Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([CH3:20])[N:5]=[C:4]([Cl:21])[C:3]=1[Cl:22].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(O)C>[Cl:1][C:2]1[C:7]([C:8]([C:10](=[CH:16][NH:26][CH:23]2[CH2:25][CH2:24]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([CH3:20])[N:5]=[C:4]([Cl:21])[C:3]=1[Cl:22]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)nc(Cl)c(Cl)c1Cl
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)nc(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
27 g (0.07 mol) of ethyl 2-(4,5,6-trichloro-2-methyl-nicotinoyl)-3-ethoxyacrylate are placed at 0° C. in 93 ml of ethanol, and 4.3 g (0.07 mol) of cyclopropylamine in 34 ml of ethanol are added dropwise. The mixture is stirred at room temperature for thirty minutes and cooled to 0° C. and the product which precipitates is isolated and washed with cold ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cccc(Cl)c4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cccc(Cl)c4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-(4-(3-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (186.7 mg, 0.41 mmol, 1.00 equiv) and sodium hydroxide (82 mg, 2.05 mmol, 5.00 equiv) in tetrahydrofuran/MeOH (1:1) (25 mL) was placed in a 50-mL round bottom flask, stirred for 8 h at 50° C. in an oil bath, and then concentrated under vacuum. This resulted in 177.7 mg (95%) of 3-(4-(3-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][O:4][C:3]1=[O:7].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C[Al](C)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][C:3](=[O:7])[C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5][OH:4]
Reactant: CC1(C)CCOC1=O
Reactant: NCc1ccccc1Cl
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(CCO)C(=O)NCc1ccccc1Cl
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution of 3,3-dimethyl-dihydrofuran-2(3H)-one (2.04 g, 17.9 mmol) in THF (15 mL) were added 2-chlorobenzylamine (2.4 mL, 19.9 mmol, 1.1 equiv.) and AlMe3 (2M in toluene, 4.5 mL, 9 mmol, 0.5 equiv.). The reaction mixture was stirred for 3 days. The reaction mixture was saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4, and concentrated to give N-(2-chlorobenzyl)-4-hydroxy-2,2-dimethylbutanamide as a white solid (3.8 g, 83%), which was used without further purification. LRMS (M+H+) m/z 256.0.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[CH2:22]([O:24][CH:25]([O:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH2:28][NH2:29])[CH3:23]>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:31]([O:30][CH:25]([O:24][CH2:22][CH3:23])[CH2:26][CH2:27][CH2:28][NH:29][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[CH3:32]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CCOC(CCCN)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CCCNc1c([N+](=O)[O-])cnc2cccnc12)OCC
Temperature: 5 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
Triethylamine (3.9 mL, 27.9 mmol, 1.2 eq) was added to a suspension of 4-chloro-3-nitro[1,5]naphthyridine (4.87 g, 23.3 mmol, 1.0 eq) in dichloromethane (100 mL). The resulting solution was cooled to 5° C. and 4,4-diethoxybutylamine (5.36 mL, 27.9 mmol, 1.2 eq) was added dropwise over a period of 5 minutes. The reaction mixture was allowed to stir at ambient temperature for 2 hours and then diluted with saturated aqueous sodium bicarbonate (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 7.93 g of (4,4-diethoxybutyl)(3-nitro[1,5]naphthyridin-4-yl)-amine as a red solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22](OCC)=[O:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][OH:23])[N:20]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)Cc1csc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2nc(CCO)cs2)cc(C(C)(C)C)c1O
Yield: 99.4 %

Procedure:
The compound of Step D 5.0 g (13.33 mmole), was dissolved in 95 ml tetrahydrofuran with stirring, under nitrogen. Solid lithium aluminum hydride, 760 mg (20 mmole), was cautiously added. There was much bubbling. The mixture was stirred under nitrogen for 1 hour. Water, 0.76 ml H2O, was cautiously added followed by 0.76 ml 15% sodium hydroxide, followed by 2.3 ml water. The inorganics were filtered off and the filtrate was stripped, dissolved in ethyl acetate, washed once with 1 N hydrochloric acid, twice with brine, and stripped to give 4.42 g (99%) product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1([Cl:21])[C:5](=O)[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.[CH2:22]1COCC1>[CH3-].C[Al]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+4]>[Cl:1][C:2]1([Cl:21])[C:3]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]1=[CH2:22]
Reactant: C1CCOC1
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C2(Cl)Cl)cc1
Agent: [Ti+4]
Agent: C[Al]C
Agent: [CH3-]
Product: C=C1C(c2ccccc2)=C(c2ccc(SC)cc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 1 (810 mg) in THF (20 mL) at 0° C. was added Tebbe's reagent (0.5M, 5 mL) dropwise. The mixture was stirred at r.t. for 30 min., quenched with NaOH 0.5N at 0° C. and diluted with Et2O. The organic phase was washed with H2O, brine, dried (MgSO4) and the solvents evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (95:5)) provided the title compound as a yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[CH:17][C:18]([CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31])=O.[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].C([NH+]1C2=NC3C(N=C2N(CC)C1C#CC=C1N(CC)C2=NC4C(N=C2N1CC)=CC=CC=4)=CC=CC=3)C.C(#N)C>N1C=CC=CC=1>[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].[CH3:6][N+:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17]#[C:18][CH:20]=[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31]
Reactant: CN1C(=CC(=O)C=C2C=Cc3ccccc3N2C)C=Cc2ccccc21
Agent: CCN1C(=CC#CC2N(CC)c3nc4ccccc4nc3[NH+]2CC)N(CC)c2nc3ccccc3nc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1C(=CC#Cc2ccc3ccccc3[n+]2C)C=Cc2ccccc21
Reaction time: 0.08 h
Yield: 35 %

