Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:24]([F:33])=[C:23]([F:34])[C:22]=1F>O1CCCC1>[CH3:18][O:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:24]([F:33])=[C:23]([F:34])[C:22]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[Cl:1]
Reactant: Nc1ccc(I)cc1Cl
Reactant: COC(=O)c1cc(S(=O)(=O)N(C)C)c(F)c(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)N(C)C)c(F)c(F)c1Nc1ccc(I)cc1Cl
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
To a stirring cold (−78° C.) solution comprised of 2-chloro-4-iodoaniline (0.143 g, 5.64×10−4 mol) in anhydrous tetrahydrofuran (5 ml) under a nitrogen atmosphere was added a commercially available lithium diisopropylamide solution (Aldrich, 2.0M in tetrahydrofuran/heptane/ethylbenzene, 0.300 ml, 6.0×10−4 mol). After stirring for 5 minutes, a solution comprised of 5-dimethylsulfamoyl-2,3,4-trifluoro-benzoic acid methyl ester (0.15 g, 5.0×10−4 mol) in tetrahydrofuran (10 ml) was added via syringe. The cold bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was then partitioned between diethyl ether (125 ml) and saturated aqueous sodium bicarbonate (125 ml). The aqueous bicarbonate phase was extracted with an additional portion (125 ml) of diethyl ether. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was crystallized from heptane-ethyl acetate to afford 0.060 g of an off-white powder; 23% yield; mp 154-156° C.; 1H-NMR (400 MHz; CDCl3) δ 9.74 (s, 1H), 8.30 (d, 1H, J=7.1 Hz), 7.72 (s, 1H), 7.49 (d, 1H, J=8.3 Hz), 6.73-6.69 (m, 1H), 3.92 (s, 3H), 2.84 (s, 3H), 2.83 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ−123.90 (d), −139.55 (d).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH2:16]([NH2:19])[CH2:17][CH3:18].Cl>CS(C)=O>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]2[C:2]=1[N:19]([CH2:16][CH2:17][CH3:18])[C:13](=[O:15])[CH2:12]2
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Reactant: CCCN
Agent: Cl
Solvent: CS(C)=O
Product: CCCN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Crude (2,3-difluoro-5-nitrophenyl) acetic acid (2.00 g, 9.2 mmol) and n-propylamine (6 eq., 4.54 ml, 0.0553 mol) are mixed in DMSO (10 ml) and stirred at 50° C. for 2 hours. 2N Hydrochloric acid (40 ml) is added in one portion and the mixture stirred at room temperature for 2 hours. The resulting light yellow precipitate is filtered, washed with water and dried under vacuum. The residue is purified by flash column chromatography (20% Ethylacetate/hexane) to give the title compound as a yellow solid. HPLC r.t. 5.40 min; MS for C11H11FN2O3 m/z 239.1 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:37])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:38]([CH2:40][NH2:41])[OH:39]>CS(C)=O>[OH:39][CH2:38][CH2:40][NH:41][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][C:30]5[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=5)[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:37])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4cn(Cc5ccc(Cl)cc5)nn4)ccc3C)csc12
Solvent: CS(C)=O
Product: Cc1ccc(-c2cn(Cc3ccc(Cl)cc3)nn2)cc1OCc1csc2c(C(=O)NCCO)cnc(N)c12
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.050 g, 0.09 mmol) (from Example 36 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The precipitate was filtered, washed with methanol and dried to give 4-amino-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 34.5 mg, 68%).
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[C:9]1([CH:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16][NH:17][C:18]2[N:19]=[CH:20][NH:21][C:22]=2C(N)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CO>[C:9]1([CH:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16][N:17]2[C:18]3[N:19]=[CH:20][NH:21][C:22]=3[C:4](=[O:5])[NH:6][C:7]2=[S:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)N=C=S
Reactant: NC(=O)c1[nH]cnc1NCC(c1ccccc1)c1ccccn1
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(CC(c2ccccc2)c2ccccn2)c2nc[nH]c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 11.4 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.12 mL, 0.99 mmol) was added to 4-[(2-phenyl-2-pyridin-2-ylethyl)amino]-1H-imidazole-5-carboxamide (0.28 g, 0.9 mmol, obtained from Example 23(a)) in dry dichloromethane (10 mL) and dry methanol (0.11 mL). The mixture was stirred for 5 h and then concentrated, redissolved in aqueous potassium hydroxide (1.2 N, 7 mL) and heated at 80° C. for 3 h. After cooling to r.t., pH was adjusted to 7 using hydrochloric acid (2 N). The mixture was filtered and the solid was purified using preparative HPLC, giving the title compound 36 mg (11% yield) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:12]1[C:13]([CH3:24])=[CH:14][C:15]2[CH:20]=[C:19]3[O:21][CH2:22][O:23][C:18]3=[CH:17][C:16]=2[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[N:11]1)(=[O:27])[CH3:26]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C=C1C)OCO3
Yield: 70 %

