Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19][NH:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCn1nccc1N
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC

Procedure:
245 g of 1-ethyl-5-aminopyrazole (2.2mol) and 476 g of ethoxymethylene malonic acid diethyl ester (2.2 mol) are heated to 120° (bath temperature) for 2 hours with stirring. The ethanol formed by this reaction is removed by means of a water aspirator. Vacuum distillation (b.p.0.1 154°-160°) yields 520 g (84% of theory) of a quickly crystallizing oil of [[(1-ethyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester, m.p. 50°-53°. The compound is recrystallized from N-hexane, and has a melting point of 55°-57°.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:16][O:17][C:18](=[O:29])[CH:19]([NH:20][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Agent: [Pd]
Solvent: COc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 40.1 %

Procedure:
To a mixture of 2-benzoylcyclohexanone (90.9 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-((2-benzoylphenyl)-amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (60.2 g, 40.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].I[C:34]1[C:39]([CH3:40])=[CH:38][N:37]=[C:36]([O:41][CH3:42])[C:35]=1[CH3:43].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[F:1][C:2]1[CH:7]=[C:6]([C:34]2[C:39]([CH3:40])=[CH:38][N:37]=[C:36]([O:41][CH3:42])[C:35]=2[CH3:43])[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1ncc(C)c(I)c1C
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: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(-c2c(C)cnc(OC)c2C)cc1F
Temperature: 25 °C

Procedure:
Ethyl 5-(4-bromo-2,5-difluorophenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate obtained in Preparation Example 11-1 (4.31 g), bis(pinacolato)diboron (3.27 g), potassium acetate (3.16 g) and Pd(dppf)Cl2-DCM complex (439 mg) were added to DMF (41.6 mL), and the mixture was stirred at 95° C. in a nitrogen atmosphere. After two hours, the reaction mixture was stirred at 105° C. for four hours. The reaction mixture was cooled to room temperature and filtered through Celite™. The filtrate was concentrated under reduced pressure, brine and ethyl acetate were added to the residue, and the mixture was then stirred at room temperature for five minutes. The mixture was filtered again through Celite™, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered through Celite™. The filtrate was concentrated. The residue was purified by silica gel chromatography (n-heptane/ethyl acetate, 20% to 30% to 80%) to give ethyl 5-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (2.95 g). The resulting ethyl 5-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (900 mg), 4-iodo-2-methoxy-3,5-dimethylpyridine obtained in Preparation Example 29(3) (634 mg), Pd(PPh3)4 (116 mg) and cesium carbonate (1.96 g) were added to a mixed solvent of 1,4-dioxane (9.3 mL) and water (3.1 mL), and the mixture was heated under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and partitioned by adding ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, first time: 15% to 36% to 47%, second time: 10% to 30% to 35%) to give the title compound (280 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13].[Br:17]Br>C(O)(C)C>[Br:17][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11](=[O:16])(=[O:15])[N:12]([CH3:13])[CH3:14])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Reactant: BrBr
Solvent: CC(C)O
Product: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl

Procedure:
7.9 g of 4'-chloro-3'-dimethylsulfamoylacetophenone were reacted according to Example 1(a) with 4.8 g of bromine and worked up. Colorless crystals from isopropanol, melting point: 98° C.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].[BH4-]>C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)=Cc1ccc(CO)cc1