Procedure:
Phosphoryl chloride (1.0 ml) is added to a stirred suspension of 1,3-Bis(1-methyl-2-(1H)-quinolylidene)acetone (0.68 g, 0.002 mol) in pyridine (10 ml). The mixture is stirred for 5 min., then the solid is collected and washed with a little pyridine, then with ether. The dye is converted to its perchlorate salt by solution in methanol, followed by addition of aqueous sodium perchlorate solution. After recrystallization from acetonitrile, the yield of purified dye is 0.30 g (36%) with the melting point indistinct. The following two dyes were prepared by procedures similar to that described above: 1,3-Diethyl-2-[(1,3-diethyl-1H-imidazo[4,5-b]quinoxalin-2-(3H)-ylidene)-1-propynyl]-1H-imidazo[4,5-b]quinoxalinium perchlorate. ##STR20##Recrystallized from acetonitrile. Purified yield 35%. mp > 300°. 1,3,3-Trimethyl-2-[(1,3,3-trimethyl-2-indolinylidene)-1-propynyl]-3H-indolium perchlorate. ##STR21##Recrystallized from methanol. Purified yield 43% mp 194°-7° dec.
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[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[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[CH2:27][CH2:28][C:29](=[O:30])[NH:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Reactant: NCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and benzylamine.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I-].[Na+].[C:30]([O:33][CH2:34][C@H:35]([CH3:38])[CH2:36]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:36][C@@H:35]([CH3:38])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: CC(=O)OC[C@H](C)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.1 %

Procedure:
3.87 g of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-yl-pyrimidine (14.1 mmol) were stirred in 30 ml of dimethylformamide at room temperature. 3.18 g of triethylamine (63.1 mmol), 0.235 g of sodium iodide (1.57 mmol), 3.01 g of (S)-(+)-1-acetoxy-3-bromo-2-methyl-propane (15.7 mmol) were added. The reaction mixture was stirred for 16 h at room temperature. Stirring was continued for 2 h at 95-105° C. The dimethylformamide was removed by evaporation under reduce pressure. The residue was partitioned between 100 ml of dichloromethane and 100 ml of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give the crude product as a brownish oil (5.81 g).
Reaction SMILES: [C:1]1([CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.CSC>O1CCCC1>[CH:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][OH:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCC(c1ccccc1)C1CCCCC1

