Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][C:8](=[O:17])[C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(O)=[O:2].C([O-])(=O)C.[NH4+].O[N:30]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O1CCCC1.O.C(N(CC)CC)C>[NH2:30][C:1]([CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][C:8](=[O:17])[C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Agent: CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.3 %

Procedure:
To a solution of 4-carboxymethoxy-7-chloro-3-phenyl--2(1H)-quinolone (0.93 g Example 15) in tetrahydrofuran (50 ml) under nitrogen at room temperature, was added triethylamine (1.90 ml), ammonium acetate (0.50 g), 1-hydroxybenzotriazole (0.60 g) and 1-(3 dimethylaminopropyl)-3-ethyl carbodiimide (0.90 g). The reaction mixture was stirred at room temperature for 3 days, then poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with 1N citric acid (1×75 ml), water (1×75 ml), saturated sodium hydrogen carbonate (1×75 ml) and brine (1×75 ml), then dried (MgSO4), filtered and the solvent was removed in vacuo to leave a solid residue. Recrystallisation from MeOH gave the title compound (0.29 g). Mp 262°-264° C. Found: C, 66.31; H, 5.95; N, 7.46; C19H19N2O2Cl 0.1C6H14 0.6H2O requires C, 65.97; H, 5.93; N, 7.85%. δ (360 MHz, DMSO-d6) 3.91 (2H, s, OCH2CONH2), 7.25-7.45 (9H, m, Ph+6H+8-H+OCH2CONH2), 8.01 (1H, d, J=8.66 Hz, 5-H), 11.92 (1H, bs, NH). m/z (CI+), 329, (M+1).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].F[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20].O>C(O)C>[CH2:1]([NH:3][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])[CH3:2]
Reactant: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Reactant: CCN
Solvent: CCO
Solvent: O
Product: CCNc1ccc(-c2cc(OC)ccn2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethylamine in ethanol (20% w/w, 2 ml) was added 1-fluoro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (200 mg). The mixture was stirred at ambient temperature for 4 hours and poured into water. The precipitate was collected by filtration and dried to give 1-ethylamino-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (206 mg).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:20][NH2:21]>>[NH:20]([C:13]([C:12]1[CH:17]=[CH:18][C:9]([NH:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][CH:11]=1)=[O:14])[NH2:21]
Reactant: CCCCCC(=O)Nc1ccc(C(=O)OC)cc1
Reactant: NN
Solvent: O
Product: CCCCCC(=O)Nc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a suspension of methyl 4-(hexanoylamino)benzoate (583 mg, 2.34 mmol) in ETOH (8 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 321 mg of the title compound (55%) as a white solid in 96.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:25]2[CH:26]=[C:21]([Cl:20])[N:22]=[CH:23][N:24]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1cc(Cl)ncn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a solution of 2a (0.76 g, 4.06 mmol) in 10 mL of THF at room temperature, was added potassium tert-butoxide (0.65 g, 1.4 eq). The resulting mixture was stirred at room temperature for 30 minutes then 4,6-dichloropyrimidine (0.8 g, 1.3 eq) was added. The reaction mixture was stirred at room temperature for 16 h then the solvent was removed under a stream of nitrogen. The residue was taken up with DCM and purified by flash chromatography (elution with 0-40% ethyl acetate and 0.1% TEA in hexanes) to give 0.51 g of 2b (42% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:32][N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:31][CH2:30]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCN(Cc2nnc3ccc(F)cn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Intermediate A (200 mg, 1.22 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 146 mg, 3.66 mmol) in DMF (6.0 mL) and stirred for 20 min. Intermediate 14b (305 mg, 1.22 mmol) was added and the reaction heated to 60° C. for 90 min. The mixture was cooled and quenched by dropwise addition of MeOH. The solution was diluted with MeOH and loaded onto an SCX-2 cartridge, washing with MeOH and eluting with 2M NH3 in MeOH. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (240 mg, 0.61 mmol, 50%). LCMS (Method 4): Rt 0.29 min, m/z 393 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1

Procedure:
Tetrakis(triphenylphosphine)palladium (1 g) was added to a mixture of 5 g of 2-methoxyphenylboronic acid, 6.6 g 5-bromo-2-fluoronitrobenzene and 30 mL 2 M sodium carbonate solution in 50 mL toluene and 50 mL ethanol. The mixture was refluxed for 2 hours, concentrated, and the residue extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried, and concentrated to give a dark green oil which solidified on standing give crude 4-fluoro-2′-methoxy-3-nitrobiphenyl.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:31](C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:31][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 257.9 %