Procedure:
A suspension of 1.0 g (3.1 mmol) of 5-(4-nitrophenyl)-8-methyl-9H-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine is heated in 10 ml of acetic anhydride for 7 hours to 130°-140° C. The solution is poured on ice, and the precipitate is suctioned off. 0.99 g (87% of theory) of a yellow powder is obtained. After combining the corresponding fractions and concentration by evaporation, flash chromatography of this crude product on silica gel 60 with benzene/ethyl acetate (4:1) as a mobile solvent yields 0.78 g (70% of theory) of 7-acetyl-5-(4-nitrophenyl)-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine as a solid with a melting point of 200°-202° C. A sample is recrystallized from ethanol and then has a melting point of 205°-207° C. (minor decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)CCC.C([O-])(=O)C.[NH4+:40]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:40]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Agent: CC(=O)[O-]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 160 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of 4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (29.4 g; 1.00 equiv; 67.99 mmol) in 1-butanol (150 mL; 1.64 mol), add ammonium acetate (15 equiv; 1.02 mol; 78.61 g) followed by TEA (1 equiv; 67.99 mmol; 9.48 mL). Stir the mixture at 160° C. in a sealed tube. After 3 h, cool to RT and partition between EA and water and wash the organic layer with water and brine. Concentrate in vacuo. Triturate the residue in MTBE, filter and dry in vacuo to give the title compound (18.23 g; 44.10 mmol; 64.86%) as a white solid. 1H NMR (300 MHz, DMSO): 12.01 (s, 1H), 8.08-8.04 (m, 2H), 7.70 (d, J=1.4 Hz, 1H), 7.49-7.43 (m, 1H), 3.99 (d, J=12.6 Hz, 2H), 2.92-2.85 (m, 3H), 1.91-1.87 (m, 2H), 1.64-1.51 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19]Cl)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH2:30]([C:33]1([O:39][CH2:40][CH2:41][OH:42])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:31][CH3:32]>C(C(C)=O)C.[I-].[Na+]>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:36]3[CH2:37][CH2:38][C:33]([O:39][CH2:40][CH2:41][OH:42])([CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35]3)[C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: CCCC1(OCCO)CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCCC1(OCCO)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Yield: 99.6 %

Procedure:
10 g of 2-trifluoromethyl-10-(3-chloropropyl)-phenothiazine were dissolved in 50 ml of methyl ethyl ketone and 4.36 g of sodium iodide, 2.9 g of triethylamine, then dropwise a solution of 5.4 g of 2-(4-propyl-4-piperidyloxy)-ethanol in 50 ml of methyl ethyl ketone were added successively thereto. The mixture was refluxed for 24 hours and after cooling, the precipitate formed was removed by vacuum filtration. The precipitate formed was removed by filtration and the filtrate was evaporated in vacuo and the residue was dissolved in methylene chloride. The organic solution was washed with an aqueous solution of sodium bicarbonate, then with water and the solution was dried and concentrated in vacuo to obtain 14.2 g of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxy-4-propylpiperidino)-propyl]-phenothiazine as a beige product which was dissolved in 50 ml of ethanol. The resulting solution was reacted with an ether solution of hydrogen chloride and the hydrochloride was precipitated by the addition of ether. The said precipitate was recovered by vacuum filtration and was washed with ether and crystallized from acetonitrile to obtain 7 g of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxy-4-propylpiperidino)-propyl]-phenothiazine hydrochloride as white crystals melting at 192° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][CH:18]([OH:27])[CH:19]([OH:26])[CH:20]([OH:25])[CH:21]([OH:24])[CH2:22][OH:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([N:8]([CH2:17][CH:18]([OH:27])[CH:19]([OH:26])[CH:20]([OH:25])[CH:21]([OH:24])[CH2:22][OH:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCN(Cc1ccccc1)CC(O)C(O)C(O)C(O)CO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCN(Cc1ccccc1)CC(O)C(O)C(O)C(O)CO
Temperature: 80 °C
Reaction time: 2 h

