Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.[F:10][C:11]([F:18])([F:17])[CH2:12][CH2:13][C:14](O)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([F:18])([F:17])[F:10]
Reactant: O=C(O)CCC(F)(F)F
Reactant: Cc1cc(O)cc(=O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(C(=O)CCC(F)(F)F)c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
In 240 ml of toluene, 14.1 g of 4-hydroxy-6-methyl-2-pyrone was suspended, and 1.94 g of 4-dimethylaminopyridine, 16.6 g of 4, 4,4-trifluorobutyric acid and 21.9 g of dicyclohexylcarbodiimide were added thereto. The reaction mixture was stirred for 1 hour at room temperature and further stirred for 20 hours at 70° C. After cooling to room temperature, it was subjected to filtration. The filtrate was washed with 1% hydrochloric acid twice and saturated brine once in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 5.38 g of 4-hydroxy-6-methyl-3-(4,4,4-trifluorobutyryl)-2-pyrone (hereinafter, referred to as the present compound (A)) mp 104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C@H:8]([O:21]S(C)(=O)=O)[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4](OC(=O)C)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[O:6][CH2:7][C@H:8]([CH2:9][N:10]3[C:14](=[O:15])[C:13]4=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]4[C:11]3=[O:20])[O:21][C:4]=2[CH:3]=1
Reactant: CC(=O)Oc1cc(Cl)ccc1OC[C@@H](CN1C(=O)c2ccccc2C1=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1COc2ccc(Cl)cc2O1
Temperature: 50 °C
Reaction time: 9 h
Yield: 69.1 %

Procedure:
To a reaction vessel were added crude (R)-1-(4-chloro-2-acetoxyphenoxy)-2-methanesulfonyloxy-3-phthalimidopropane 242 mg (0.50 mmol), sodium carbonate 58.3 mg (0.60 mmol) and methanol 2 mL, and the mixture was stirred at 50° C. for 9 hours. To the reaction mixture was added ethyl acetate and the mixture was washed with water. The solvent was evaporated and recrystallized to give (S)-7-chloro-2-(phthalimidomethyl)-1,4-benzodioxane 114 mg (yield 70%, chemical purity 98%, optical purity 98% ee) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:15]([OH:17])=O)=[CH:5][N:6]=[C:7]2[O:12][CH2:13][CH3:14].CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1.O>C(O)(=O)C>[CH2:13]([O:12][C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]3[N:1]4[C:20]([C:15](=[O:17])[C:4]([C:3]=23)=[CH:5][N:6]=1)=[CH:24][CH:23]=[CH:22]4)[CH3:14]
Reactant: COC1CCC(OC)O1
Reactant: CCOc1ncc(C(=O)O)c2c(N)cccc12
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ncc2c(=O)c3cccn3c3cccc1c23
Temperature: 20 °C

Procedure:
A solution of 5-amino-4-carboxy-1-ethoxyisoquinoline (50.8 g) and 2,5-dimethoxytetrahydrofuran (32 cc) in acetic acid (250 cc) is kept at a temperature between 90° and 95° C. for 35 minutes, whilst stirring. The solution is cooled to about 20° C. and then poured into water (1250 cc). The yellow crystals which precipitate are filtered off and washed with water (5 × 50 cc). After drying under reduced pressure (1 mm Hg) at 20° C., crude 4-ethoxy-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (52.7 g) is obtained. After recrystallisation from ethanol, the pure product melts at 188° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[N:10](S(C)(=O)=O)[C:4]=2[CH:3]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:15]([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)c1cc2cnc(Br)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1cc2cnc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
6-Bromo-2-(diethoxymethyl)-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (Preparation 136, 202 mg, 0.54 mmole) was stirred in methanol (2.4 mL) and 1M sodium hydroxide in water (0.62 mL, 0.62 mmole) was added. The reaction was stirred at 25° C. for 6 hours. The methanol was evaporated and the residue taken up in ethyl acetate (25 mL). The solution was washed with water and brine, the organic layer was concentrated in vacuo to afford the title compound (142 mg, 89%). 1H-NMR (CDCl3, 500 MHz): δ 1.27 (t, J=6.94 Hz, 6H), 3.58-3.72 (m, 4H), 5.73 (m, 1H), 6.59 (m, 1H), 7.48 (m, 1H), 8.65 (s, 1H), 8.84 (br s, 1H, NH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([O:33]C(C2C=CC=CC=2)C2C=CC=CC=2)=[C:19]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][C:20]=12)=[O:10].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([OH:33])=[C:19]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][C:20]=12)=[O:10]
Reactant: O=C(NCc1ccccn1)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccn1)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Yield: 56.3 %