Procedure:
To a suspension of 10.0 g of 50% sodium hydride (dispersion in mineral oil) in freshly distilled dimethyoxyethane (DME, 350 ml) stirred under nitrogen at 10° is added 53.6 ml of triethyl 2-phosphonopropionate in ca. 40 minutes. The mixture is stirred for 0.5 hour at 10° and for an additional 1.5 hours during which time the temperature is allowed to rise to room temperature. This solution is transferred under nitrogen by cannula to a 500 ml addition funnel and is added dropwise to a solution of terephthalaldehyde (33.53 g) in dry DME (475 ml) over a period of 1 hour at 22-341. After addition is complete the reaction mixture is stirred mechanically at room temperature for 2 hours, poured into 1L of water and extracted with 4×500 ml of ether. The ether extract is washed with a saturated sodium chloride solution (700 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil which partially crystallizes on standing. This crude mixture is purified by suspending in petroleum ether and ethyl acetate (93:7). The filtrate, after removal of unreacted dialdehyde, is concentrated in vacuo to give a mixture which is further purified by high pressure liquid chromatography (using petroleum ether/ethyl acetate 93:7). There is obtained pure ethyl 4-formyl-α-methylcinnamate. A solution of the aldehyde (34.80 g) in 820 ml of absolute ethanol is treated with 12.11 g of granular sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred at room temperature for 3 hours (or until all borohydride has dissolved) and then concentrated to ca. 200 ml volume, diluted with 400 ml of water, and extracted with 3×200 ml of ether. The ether extract is washed with 100 ml of water and brine (100 ml), is dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to give ethyl 3-(p-hydroxymethylphenyl)-2-methylacrylate. To a solution of this product in 350 ml of methylene chloride is added at room temperature 11.53 ml of thionyl chloride dropwise over 25 minutes. The clear, colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated sodium bicarbonate, 100 ml of water, and 100 ml of brine. The organic layer after drying and removal of solvent yields ethyl 3-(p-chloromethylphenyl)-2-methylacrylate which can be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][CH2:24][C:25]#[N:26])=[O:12])=[CH:5]2.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].CCOC(C)=O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]1[NH:23][CH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)=[O:12])=[CH:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCNC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1Cc2ccccc2[C@H]1NCc1nnn[nH]1)c1cc2cc(Cl)ccc2[nH]1
Yield: 17.2 %

Procedure:
5-Chloro-N-{1-[(cyanomethyl)amino]-2,3-dihydro-1H-inden-2-yl}-1H-indole-2-carboxamide (Example 25; 182 mg, 0.5 mmol), sodium azide (195 mg, 3.0 mmol) and ammonium chloride (163 mg, 3.05 mmol) in DMA (5 mL) were heated in a microwave at 180° C. for 1 min. EtOAc (50 mL) was added and the mixture washed with water (6×10 mL), brine (25 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure. The desired component was isolated by preparative HPLC (CH3CN:water) to give the title compound (35 mg, 14%) as a pale orange powder.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH3:20][CH:21]([S:23]([NH:26][C@@H:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:36](Cl)=[O:37])[CH:33]=2)[CH2:28]1)(=[O:25])=[O:24])[CH3:22].O>C(Cl)Cl>[CH3:22][CH:21]([S:23]([NH:26][C@@H:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:36]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[O:37])[CH:33]=2)[CH2:28]1)(=[O:25])=[O:24])[CH3:20]
Reactant: CS(=O)(=O)Nc1ccccc1N
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(C(=O)Cl)cc2C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(C(=O)Nc3ccccc3NS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A mixture of triethylamine (0.083 mmol, 0.012 mL, 8.38 mg) and N-(2-aminophenyl)methanesulfonamide (0.083 mmol, 15.43 mg) in DCM (2 mL) was added to a solution of (S)-2-(1-methylethylsulfonamido)-2,3-dihydro-1H-indene-5-carbonyl chloride (0.083 mmol, 25 mg) in DCM (1 mL) was added. The reaction mixture was stirred at room temp overnight. H2O was added and the reaction mixture filtered through a hydrophobic frit and the DCM layer was concentrated under reduced pressure. The residue was purified by prep-HPLC to give desired product (10.7 mg, 28.6%). MS (ESI): m/z [M−H]− 450.2
Reaction SMILES: [OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[C:23](=[O:29])[CH2:22][C@@:21]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:20])[CH2:13][CH2:14][O:15][C:16](=[O:19])[CH2:17]I)[CH2:3]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl>[OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[C:23](=[O:29])[CH2:22][C@@:21]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:20])[CH2:13][CH2:14][O:15][C:16](=[O:19])[CH2:17][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:3]1
Reactant: C1COCCN1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCOC(=O)CI)[C@@]3(C)CC(=O)[C@@H]12
Solvent: ClCCl
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCOC(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3α-Hydroxy-21-iodoacetoxymethyl-5α-pregnane-11,20-dione (230 mg) in dry dichloromethane (25 ml) was treated with morpholine (1.0 ml) and the solution was stirred at room temperature for 30 minutes. The solution was diluted with dichloromethane, washed twice with water, dried over sodium sulphate and evaporated to a colourless gum (230 mg) which was purified by preparative t.l.c. in acetone/petrol 1:1. The main band was separated to give title compound (172 mg) as a white foam, [α]D + 79° (c 0.68).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)c(F)c1
Temperature: 75 °C
Reaction time: 12 h
Yield: 76.5 %

