F)ccc2N1
Yield: 93.1 %

Procedure:
2-Amino-5-flourophenol (111MF10) (10.3 g, 81 mmol), 2-chloroacetyl chloride (10.1 g, 89 mmol) and K2CO3 (23.5 g, 170 mmol) were mixed according to GP1. CC (SiO2; Heptane/EtOAc 4:1-4) to give the title compound (111MF12) (12.6 g, 93%); 1H NMR (DMSO) d 10.68 (s, 1H, 6.83-6.91 (m, 2H, 6.75-6.80 (m, 1H, 4.57 (s, 2H; 13C NMR (DMSO) d 164.2, 157.8 (d, J=238.6 Hz), 144.0 (d, J=12.4 Hz), 123.9 (d, J=2.7 Hz), 116.3 (d, J=9.6 Hz), 108.6 (d, J=22.7 Hz), 104.0 (d, J=26.5 Hz), 66.7.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][N:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][N:27]5[CH3:26])(=[O:37])=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cn1ccc2c(S(=O)(=O)Cl)cccc21
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5c4ccn5C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1-methyl-1H-indole-4-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]([F:29])([F:28])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH:19]3[CH2:22]S[CH2:20]3)=[O:17])=[C:14]([F:25])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[O:31][S:32]([O-:34])=O.[K+]>CC(C)=O.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]([F:29])([F:28])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH:19]3[CH2:22][S:32](=[O:34])(=[O:31])[CH2:20]3)=[O:17])=[C:14]([F:25])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NC1CSC1)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CS(=O)(=O)C1)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluoro-N-(thietan-3-yl)benzamide (100 mg, 0.2159 mmol) in acetone/water (1:1, 5.0 mL) was added oxone (266 mg, 0.4319 mmol) and the resultant reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) afforded the title compound as an off white solid (70.0 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 8.07 (t, J=8.4 Hz, 1H), 7.39 (t, J=1.6 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, J=1.6 Hz, 1H), 6.60 (d, J=16.8 Hz, 1H), 6.49 (dd, J=16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H); ESIMS m/z 493.83 ([M−H]−); IR (thin film) 1527, 1113, 801, 1167, 1321 cm−1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]([OH:11])[CH3:10])=[CH:12][CH:13]=1
Reactant: CC(=O)COc1ccc(CO)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 1-(4-hydroxymethylphenoxy)-propan-2-one (1.26 g, 6.99 mmol) dissolved in methanol (60 mL) was added solid NaBH4 (0.32 g, 8.39 mmol). After completion of addition the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil (1.24 g, 6.81 mmol), which was used in the next step without any further purification (98% yield). 1H (CDCl37.29, 600 MHz): δ (2H, d, J=8.4 Hz), 6.90 (2H, d, J=8.5 Hz), 4.62 (2H, s), 4.21 (1H, m), 3.94 (1H, dd, J=9.2, 3.1 Hz), 3.82 (1H, m), 1.29 (3H, d, J=6.4 Hz).
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH2:21])[C:12]1=[O:22])[CH2:7][CH:8]([CH3:10])[CH3:9])(=O)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([CH3:34])[C:31](O)=[O:32])=[CH:26][CH:25]=1.CN(C)C=O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>CO>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C@@H:30]([CH3:34])[C:31]([NH:21][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[CH:19]=[CH:20][N:11]([C@@H:6]([CH2:5][OH:4])[CH2:7][CH:8]([CH3:9])[CH3:10])[C:12]3=[O:22])=[O:32])=[CH:28][CH:29]=1
Reactant: CC(=O)OC[C@@H](CC(C)C)n1ccc2c(N)cccc2c1=O
Reactant: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)C[C@H](CO)n1ccc2c(NC(=O)[C@H](C)c3ccc(Cl)cc3)cccc2c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 20 ml reaction vial reaction vial was combined (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-4-methylpentyl acetate (0.23 g, 0.00076 mol), (R)-2-(4-chlorophenyl)propanoic acid (0.175 g, 0.000949 mol) N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.58 g, 0.0015 mol) N,N-diisopropylethylamine (0.26 mL, 0.0015 mol), and N,N-dimethylformamide (4 mL, 0.06 mol). The mixture was heated at 50° C. for 3 hours and allowed to cool to room temperature. The mixture was poured on to saturated sodium bicarbonate (200 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were dried over sodium sulfate and reduced in vacuo to yield a light brown oil. The oil was taken up in methanol (10 ml) and 2N NaOH (10 ml) was added. The mixture was allowed to stir overnight. The volatiles were removed and the mixture was extracted with methylene chloride (2×20 ml). The combined extracts were reduced in vacuo and the mixture was purified by reversed phase prep HPLC using an acetonitrile: water gradient at pH 10. The combined pure fractions were reduced in vacuo to yield the title compound as yellow solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].FC(F)(F)C(O)=O.[NH2:13][C@H:14]1[CH2:17][O:16][C:15]1=[O:18].[OH-].[Na+]>O>[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:17][C@@H:14]([C:15]([OH:18])=[O:16])[NH2:13]
Reactant: NCCS
Reactant: N[C@H]1COC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCCSC[C@H](N)C(=O)O

Procedure:
To 2-aminoethanethiol hydrochloride (201 mg, 1.77 mmol) in degassed H2O (3.0 mL) was added (S)-3-amino-2-oxetanone trifluoroacetic acid salt (produced from BOC-L-serine β-lactone (151 mg, 0.807 mmol)) in H2O (1.0 mL). The pH of the stirred solution was maintained at 5.0-5.5 by dropwise addition of 1N NaOH. When additions of base were no longer required to maintain the pH at 5.5 (~35 min), the mixture was applied to a column of BioRad AG50-X8 (trademark) (80 mL, 3 cm dia., H+ form) and eluted with a linear gradient (0 to 0.2M over 1.0 L) of aqueous HC1 (2 mL/min). Lyophilization of the chromatographically pure fractions yielded 138 mg 85%) of S-(aminoethyl)-L-cysteine hydrochloride which was recrystallized from EtOH/acetone (85% recovery) for elemental analysis: mp 193°-194° C. (dec) (lit. mp 192°-192.5° C., 205°-207° C.); [α]D 25 +7.2 (c 1.0, H2O) (lit. [α]D +7.2 (c 1, H2O)); IR (KBr disk) 3650-2100 (s, br), 2000 (W, br), 1622 (s), 1587 (s), 1516 (s), 1494 (s), 1463 (s), 1427 (s), 1415 (s), 1400 (s), 1348 (s), 1303 (s), 560 (m) cm-1 ; 1H-NMR (300 MHz, D2O)δ 4.00 (dd, 1H, 4.8, 6.0 Hz, CH), 3.27 (t, 2H, 6.5 Hz, CH2NH3+), 3.16 (dd, 1H, 4.8, 14 Hz, CHCHHS), 3.14 (d, 6.0, 14 Hz, CHCHHS), 2.94 (t of d, 1H, 6.5, 14 Hz, SCHH), 2.92 (t of d, 1H, 6.5, 14.0 Hz, SCHH). Anal. Calc. for C5H13N2O2SCl: C, 29.92; H, 6.54; N, 13.96; Cl, 17.66; S, 15.97. Found: C, 29.59; H, 6.44; N, 13.98; Cl, 17.40; S, 15 88; POSFAB-MS (glycerol/HC1) 165 (MH+), 329 (M2H+); Rf~0.20 (System A).