Procedure:
Carboxamide 231 (0.225 g, 0.355 mmol) was dissolved in 1 mL of dichloromethane. To this was added 0.5 mL of triethylsilane and 0.25 mL of trifluoroacetic acid. Stirred at room temperature and after ten minutes complete by TLC. Concentrated off volatiles, azeotroped with toluene to give crude. Triturated twice with 1:1 diethyl ether/hexanes to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid (pyridin-2-ylmethyl)-amide 232 (0.11 g, 0.20 mmol, 56%.) 1H NMR (CD3SOCD3) δ 9.18 (s, 1H), 8.96 (d, 1H), 8.65 (dd, 2H), 8.09 (dd, 1H), 7.76 (dd, 1H), 7.64 (dd, 1H), 7.36 (dd, 2H), 7.22 (dd, 2H), 4.70 (s, 4H), 4.54 (s, 2H). 19F NMR: −75.37 MS: 443 (M+1), 441 (M−1)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[O:1]
Reactant: OCc1ccc2cc[nH]c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2cc[nH]c2c1
Reaction time: 18 h
Yield: 76.1 %

Procedure:
Manganese dioxide (240 g) was added to a mechanically stirred solution of 6-hydroxymethylindole (40.7 g) in methylene chloride (1.6 liter). The mixture was stirred for 18 hr, filtered through a pad of diatomaceous earth, the filter cake washed with methylene chloride and chloroform, and the filtrate evaporated to give 6-formylindole (30.55 g) as a yellow solid. The filter cake was washed with tetrahydrofuran and the washings evaporated to give a further crop of 6-formylindole (2.35 g, 82% combined yield); partial NMR (250 MHz, DMSO-d6): 6.58(m, 1H, H3 -indole), 10.00(s, 1H, CHO), 11.71(br s, 1H, NH).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17]
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Under the atmosphere of argon, 25.7 g of 9-bromophenathrene, 16.5 g of 2-formylphenylboronic acid and 2.31 g of tetrakis(triphenylphosphine)palladium (0) were placed in a flask. To the resulting mixture, 340 mL of DME and 170 mL of an aqueous 2M sodium carbonate solution were added, followed by stirring under reflux while heating for 8 hours. After cooling to room temperature, an aqueous phase was removed. An organic phase was washed with water and saturated saline, and dried with magnesium sulfate. After filtering off magnesium sulfate, the organic phase was concentrated. The residues were purified by silica gel column chromatography, whereby 25.0 g (yield 89%) of 9-(2-formylphenyl)phenanthrene as an intended product was obtained.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:30]([C:34](O)=O)=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1.[CH3:37][NH:38][C:39](=[S:42])[NH:40][NH2:41]>CN(C)C=O.C(N(CC)CC)C>[CH3:37][N:38]1[C:34]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:31]=2[CH:32]=[CH:33][C:24]([CH3:23])=[N:25]3)=[N:41][NH:40][C:39]1=[S:42]
Reactant: Cc1ccc2c(C(=O)O)cccc2n1
Reactant: CNC(=S)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Hydroxybenzotriazole (7.8 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11 g) and triethylamine were successively added to a stirred solution of 2-methyl-5-quinolinecarboxylic acid (10g) and 4-methyl-3-thiosemicarbazide (6.1 g) in dimethylformamide (200 ml), at 0° C. Following the addiction the reaction mixture was allowed to reach room temperature, the stirred continued over night and then the solvent was evaporated under reduced pressure. The residue was treated with an aqueous sodium hydroxide solution (500 ml, 0.5N) and the mixture was stirred at 80° C. for 3 h, after which time the mixture was cooled to room temperature and the pH adjusted to pH 6 using a aqueous hydrochloridric acid solution (2M) and the resulting precipitatye was filtered and dried in vacuo to give the title compound (11 g) as an off-white solid.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:26][C:27]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>CN(C)C=O>[F:26][C:27]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][N:11]1[CH2:12][CH2:13][N:8]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:9][CH2:10]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Cc1cccc(CBr)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(CN2CCN(c3cccc4nc(N)nc(N)c34)CC2)c1F
Temperature: 60 °C
Yield: 50.5 %