Procedure:
At room temperature, 0.46 g of methyl 5-[benzyl-(2,3,4,5,6-pentahydroxyhexyl)amino]pentanoate is dissolved in a mixture of 5 ml of ethanol and 5 ml of water, 0.4 g of potassium hydroxide is added and the mixture is stirred at 80° C. for 2 h. The cooled reaction mixture is then concentrated under reduced pressure and the residue is taken up in water, neutralized with hydrochloric acid and again concentrated. The crude product is suspended in ethanol, the suspension is filtered and the filtrate is concentrated under reduced pressure. This gives 5-[benzyl-(2,3,4,5,6-pentahydroxyhexyl)amino]pentanoic acid of molecular weight 371.43 (C18H29NO7); MS (ESI): 372.2 (M+H+).
Reaction SMILES: [CH:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([CH3:13])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]1([C:17](=O)[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1>>[CH:1]1([N:7]2[C:11]3[N:12]=[C:17]([CH:14]4[CH2:15][CH2:16]4)[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]=3[C:9]([CH3:13])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(C2CCCCC2)n1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCCC1

Procedure:
The title compound was prepared in the same manner as described for intermediate 37 using 1-(1-cyclohexyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 2.79 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (514 mg, 2.79 mmol). The final product was collected as a solid, 0.827 g (91%). LCMS E-S (M+H)=328.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.10 (m, 3H), 1.20-1.30 (m, 1H), 1.37 (t, J=7.07 Hz, 3H), 1.41-1.52 (m, 2H), 1.70 (d, 1H), 1.79-1.98 (m, 6H), 2.30-2.38 (m, 1H), 2.54 (s, 3H), 4.42 (q, J=7.07 Hz, 2H), 4.60-4.74 (m, 1H), 7.44 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=O)=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:24]([C:26]1[C:27](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[O:28][C:29]([CH3:36])([C:32]([F:35])([F:34])[F:33])[C:30]=1[CH3:31])#[N:25]>C(O)C>[CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:31][C:30]2[C:29]([CH3:36])([C:32]([F:35])([F:33])[F:34])[O:28][C:27](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[C:26]=2[C:24]#[N:25])=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=CC=CC=O)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Yield: 82.8 %

Procedure:
To 5 ml of ethanol were added 130 mg (0.41 mmol) of 5-(4-dibutylamino-2-methoxyphenyl)-2,4-pentadienal and 115 mg (0.45 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene) propanedinitrile, and the mixture was stirred with heating at 50° C. for 2 hours. The precipitate was separated by filtration and purified by silica gel column chromatography to give 187 mg of a greenish brown crystal (yield: 82.5%; mp: 168-172° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[CH2:12]([CH:16]1[CH2:20][O:19][C:18](=[O:21])[CH2:17]1)[CH2:13][CH2:14][CH3:15]>C1(C)C=CC=CC=1>[C:2]1([NH:1][C:18](=[O:21])[CH2:17][CH:16]([CH2:20][OH:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC1COC(=O)C1
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCCC(CO)CC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
To a solution of aniline (0.36 mL, 4.0 mmol) in toluene (10 mL) was added trimethylaluminum in toluene (2M, 2.5 mL, 5 mmol). After 20 min, a solution of (+/−)-4-butyldihydrofuran-2-one (0.4 g, 4 mmol) in toluene (1 mL) was added and the reaction mixture was refluxed for 3 h. The reaction was cooled to 0° C. and carefully quenched with 1 M HCl (15 mL), and then extracted with dichloromethane (3×15 mL). The combined extractions were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 3:2) to afford 3-hydroxymethylheptanoic acid phenylamide as a white solid (0.66 g, 70%). MS(ES) m/e 236 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>CO>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:3])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccccn1
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccccn2)cc1
Reaction time: 14 h

Procedure:
7.4 g 2-acetylpyridine is added to a solution of 8.3 g 4-methoxybenzaldehyde in 100 ml methanol at 0° C. 100 ml of a 2 N sodium hydroxide solution is added with strong agitation. After 14 hours of agitation at room temperature, the yellow precipitate is filtered off, washed with 10 ml methanol and washed three times with 50 ml water, and dried in a vacuum.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:18][C:17]2=[O:33])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH:34](Cl)(Cl)[Cl:35].C(OCC)(=O)C>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:26]=[CH:27][C:28](/[CH:31]=[CH:34]/[Cl:35])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:18][C:17]2=[O:33])[CH2:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(C=O)cc3)CC2=O)CC1
Reactant: ClC(Cl)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(/C=C/Cl)cc3)CC2=O)CC1