Procedure:
A mixture of 1,2-difluoro-4-nitrobenzene (1.0 g, 6.29 mmol), 2-morpholinoethanol (1.0 g, 7.62 mmol) and Cs2CO3 in DMF (10 mL) was stirred at 75° C. for 12 h. 30 mL of water was then added and the resulting mixture was extracted with DCM (30 mL×2). The combined organic phases were washed with brine (30 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as yellow oil (1.30 g, 76%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][CH:15]2[C:27](=[O:28])[N:19]3[C:20]4[C:25]([CH:26]=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31].[CH2:32]=O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][CH:15]2[C:27](=[O:28])[N:19]3[C:20]4[C:25]([C:26]([CH2:29][N:30]([CH3:32])[CH3:31])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CNC
Reactant: Cc1c(CC2CCc3cc4ccccc4n3C2=O)ncn1Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1c(CC2CCc3c(CN(C)C)c4ccccc4n3C2=O)ncn1Cc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 7-[(1-benzyl-5-methyl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (451 mg) in acetic acid (2.5 ml) at 10° C. were added successively aqueous 50% dimethylamine solution (0.17 ml) and aqueous 35% formaldehyde solution (0.16 ml). The mixture was heated at 60° C. for 16 hours. After evaporation of the solvent, the residue was dissolved in water, made basic with aqueous 3N sodium hydroxide solution, and extracted twice with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (methanol-chloroform) to give 7-[(1-benzyl-5-methyl-1H-imidazol-4-yl)methyl]-10-[(dimethylamino)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (233 mg) as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH3:39])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH:29]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]([CH3:39])[CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:36][CH2:37]1)([CH3:31])[CH3:30]
Reactant: CNC1CCN(C(C)C)CC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN(C)C3CCN(C(C)C)CC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-isopropyl-N-methylpiperidin-4-amine via General Procedure E to give 22.1 mg of 295 following reverse phase purification. MS (Q1) 518.3 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:32])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([C:28]([F:30])([F:31])[F:29])[CH2:26][CH2:27]3)[C:17]([OH:19])=[O:18])[C:10](=[O:32])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
295 mg (594 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoate (racemate) in 6 ml of dichloromethane and 915 μl (11.9 mmol) of TFA were reacted according to General Method 6A. Yield: 258 mg (purity 92%, 91% of theory)
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>C(#N)C.[F-].[K+]>[Br:20][C:14]1[CH:15]=[C:16]([C:4]2[CH:3]=[C:2]([F:1])[N:7]=[CH:6][C:5]=2[NH2:8])[C:11]([F:10])=[N:12][CH:13]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: Nc1cnc(F)cc1I
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cnc(F)cc1-c1cc(Br)cnc1F
Temperature: 80 °C
Yield: 28.6 %

