Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([C:18](O)=[O:19])[C:12](=[CH:16][CH:17]=1)[C:13](O)=[O:14]>C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]2[C:18](=[O:19])[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:13](=[O:14])[C:12]2=[CH:16][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)O
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccccc1
Temperature: 5 °C

Procedure:
To a suspension of 750 g of monosodium-4-chlorophthalate and 1200 ml water was added 120 ml conc. sulfuric acid. The resulting brown solution was extracted with three 400 ml portions of ether. The combined extracts were treated with carbon black, filtered and the ether distilled. The 4-chlorophthalic acid obtained was dehydrated by heating to 170°C for two hours to give 548 g of anhydride. To a solution of the anhydride in 2250 ml of xylene was added 279 g of aniline diluted with an equal weight of xylene. The solution was refluxed for 16 hours and the water formed was collected in a Dean-Stark trap. After treatment with carbon black the hot xylene solution was cooled to 5°C to give 475 g of crude 4-chloro-N-phenyl phthalimide. Recrystallization from 2000 ml toluene, twice, provided 364 g of 92% pure imide.
Reaction SMILES: C(OC([C:6]1[N:10]2[C:11]3[CH:25]=[CH:24][C:23](Cl)=[CH:22][C:12]=3[C:13](C3C=CC=CC=3)=[N:14][CH2:15][C:9]2=NN=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-:33].[Na+]>O1CCCC1>[N:10]1([CH2:6][OH:33])[C:11]2[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=2[CH:13]=[N:14][CH:15]=[CH:9]1
Reactant: [OH-]
Reactant: CCOC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCN1C=CN=Cc2ccccc21
Reaction time: 0.75 h

Procedure:
A solution of 0.37 g of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxylic acid ethyl ester in 5 ml of absolute tetrahydrofuran is added dropwise in the course of 15 minutes, with ice cooling and with stirring, to a suspension of 0.078 g of lithium aluminium hydride in 5 ml of absolute tetrahydrofuran. After a further 45 minutes of stirring at 0°-5°, 0.40 ml of 1-n sodium hydroxide solution are added dropwise. The inorganic salts are filtered off, the filtrate is concentrated in vacuo, and the residue dissolved in 10 ml of chloroform. The solution is washed with 1-n sodium hydroxide solution and then with water, dried over sodium sulphate, and concentrated by evaporation. The residue is recrystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4benzodiazepine-1-methanol, M.P. 210°-211°.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:25]C(=O)OC(C)(C)C)[CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:20]4[C:15](=[C:16]([CH3:21])[N:17]=[CH:18][CH:19]=4)[C:14](=[O:22])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[CH2:3][CH2:2]1.Cl>C(OCC)C>[NH2:25][C@@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[C:16]([CH3:21])[N:17]=[CH:18][CH:19]=3)[C:14](=[O:22])[N:13]([CH3:23])[C:12]=2[CH:24]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC3CC3)NC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: CCOCC
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC3CC3)ccc21
Reaction time: 1 h
Yield: 22 %