Procedure:
A mixture of 4 g (21 mmol) of the preceeding diamine, 4.6 g (21 mmol) of di-tert-butyl dicarbonate, and 100 mL of dry CH2Cl2 was stirred for 12 hours at room temperature. Solvent and volatile by-products were removed by evaporation under reduced pressure, leaving 6 g (100% yield) of 6-(tert-butyloxycarbonylamino)-1-diethylamino-2-hydroxyhexane as an oil which was not further purified. It was dissolved in 100 mL of dry tetrahydrofuran (THF) along with 3.27 g (22 mmol) of phthalimide, 5.77 g (22 mmol) of triphenylphosphine, and 3.83 g (22 mmol) of diethyl azodicarboxylate (DEAD). The solution was stirred at room temperature for 12 hours at which point, to complete the reaction, an additional 1.64 g (11 mmol) of phthalimide and 1.92 g (11 mmol) of DEAD were added and stirring continued for 1 hour. Solvent was removed and the residual oil partitioned between ether and 1% hydrochloric acid. The aqueous phase was separated, made basic with NaOH solution, and extracted with ether. The ether extract was dried over anhydrous MgSO4, filtered and evaporated. A pale yellow oil resulted which was dried under high vacuum to afford 9.2 g of the protected amino-phthalimide as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ncccc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ncccc2F)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
0.63 g of 5-(4-chlorophenyl)-4-(3-fluoro-2-pyridyl)-6-methyl-2H-pyridazin-3-one and 7.2 g of phosphorus oxychloride were mixed. The mixture was stirred for 1.5 hours on an oil bath of 120° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.64 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.51 g of 3-chloro-5-(4-chlorophenyl)-4-(3-fluoro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (16) of the present invention.).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]([NH:14][C:15]([CH3:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].[I-].[Na+].[C:20]([NH:23][CH2:24][C:25]#[C:26][CH2:27]Cl)(=[O:22])[CH3:21]>O1CCOCC1.C(O)C>[CH2:12]([O:11][C:9](=[O:10])[C:8]([NH:14][C:15](=[O:16])[CH3:17])([CH2:27][C:26]#[C:25][CH2:24][NH:23][C:20](=[O:22])[CH3:21])[C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH3:13]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC(=O)NCC#CCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(CC#CCNC(C)=O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of sodium hydride (60% dispersion in mineral oil, 3.48 g) in dioxane (70 ml) was added dropwise absolute ethanol (70 ml). The mixture was allowed to warm to room temperature and a solution of diethyl acetamido malonate (20.5 g) in dioxane (70 ml) was added dropwise. Sodium iodide (9.07 g) was added and a solution of 1-acetylamino-4-chloro-2-butyne (11 g) in dioxane (140 ml) was added dropwise at room temperature. After addition of another 100 ml of ethanol the mixture was refluxed for 2.5 h. The reaction mixture was cooled and the precipitate formed was filtered off. Purification using chromatography on silica (eluent: ethyl acetate/methanol 9/1 v/v) yielded acetamido(4-acetamido-2-butynyl)-malonic acid diethyl ester. (15.9 g).
Reaction SMILES: Cl.[C:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27]C(=O)C)=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[NH4+]>C(O)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Temperature: 20 °C
Yield: 26 %

Procedure:
4-Amino-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 1.5 ml of an aqueous 5N hydrochloric acid solution are added to a suspension of 0.3 g of N-[4-(3-phenyl-1H-indazol-5-ylsulfamoyl)-phenyl]acetamide in 6 ml of 95% ethanol. The reaction mixture is then refluxed for 30 minutes then cooled to a temperature in the region of 20° C. 20 ml of water and 1 ml of an aqueous 32% ammonium hydroxide solution are then added to the reaction mixture, which is then extracted successively with 30 ml and 15 ml of ethyl acetate. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 40-63 μm), eluting with a dichloromethane/methanol (95/5 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The solid thus obtained is taken up in 9 ml of ethanol in the presence of 3S black and dissolved under hot conditions, and the mixture is filtered under hot conditions through sintered glass and then recrystallized. The crystals are filtered off through sintered glass, washed with 0.5 ml of 95% ethanol then with 2 times 2 ml of diisopropyl ether, partially dried and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. 70 mg of 4-amino-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a light beige powder melting at 249° C. (Cl mass analysis: m/z 365 (M+H)+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)O)[CH:16]=3)[N:11]=[C:10]([O:33]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([NH:46][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([O:40][CH3:39])=[CH:42][CH:43]=4)[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:16]=3)[NH:11][C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)nc3)c3cncn3C)ccc2n1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CNC(c2ccc(Cl)nc2)(c2ccc3[nH]c(=O)cc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
To [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanol (1.08 g, 2.21 mmol) in toluene (8.5 ml) under an atmosphere of dry N2 was added thionyl chloride (1.61 ml, 22.06 mmol) dropwise. The reaction mixture was heated at 85° C. for 15 hours. Solvent and the excess thionyl chloride were removed under reduced pressure. The crude chloride was taken up in toluene and concentrated under vacuum. The resulting solid was dissolved in THF (10 ml) and to this solution at −78° C. was added p-methoxybenzylamine (1.44 ml, 11.03 mmol) in THF (2 ml). The reaction mixture was stirred at −78° C. for 3 hours under an atmosphere of N2 for 3 hours. After removal of THF, the product mixture was partitioned between CHCl3 and water. The organic layer was washed, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (2:98:0.1) as eluents to afford the titled compound of Example 46A (0.482 g, 52% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=5)=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CCn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCn1nccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 82.9 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-1H-pyrazole-5-carboxylic acid (269 mg, 1.92 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (231 mg, 83%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[CH3:13]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[CH:5][C:6]([NH2:10])=[CH:7][C:8]=1[CH3:9]
Reactant: COc1c(C)cc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)cc(N)cc1C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 2-methoxy-1,3-dimethyl-5-nitrobenzene (12 g) in ethanol in a Parr hydrogenation bottle, was added Pd/C (0.24 g, 10%). The mixture was shaken at 50 psi of H2 in the hydrogenator overnight. The reaction mixture was filtered through Celite® and the solvent was removed by evaporation. The crude residue was purified by column chromatography (10% ethyl acetate/hexane), giving 4-methoxy-3,5-dimethylaniline as a light yellow solid (8.2 g). 1H-NMR (300 MHz, CDCl3) δ=6.18 (s, 1H), 3.711 (s, 3H), 2.29 (s, 6H) ppm. MS: m/z 152 (100, M+H)+
Reaction SMILES: [N+]([C:4]([CH3:15])=[CH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[CH:13][N:14]=2)[CH:11]=1)([O-])=O.Cl.[OH2:17]>CCO>[N:14]1[CH:13]=[CH:12][N:10]2[CH:11]=[C:6]([CH2:5][C:4](=[O:17])[CH3:15])[CH:7]=[CH:8][C:9]=12
Reactant: CC(=Cc1ccc2nccn2c1)[N+](=O)[O-]
Reactant: O
Agent: Cl
Solvent: CCO
Product: CC(=O)Cc1ccc2nccn2c1