Procedure:
To a 500 mL round-bottomed flask equipped with condenser and N2 inlet were added 15 g (68.8 mmol) α-phenylcyclohexylacetic acid, 110 mL dry tetrahydrofuran, and 137 mL (275 mmol) of a 2M solution of borane-methyl sulfide in tetrahydrofuran. The solution was refluxed 60 hr, cooled, and evaporated. The residue was taken up carefully in 200 mL ethanol, treated with 2 g sodium carbonate, and refluxed 3 hr. The reaction was cooled, evaporated, taken up in ethyl acetate/water, separated, and the aqueous phase extracted with fresh ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and evaporated to an oil which solidified on standing. The yield was 12.27 g (87%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)O1>COCCOC.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:27]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]3[CH:10]=[N:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH:29]=[N:28]1
Reactant: Brc1cc2cn[nH]c2cn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Product: c1n[nH]cc1-c1cc2cn[nH]c2cn1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (100 mg, 0.5 mmol) in DME:EtOH (5:1, 5 mL) was added Pd(dppf)Cl2 (20 mg), saturated solution of Na2CO3 (1 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (116 mg, 0.6 mmol). Under argon, the mixture was stirred under microwave irradiation for 60 min at 150. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography (mobile phase: EA:PE=1:1) to afford 5-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (40 mg, 43%). 1H NMR (500 MHz, MeOD) δ 9.17 (s, 1H), 8.98 (s, 1H), 8.17 (m, 3H), 8.05 (d, J=1.5, 1H). ESI MS m/z=186.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C.CS(Cl)(=O)=O.CS(OC(C1C(C2C=CC=C(F)C=2)=C2C(C=CN=C2)=C(Cl)C=1)C)(=O)=O.[N-:59]=[N+:60]=[N-:61].[Na+]>C(Cl)Cl.CN(C)C=O>[N:59]([CH:12]([C:10]1[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]([CH:4]=[CH:5][N:6]=[CH:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13])=[N+:60]=[N-:61]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Agent: CC(OS(C)(=O)=O)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a mixture of 1-[5-chloro-8-(3-fluorophenyl)isoquinolin-7-yl]ethanol (0.100 g, 0.331 mmol) in methylene chloride (0.6 mL) was added triethylamine (0.092 mL, 0.66 mmol) followed by methanesulfonyl chloride (0.038 mL, 0.50 mmol) at 0° C. The reaction was stirred at room temperature for 30 minutes, then diluted with dichloromethane and washed with water. The organic layers were dried over magnesium sulfate and concentrated to dryness under reduced pressure. The resulting sulfonate was used in the next step. LCMS (M+H)+380.1. To the this crude 1-[5-chloro-8-(3-fluorophenyl)isoquinolin-7-yl]ethyl methanesulfonate in N,N-dimethylformamide (0.6 mL) was added sodium azide (0.11 g, 1.6 mmol). The reaction was stirred at room temperature for 1 hour, then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness to provide crude desired azide (0.105 mg, 97%). LCMS calculated for C17H13ClFN4 (M+H)+: m/z=327.1; Found: 327.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([OH:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([O:32][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CCOC(=O)CCCCCBr
Product: CCOC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from ethyl 6-bromohexanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 4.02 (q, 2H), 3.97 (t, 2H), 3.91 (s, 3H), 2.39 (t, 2H), 1.67 (m, 2H), 1.57 (m, 2H), 1.46 (m, 2H), 1.15 (t, 3H); MS (ESI): 494.9.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH:12]3[CH2:14][CH:10]([C:11]3([CH3:16])[CH3:15])[CH:9]2[CH3:17])[C:5](=[CH:18][C:19]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[O:20])[NH:4][C:3]1([CH2:54][C:55]1[N:56]=[CH:57][N:58](CC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:59]=1)[CH2:29][C:30]1[N:31]=[CH:32][N:33](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:34]=1.[NH4+].[F-].C([SiH](CC)CC)C>C(Cl)Cl>[NH:58]1[CH:59]=[C:55]([CH2:54][C:3]2([CH2:29][C:30]3[N:31]=[CH:32][NH:33][CH:34]=3)[C:2](=[O:1])[N:6]([CH2:7][CH:8]3[CH2:13][CH:12]4[CH2:14][CH:10]([C:11]4([CH3:16])[CH3:15])[CH:9]3[CH3:17])[C:5](=[CH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=3)=[O:20])[NH:4]2)[N:56]=[CH:57]1
Reactant: CC1C(CN2C(=O)C(Cc3cn(CC(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Agent: CC[SiH](CC)CC
Agent: [F-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC1C(CN2C(=O)C(Cc3c[nH]cn3)(Cc3c[nH]cn3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C

Procedure:
To a solution of the title compound of 1E (0.101 g, 0.108 mmol) in CH2Cl2 (1 ml) was added NH4F (0.010 g, 0.43 mmol) and triethylsilane (0.069 ml, 0.43 mmol) followed by addition of 2 ml TFA. The reaction mixture was stiired at ambient temperature for 12 h. It was partitioned between CH2Cl2 and saturated sodium bicarbonate (NaHCO3) solution. The CH2Cl2 layer was dried over MgSO4, filtered, and concentrated under vacuum to give the crude product. The crude product was chromatographed on silica gel with CH3OH--CHCl3 --NH4OH (6:94:0.1) as eluents to afford the title compound of example 1, 10 mg (0.019 mmol, 19% yield for two steps).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[CH:8]=2)OCC[O:3]1.Cl>CC(C)=O>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([C:2](=[O:3])[CH3:1])=[CH:8][C:9]=1[O:16][C:17]1[C:18]([Cl:25])=[CH:19][C:20]([Cl:24])=[CH:21][C:22]=1[Cl:23])([O-:15])=[O:14]
Reactant: CC1(c2ccc([N+](=O)[O-])c(Oc3c(Cl)cc(Cl)cc3Cl)c2)OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Oc2c(Cl)cc(Cl)cc2Cl)c1
Yield: 99 %