Procedure:
In an 8 mL vial with stir bar, triethylamine (40 mg; 0.4 mmol) was added to a mixture of 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-fluoro-3-methylbenzyl bromide (54 mg; 0.27 mmol) in dimethylformamide and heated to 60° C. for 16 hours. Mixture was quenched with 1 mL of 1N NaOH and after 1.5 hours solids were collected by filtration and triturated with ethanol to obtain 37 mg of title compound. (51% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.2 (m, 3H), 7.07 (t, J=7.6 Hz, 1H), 6.95 (dd, J=8.4, 0.8 Hz, 1H), 6.84 (dd, J=7.6, 0.8 Hz, 1H), 5.90 (br s, 2H), 3.59 (s, 2H), 2.98 (d, J=11.2 Hz, 2H), 2.89 (d, J=12.0 Hz, 2H), 2.81 (t, J=9.6 Hz, 2H), 2.313 (t, J=9.2 Hz, 2H), 2.24 (s, 3H). ESIMS+367.6 m/z
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:6]([CH:13]([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:7][C:8](=[N:11][OH:12])[CH:9]=O)[CH3:5]>C(Cl)(Cl)Cl.CO>[CH2:4]([C:6]([CH:13]([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:7][C:8](=[N:11][OH:12])[CH:9]=[N:2][OH:3])[CH3:5]
Reactant: NO
Reactant: CCC(=CC(C=O)=NO)C(C)[N+](=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(=CC(C=NO)=NO)C(C)[N+](=O)[O-]
Temperature: 25 °C
Yield: 60.5 %

Procedure:
Hydroxylamine hydrochloride (69.5 mg) was added to a solution of 4-ethyl-2-hydroxyimino-5-nitro-3-hexenal (100 mg) in a mixture of chloroform (3 ml) and methanol (2 ml) with stirring at room temperature. The resulting mixture was stirred at the same temperature overnight and evaporated to dryness. The residue was washed successively with water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was distilled under reduced pressure to give a residue which was purified by preparative thin layer chromatography [solvent: methanol-chloroform (10:90)] to give 4-ethyl-2-hydroxyimino-5-nitro-3-hexenaldehyde oxime (65 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([O:15]C(OC(C)(C)C)=O)=O)([CH3:11])([CH3:10])[CH3:9].[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:23][S:24]([NH:27][C:13](=[O:15])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Triethylamine (2.2 mL, 16 mmol), di-tert-butyldicarbonate (2.65 g, 12.1 mmol) and 4-dimethylaminopyridine (0.096 g, 0.79 mmol) were added sequentially to a solution of methanesulfonamide (0.75 g, 7.9 mmol) in methylene chloride (20 mL) at room temperature. The reaction was stirred at room temperature for 2 h and then concentrated. EtOAc was added, and the resultant mixture was washed with 1N aq. HCl solution, dried over MgSO4 and concentrated to give the desired product (1 g) to be used in the next step directly.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([C:10]([NH2:12])=[O:11])[NH:4][N:3]=1.[CH2:13]([OH:15])C.O>C(O)=O.[Pd]>[CH:13]([NH:7][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[C:10]([NH2:12])=[O:11])=[O:15]
Reactant: Cc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Solvent: O
Solvent: O=CO
Product: Cc1n[nH]c(C(N)=O)c1NC=O
Reaction time: 8 h