Procedure:
To a suspension of chromiun (II) chloride (737 mg) in THF (10 ml) was added a solution of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-formylbenzenesulfonyl]-2-piperazinone (466 mg) and chloroform (0.160 ml) in THF (7 ml), and the mixture was refluxed for 1 hour. To the reaction solution was added ethyl acetate, and the mixture was washed with water and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless crystals of the title compound (235 m g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5].P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][C:15]1[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Solvent: ClC(Cl)Cl
Product: COCC(=O)c1cnc2c(OC)cccc2c1Cl
Yield: 45.8 %

Procedure:
3-Methoxyacetyl-8-methoxy-4-(1H)-quinolone (39 g, 0.16 mol) was heated under reflux in a mixture of phosphoryl chloride (150 ml) and chloroform (200 ml) for 45 minutes. The solvent was evaporated and the mixture was partitioned between chloroform and sodium hydrogen carbonate solution. The aqueous layer was separated and extracted with chloroform. The combined organic solutions were washed with sodium hydrogen carbonate solution and brine. Evaporation gave an oil which afforded yellow crystals of 4-chloro-8-methoxy-3-methoxyacetylquinoline (19.2 g, 45.8%), m.p. 96°-8°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1B(O)O>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: [O-][n+]1ccc(-c2ccc(Cl)cc2Cl)cc1
Yield: 48.6 %

Procedure:
4-Chloropyridine-N-oxide (1.5 g, 12 mmol), 2,4-dichlorophenylboronic acid (5.4 g, 29 mmol) were reacted according to the procedure of Example 39 (step a) to provide the title compound (1.40 g, 50%) as a grey solid: 1H NMR (500 MHz, CD3OD) δ 8.26 (d, J=6.9 Hz, 2H), 7.53 (d, J=2.0 Hz, 1H), 7.37-7.35 (m, 3H), 7.29 (d, J=8.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:10][C:9]([NH:8][C:7]1[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[N:3][CH:4]=[CH:5][N:6]=1)([CH3:12])[CH3:11]
Reactant: C1CNCCN1
Reactant: CC(C)(C)Nc1nccnc1Cl
Product: CC(C)(C)Nc1nccnc1N1CCNCC1

Procedure:
Following the general procedure of PREPARATION 25 and making non-critical variations but starting with 2-chloro-3-(1,1-dimethylethylamino)pyrazine (PREPARATION 26, 0.95 g) and piperazine, the title compound is obtained, NMR (CDCl3) 1.47, 1.70, 2.99, 5.02, 7.46 and 7.69δ.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH2:43][CH2:42][C:41](=[O:44])[CH:40]=2)O1>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:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:39]4[CH2:43][CH2:42][C:41](=[O:44])[CH:40]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CC1(C)OB(C2=CC(=O)CC2)OC1(C)C
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
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+]
Product: O=C1C=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, Cesium carbonate, 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopent-2-enone and tetrakis(triphenylphosphine)palladium (0). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.89-8.92 (m, 1H), 8.12-8.24 (m, 2H), 7.88 (d, J=9.12 Hz, 1H), 7.11 (d, J=3.43 Hz, 1H), 3.28-3.32 (m, 2H), 3.19-3.21 (m, 2H), 2.54-2.56 (m, 2H), 1.98-2.05 (m, 2H), 1.75-1.87 (m, 4H), 1.15-1.34 (m, 2H). m/z: 423 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: COC(=O)C(C)c1ccc(-c2ccccc2[N+](=O)[O-])c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(-c2ccccc2[N+](=O)[O-])c(F)c1

Procedure:
8.5 g. of methyl 2-(2-fluoro-2'-nitro-4-biphenylyl)propionate dissolved in 180 ml. of methanol is treated with 36 ml. of 10% aqueous sodium hydroxide solution at reflux temperature for 1 hour. The mixture is concentrated to remove most of the methanol, chilled and acidified with a mixture of 50 ml. of concentrated HCl and 50 g. of ice. The mixture is extracted four times with methylene chloride, the extract washed with water and dried (Na2SO4). Following removal of solvent, the residue crystallizes and is decolorized with activated carbon and crystallized from ether-pentane. 2-(2-fluoro-2'-nitro-4-biphenylyl)propionic acid crystallizes, m.p. 106°-108°.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:23](=[O:25])[CH3:24])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a solution of trans-1-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine (200 mg, 0.994 mmol) and triethylamine (208 μL, 1.49 mmol) in tetrahydrofuran (10 mL) was added acetic anhydride (113 μL, 1.20 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and recrystallization (ethyl acetate/hexane) to give the title compound (131 mg, yield 54%).