Procedure:
A mixture of 2-methyl-2-[4-nitro-3-(2,4,6-trichlorophenoxy)phenyl]-1,3-dioxolane (1.7 g) and 3N-hydrochloric acid (5 ml) in acetone (15 ml) was refluxed for 2 hours. The mixture was concentrated under reduced pressure. To the residue were added water and ethyl acetate. The organic layer was dried and concentrated to give a powder of 4'-nitro-3'-(2,4,6-trichlorophenoxy)acetophenone (1.5 g).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[NH:20]2)=[CH:9]1)(C)(C)C.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:20]2[CH:19]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[CH:9]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:28])=[O:29])=[CH:34][CH:33]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Product: COc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1Cc1ccc(F)cc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 4, step c) and 4-fluorobenzyl bromide. MS: ESI (negative): 479 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[C:8]([CH:13]([CH3:15])[CH3:14])[NH:7][N:6]=1)=[O:4]>C(O)CC.O.Cl.O=[Pt]=O>[NH2:10][C:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][NH:7][C:8]=1[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1n[nH]c(C(C)C)c1[N+](=O)[O-]
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CCCO
Product: COC(=O)c1n[nH]c(C(C)C)c1N
Reaction time: 9 h
Yield: 95 %

Procedure:
To a solution of methyl-5-isopropyl-4-nitropyrazol-3-carboxylate (7.34 g, 34.4 mmol) in 36 mL n-propanol, 6 mL water and 5.6 mL 10 M HCl was added 0.55 g PtO2. The mixture was stirred under hydrogen atmosphere (760 torr) for 9 hours. The reaction mixture was filtered and the filtrate was concentrated t dryness in vacuo. The desired amine was liberated by treatment of aq. ammonia during extraction into chloroform. The product crystallized after evaporation; yield 95%; mp=122-123. MS (EI, 70 eV, direct inlet): 183 (88; C8H13N3O2+; −1.0), 168(59), 152(3), 136(100), 108(8), 80(16), 68(20). 1H NMR (400 MHz, CDCl3): 1.31 d (6H; J=6.9 Hz), 2.93 sept (1H), 3.9 s (3H). IR (KBr, cm−1): 3399, 3296, 1710, 1626, 1584, 1302.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:9]=[N:8][N:7]([CH3:10])[C:6]=1[C:11]([OH:13])=[O:12])=[O:4].CN1C=C(C(N2C[CH2:27][O:26][CH2:25]C2)=O)C=N1>>[CH3:10][N:7]1[C:6]([C:11]([OH:13])=[O:12])=[C:5]([C:3]([N:2]2[CH2:14][CH2:27][O:26][CH2:25][CH2:1]2)=[O:4])[CH:9]=[N:8]1
Reactant: CN(C)C(=O)c1cnn(C)c1C(=O)O
Reactant: Cn1cc(C(=O)N2CCOCC2)cn1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)O

Procedure:
This compound was prepared in analogy to 4-dimethylcarbamoyl-2-methyl-2H-pyrazole-3-carboxylic acid (Example 97, step b) from (1-methyl-1H-pyrazol-4-yl)-morpholin-4-yl-methanone (1.20 g, 6.15 mmol). Yield: 1.05 g (71%); off-white solid; MS: m/z=240.2 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@:26]([CH3:32])([C:28](OC)=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:48]>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@:26]([CH3:32])([C:28]([NH2:48])=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:45])[F:1])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc([C@H]2CC[C@@](C)(C(N)=O)N2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 68.3 %

Procedure:
Methyl (5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-L-prolinate (Intermediate 10, 42 mg, 0.066 mmol) was dissolved in 7N ammonia solution in MeOH (3 ml, 21.0 mmol) and the reaction mixture was stirred for 48 hours at 60° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (Companion system; eluent: from 99:1 Dichloromethane/MeOH to 95:5 Dichloromethane/MeOH; 12 g cartridge) affording the title compound (28 mg, 0.045 mmol, 68.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1H) 8.04 (s, 1H) 7.89-7.99 (m, 1H) 7.60-7.87 (m, 2H) 7.44 (s, 1H) 6.90-7.24 (m, 4H) 4.39-4.60 (m, 1H) 3.21-3.32 (m, 1H) 2.53 (s, 3H) 2.21 (s, 3H) 1.45 (s, 6H) 1.38 (s, 3H) 1.16-2.37 (m, 4H), The relative stereochemistry syn was confirmed by dipolar correlations between CH3(8) and CH(5). HPLC: Rt 5.48 min. MS: m/z 625 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[NH:5][C:4](=[O:15])[CH2:3]1>[Pd].CO>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:15])[CH2:3][C:2]2([CH3:16])[CH3:1]
Reactant: CC1(C)CC(=O)Nc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(=O)Nc2ccc(N)cc21

Procedure:
22 g. (0.1 mole) 1,2,3,4-tetrahydro-4,4-dimethyl-6-nitroquinolin-2-one in 500 ml. methanol are, after the addition of 2 g. palladium on charcoal (10%), hydrogenated at atmospheric pressure. After separating off the catalyst, the solvent is removed in a vacuum. Yield 18.4 g. (97% of theory); m.p. 126°-130° C.