Procedure:
An ambient temperature suspension of (S)-tert-butyl (1-cyclopropyl-3-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)propan-2-yl)carbamate (50 mg, 0.114 mmol) (prepared as described in Example 16 using (S)-tert-butyl (1-cyclopropyl-3-hydroxypropan-2-yl)carbamate (0.287 g, 1.334 mmol) in Part H) in diethyl ether (1 mL) was treated with HCl (4M in 1,4-dioxane) (0.571 mL, 2.286 mmol) and stirred for 1 h. The resulting mixture was concentrated under reduced pressure to a yellow solid. The crude material was purified by reverse phase high performance liquid chromatography (Phenomenex Luna C18 30×100 mm 10 micron; water/methanol/TFA gradient elution). Fractions containing product were concentrated under reduced pressure. The resulting residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous was extracted twice more with ethyl acetate. The pooled organics were washed once with brine, dried over magnesium sulfate, filtered, and concentrated to afford (S)-8-(2-amino-3-cyclopropylpropoxy)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (9.0 mg, 0.025 mmol, 22% yield for the final step) as a white solid. LC/MS, (ESI) m/z 338.2 [(M+H)+, calcd for C20H24N3O2 338.2]; HPLC retention time (method C): tR=13.05 min; HPLC retention time (method D): tR=13.88 min; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.65 (d, J=5.8 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.83 (d, J=5.5 Hz, 1H), 6.92 (dd, J=8.9, 2.4 Hz, 1H), 6.87 (d, J=2.3 Hz, 1H), 4.15 (dd, J=8.9, 3.9 Hz, 1H), 3.97 (dd, J=8.8, 7.0 Hz, 1H), 3.75 (s, 3H), 3.48-3.35 (m, 1H), 3.17 (s, 3H), 1.59-1.42 (m, 2H), 0.87-0.74 (m, 1H), 0.64-0.47 (m, 2H), 0.25-0.17 (m, 1H), 0.16-0.10 (m, 1H).
Reaction SMILES: C(NC(C)C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1.Br[CH2:17][CH:18]([CH3:20])[CH3:19].O>C1COCC1>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:17][CH:18]([CH3:20])[CH3:19])[N:10]=1
Reactant: CC(C)CBr
Reactant: Cc1cccc(Br)n1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)CCc1cccc(Br)n1
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
A 2.5M solution of n-buthyllithium (0.44 mL, 1.1 mmol) was added dropwise to a stirred solution of diisopropylamine (0.16 mL, 1.15 mmol) in THF (2 mL) at −78° C. The mixture was stirred for 15 minutes and 2-bromo-6-methylpyridine (0.11 mL, 1 mmol) was added dropwise. The mixture was stirred for 15 minutes and 1-bromo-2-methylpropane (0.21 mL, 2 mmol) was added dropwise. The mixture was stirred for 1 hour at this temperature and at room temperature for 60 hours. The mixture was treated with water and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-bromo-6-(3-methyl-butyl)-pyridine (82 mg, 36% yield) as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(C(C)(C)C)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-tert-butyl-phenylboronic acid to give [1-(4-tert-butyl-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 357(MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:50]=[CH:49][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[C:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[N:38]=[C:39]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[O:40][C:41]=4[CH3:42])=[CH:31][CH:30]=3)=[N:21]2)=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:50]=[CH:49][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH:25]=[O:26])[C:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[N:38]=[C:39]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[O:40][C:41]=4[CH3:42])=[CH:31][CH:30]=3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)cc2CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)cc2C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]methanol (27.02 g), activated manganese dioxide (52.29 g), chloroform (50 ml), and tetrahydrofuran (300 ml) was stirred at room temperature for 3 hours. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to yield 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazole-4-carbaldehyde (25.69 g, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 155–156° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH:12]([OH:16])[C:13]#[C:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[CH2:1]([O:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH:12]([OH:16])/[CH:13]=[CH:14]\[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#CC(O)CC(C)COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: C/C=C\C(O)CC(C)COCc1ccccc1