Procedure:
In 25 ml of water and 25 ml of EtOH, 1.14 g of 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine was heated to 80° C. together with 100 mg of ferrous chloride. With stirring, 2.5 ml of conc. hydrochloric acid was added at a refluxing rate and the mixture was stirred of 1 hour. Upon heating, insoluble matter was removed by filtration. After the insoluble matter was thoroughly washed with ethanol, the solvent was removed by distillation under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was purified by column chromatography to obtain 500 mg of 1-(imidazo[1,2-a]pyridin-6-yl)-2-propanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](=[O:32])[C:22]5[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.O1CCOCC1.CO.ClCCl>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:22]5[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][N:23]=5)=[O:32])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2cc(C(F)(F)F)ccn2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)ccn1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
(R)-tert-butyl 1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (2 g, 2.65 mmol) was dissolved in a solution of HCl in dioxane (4M) (13.27 ml, 53.1 mmol) and the reaction mixture was stirred at room temperature for 45 minutes. The solvent was removed in vacuo to give an orange gum. This was treated with a mixture of 10% methanol (containing 1% of ammonia)/dichloromethane until complete dissolution of the gum, then the solvent was removed in vacuo to give an orange solid. The crude product was purified by chromatography on silica gel (gradient: 0-10% methanol (containing 1% of ammonia) in dichloromethane) to give (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (810 mg) as a pale orange solid. LCMS (Method F, ES-API): RT 1.41 min, m+H=443.2.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.[CH3:11][C:12]([CH:15]=O)([CH3:14])[CH3:13].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:17]1([CH:15]([NH:9][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[C:12]([CH3:13])([CH3:14])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: CC(C)(C)C=O
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC(n2nnc3ccccc32)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A suspension of p-toluamide (4.11 g, 30.4 mmol), pivaldehyde (2.62 g, 30.4 mmol), and benzotriazole (3.62 g, 30.4 mmol) in toluene (200 mL) were treated with p-toluenesulfonic acid (286 mg, 1.52 mmol). The solution was heated at reflux under Dean-Stark conditions for 10 hours, cooled gradually to ambient temperature, and further cooled at 5° C. The white precipitate which formed was collected by filtration and was washed with 50% ether/hexanes (100 mL) to provide 6.67 g of the desired product as a white solid.
Reaction SMILES: [C:1](=[O:37])([O:8][CH2:9]/[C:10](/[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)=[C:11](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)\[CH2:12][O:13][Si](C(C)(C)C)(C)C)[O:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7]>CC#N.C1(C)C=CC=CC=1>[C:1](=[O:37])([O:8][CH2:9]/[C:10](/[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=1)=[C:11](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)\[CH2:12][OH:13])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCBr)=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A mixture of 5.7 g of 4-bromobutyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate and 5 mL of PyHF in 100 mL of MeCN was stirred at rt for 2 h, diluted with 500 mL of toluene, filtered through a pad of silica gel, evaporated, and purified by flash chromatography to afford 4.3 g of the titled compound. 1H NMR (acetone-d6, 500 MHz): δ 7.70 (d, 2 H), 7.36 (d, 2 H), 7.18–7.10 (m, 5 H), 5.30 (s, 2 H), 4.68 (d, 2 H), 4.15 (t, 1 H, OH), 4.13 (t, 2 H), 3.53 (t, 2 H), 3.07 (s, 3 H), 1.93–1.87 (m, 2 H), 1.80–1.70 (m, 2 H).