Procedure:
A mixture of 3-methyl-4-nitropyrazole-5-carboxamide (17.0 g, 0.1 mol) in a mixture of 20 ml of 97-100% formic acid, 160 ml of ethanol and 30 ml of water was hydrogenated overnight at 40°-60° using 150 mg of 5% palladium-on-charcoal at 50 psi. Filtration of the hot solution through Celite and evaporation gave 17.8 g of crude, ochre-colored product which was recrystallized from ethanol: 1st crop 9.3 g colorless, 2nd crop 6.7 g brownish, total yield, 16.0 g (95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].[H-].[Na+].I[CH3:35]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:18])[CH3:19])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:35]
Reactant: CI
Reactant: CN(C)c1ccc(-c2cc(=O)c3c(NCCCCCCO)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
500 mg (1.15 mmol) of Compound 60 obtained in Example 60 was dissolved in 20 ml of tetrahydrofuran under argon atmosphere, 92 mg of sodium hydride (60% oil dispersion) and 0.14 ml of iodomethane were added under ice-cooling and the mixture was stirred at room temperature for 1 hour. Thereafter, 0.22 ml of iodomethane was added and the mixture was heated at reflux for 3.5 hours. Additional 0.36 ml of iodomethane was added and the mixture was heated at reflux for 1 hour. The solvent was distilled off under reduced pressure, an aqueous saturated solution of ammonium chloride was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (chloroform:acetone=40:1), followed by recrystallization from n-hexane/ethyl acetate to give 300 mg (58%) of Compound 61.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](=[O:25])[CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:18][CH2:19][C:20](=[O:25])[CH2:21][C:22]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[O:23]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: O=C(Cl)CC(=O)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
After 191.2 g (1.25 mol) of p-nitrobenzyl alcohol is dissolved in 250 ml of methylene chloride, 98.8 g of pyridine is added, and the mixture is cooled to -5° to 0° C. A solution of 193.75 g (1.25 mol) of γ-chloroacetoacetyl chloride (γ-CAC) in 431 ml of methylene chloride is added at the same temperature over an hour and, after completion of the addition, the mixture is stirred for 30 minutes. The resulting pyridine hydrochloride is filtered off. The filtrate and washings are combined and washed with 2 l-portions of water. The organic layer is dried over sodium sulfate and the solvent is then distilled off to give 354 g of p-nitrobenzyl γ-chloroacetoacetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(C)(C)OC(=O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (145 mg, 0.5 mmol) and tert-butyl 2-aminoacetate (79 mg, 0.6 mmol). The title compound was obtained as a solid (98.0 mg, 42% yield). 1H NMR (300 MHz, d6-DMSO) δ: 8.74 (2H, s), 7.95 (1H, s), 4.06 (2H, m), 1.49 (9H, s) MS m/z: 463.80, 465.75 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:15]>>[C:1]1([CH:7]=[C:8]([S:10]([NH2:15])(=[O:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=Cc1ccccc1)S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Product: CC(=Cc1ccccc1)S(N)(=O)=O

Procedure:
The 1-phenylpropene-2-sulfonyl chloride is added to 200 ml. of concentrated ammonium hydroxide. After 1 hour the crystalline precipitate which has formed is filtered off, and washed sequentially with water and hexane. The crude product so obtained is partitioned between 150 ml. of 1N sodium hydroxide and 50 ml. of ether, giving two clear phases. The ether phase is removed and washed with 50 ml. of water, and then the water wash is added to the original aqueous phase. This combined solution is acidified using concentrated hydrochloric acid, which causes the product to precipitate. It is filtered off, and after drying this affords 10.9g. of 1-phenylpropene-2-sulfonamide, m.p. 138°-139.5°C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A mixture of ethyl 6-chloro-8-bromo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 74, Step 1) (2.0 g, 5.2 mmol), tetrakis(triphenylphosphine)palladium (0) (2.15 g, 1.7 mmol), triphenylphosphine (0.013 g, 0.05 mmol), and tributylphenyltin (1.9 mL, 5.7 mmol) in toluene (60 mL) was heated to 110° C. for 3 days. The reaction mixture was allowed to cool to room temperature and filtered through a plug of silica gel eluting with 25% ethyl acetate in hexanes. The filtrate was concentrated in vacuo and then purified by flash chromatography (silica gel, ethyl acetate-hexanes, 1:9). The fractions containing desired, product were combined and concentrated in vacuo. To remove the remaining tin impurities the mixture was taken up in THF (10 mL) and aqueous ammonium fluoride solution (10 wt %, 20 mL) and stirred at room temperature for 2 hours. The solution was extracted with ethyl acetate. The extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo to afford the ester as an oil (1.30 g, 65%). 1H NMR (CDCl3/300 MHz) 7.67 (s, 1H), 7.47–7.36 (m, 5H), 7.31 (d, 1H, J=2.6 Hz), 7.18 (d, 1H, J=2.4 Hz), 5.69 (q, 1H, J=6.8 Hz), 4.30 (m, 2H), 1.33 (t, 3H, J=7.1 Hz). 19FNMR (CDCl3/282 MHz) d −78.27 (d, J=7.2 Hz). FABLRMS m/z 383 (M+H). ESHRMS m/z 400.0937 (M+NH4, Calc'd 400.0927)
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16](N)=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:37][NH:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>C1COCC1>[CH3:37][N:38]([CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)[C:16]([C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=1)=[O:17]
Reactant: CNC1CCN(C)CC1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)N(C)C3CCN(C)CC3)cc21
Reaction time: 18 h
Yield: 3 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with methyl-(1-methyl-piperidin-4-yl)-amine (1 equivalent). After 18 additional hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-11 as an oil in 3% yield.