Procedure:
A mixture of 6-fluoro-4-iodopyridin-3-ylamine (1.57 g, 6.59 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.17 g, 9.89 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.43 g, 0.53 mmol) in acetonitrile (25 mL) and 1N aqueous potassium fluoride solution (25 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was heated at 80° C. for 3 h, allowed to cool to ambient temperature and then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-50% ethyl acetate in cyclohexane) to afford the title compound as an brown solid (0.54 g, 29%). 1H NMR (CDCl3, 300 MHz): 8.37 (dd, J=2.5, 1.4 Hz, 1H), 7.99 (dd, J=8.1, 2.5 Hz, 1H), 7.79 (d, J=1.5 Hz, 1H), 6.74 (d, J=2.8 Hz, 1H), 3.62 (s, 2H). LCMS (Method B): RT=3.01 min, M+H+=286/288.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:16])[C:8](=[O:9])[C:7]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:6]=2[O:5]1.C([O-])(=O)C.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[Br:1][C:11]1[C:12]([CH3:14])=[CH:13][C:6]2[O:5][C:4]([CH3:16])([CH3:3])[C:8](=[O:9])[C:7]=2[C:10]=1[CH3:15]
Reactant: BrBr
Reactant: Cc1cc(C)c2c(c1)OC(C)(C)C2=O
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc2c(c(C)c1Br)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
Bromine (8.7 mL, 169 mmol) was added to a mixture of acetonitrile (200 mL) containing 2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (30.7 g, 161 mmol) synthesized in Reference Example 118 and sodium acetate (14.5 g, 177 mmol), and the mixture was stirred at room temperature for 2 hours. After that, the reaction solution was poured into 5% sodium sulfite aqueous solution, and extraction was performed using ethyl acetate. The extract was washed with water and saturated saline, and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 50:1-9/1), and crystallization was performed using methanol to give 26.2 g of the title compound (yield: 61%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.O.[OH-].[Na+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH2:12])[CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])c1cccc2cnc(Cl)cc12
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc2cnc(Cl)cc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
3-chloro-5-nitro-isoquinoline (20.9 g., 0.1170 mole, prepared according to the method of Example 1 hereinabove) was suspended in glacial acetic acid (160 ml), and water (160 ml) was then added while the temperature of the mixture was being raised to 60°C. Keeping the temperature between 60° and 70°C, powdered iron (15.2 g) was added slowly to the stirred mixture, and stirring was continued for 2 hours after addition of the iron was completed. The reaction mixture was allowed to stand overnight, and was then made alkaline with 20% w/v aqueous sodium hydroxide solution, and filtered. The residue was dried overnight, over silica gel in a vacuum oven at 50°C. The dried cake was then broken up and extracted -- three times with ether under reflux. The ether extract was boiled with charcoal, dried over anhydrous sodium sulphate, filtered, and the ether evaporated off to yield 9.25 g of 3-chloro-5-amino-isoquinoline of m.p. 176° - 177°C. Further ether extraction of the filter cake yielded another 4.2 g of 3-chloro-5-amino-isoquinoline of m.p. 175° - 177°C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[Br:11]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>CN(C)C=O.O>[Br:11][CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1c(Cl)cncc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Clc1cncc(Cl)c1CBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
A cold (0° C.) solution of 4-hydroxymethyl-3,5-dichloropyridine (3.0 g) and N-bromosuccinimide (6.1 g) in dry dimethylformamide (100 mL) is treated with triphenylphosphine (8.9 g), portionwise, during 5 minutes. The resulting red solution is stirred at 0° C. for 45 minutes, and then treated with methanol (5 mL), followed by water (300 mL). The mixture is extracted with diethyl ether (4×200 mL), the combined organic washings dried over sodium sulfate, and the solvent removed under reduced pressure. The resulting residue is chromatographed on silica gel, eluting with a mixture of diethyl ether and pentane (1:2 v/v), to give 4-bromomethyl-3,5-dichloropyridine (3 g), in the form of an off-white solid, m.p. 40°-44° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH2:9]([O:11][C:12](=[O:19])[CH:13]([CH:17]=O)[C:14](=O)[CH3:15])[CH3:10].N1C=CC=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH3:15])=[N:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:17]=1)=[O:19])[CH3:10]
Reactant: CCOC(=O)C(C=O)C(C)=O
Reactant: NNc1ccccn1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(-c2ccccn2)nc1C

Procedure:
Similar to Example 1, equimolar amounts of 2-pyridylhydrazine and 2-formyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that the resulting solid was determined to be the named product (m.p. 49° C.–50° C.).