Procedure:
A mixture of 1 g. (4.31 mmoles) of rac. 1-benzyloxy-2-methylhept-5-yn-4-ol, 0.1 g. of Lindlar catalyst, 0.04 ml. of quinoline and 30 ml. of hexane was stirred in an atmosphere of hydrogen, at room temperature, for 40 minutes during which time approximately one equivalent of hydrogen was taken up. The catalyst was filtered and washed with hexane then the combined filtrate and washes were concentrated in vacuo giving 1.05 g. of oily product. This material was chromatographed on 50 g. of silica gel. Elution with 2:1 parts by volume and 1:1 parts by volume hexane-ether afforded 0.844 g. of a pale yellow oil. Evaporative distillation gave rac. Z-1-benzyloxy-2-methyl-5-hepten-4-ol as a colorless oil, b.p. 113°-123° C. (bath temperature) (0.25 mm Hg.).
Reaction SMILES: [O:1]=[C:2]([C@H:20]([CH3:36])[C@@H:21]([O:27][C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])[C@@H:22]([CH3:26])[CH2:23][CH:24]=[CH2:25])[C:3]([CH3:19])([CH3:18])[C@@H:4]([O:10][Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13])[C@H:5]([CH3:9])[C:6]([OH:8])=[O:7].[C:37](O)([CH3:40])([CH3:39])[CH3:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]=[C:2]([C@H:20]([CH3:36])[C@@H:21]([O:27][C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:33])[Cl:34])=[O:29])[C@@H:22]([CH3:26])[CH2:23][CH:24]=[CH2:25])[C:3]([CH3:19])([CH3:18])[C@@H:4]([O:10][Si:11]([CH2:12][CH3:13])([CH2:16][CH3:17])[CH2:14][CH3:15])[C@H:5]([CH3:9])[C:6]([O:8][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:7]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](CC)(CC)CC)[C@H](C)C(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](CC)(CC)CC)[C@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (2S,3S,6R,7S,8S)-5-oxo-3-(triethylsilyloxy)-2,4,4,6,8-pentamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoic acid (11.8 g), tert-butanol (4.5 g), and 4-dimethylaminopyridine (0.2 g) in 20 mL of CH2Cl2 is cooled on ice and treated with dicyclohexylcarbodiimide (4.6 g) over a 5-minute period. The mixture is allowed to warm to ambient temperature and is stirred for 3 hours. The slurry is diluted with CH2Cl2 and filtered, and the filtrate is washed sequentially with sat. aq. citric acid, 5% NaHCO3, and brine. The solution is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.C(O)(=O)C(O)=O.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]2[CH2:64][CH2:63][NH:62][CH2:61]2)=[CH:56][CH:55]=1>C(#N)C>[F:53][C:54]1[CH:55]=[CH:56][C:57]([CH:60]2[CH2:64][CH2:63][N:62]([C:14]([C:10]3[CH:11]=[N:12][O:13][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=3)=[O:16])[CH2:61]2)=[CH:58][CH:59]=1
Reactant: Fc1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccc(F)cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 3-(4-fluorophenyl)pyrrolidine oxalate (36 mg, 0.14 mmol), and stirred at 60° C. for 2 h. The residue was purified on reversed phase HPLC to yield the title compound (8 mg). HRMS (ESI, pos. ion) m/z calcd for C21H16F4N2O2: 404.1148, found 404.1152.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([OH:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=1>>[CH2:1]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([OH:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
Benzyl bromide (21.9 g) and potassium carbonate (35.3 g) were added to a solution of ethyl 3-(4-hydroxyphenyl)lactate (22.4 g) in dimethylformnamide (220 ml). The mixture was stirred at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified via chromatography silica gel column using hexane/ethyl acetate=7/3 as the eluant to give the desired compound (31.0 g) as a pale yellow oil.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:9]([Cl:18])=[N:10][CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14].[N+:19]([C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])([O-:21])=[O:20]>C(Cl)Cl>[Cl:18][C:9]1[C:8]([NH:7][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[N+:19]([O-:21])=[O:20])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1
Reactant: COC(=O)c1cnc(Cl)c(N)c1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 73 %

Procedure:
Pyridine (1.1 eq) was added to a solution of methyl 5-amino-6-chloronicotinate (1 eq) and 2-nitrobenzoyl chloride (1.2 eq) in CH2Cl2. The mixture was stirred at room temperature for 10 h and concentrated in vacuo. H2O was added and the resultant solid was collected by filtration, rinsed with CH2Cl2 and dried to give methyl 6-chloro-5-(2-nitrobenzamido)nicotinate (73% yield).
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[OH:3].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13]>O>[OH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][C:1](=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: NCCOCCO
Solvent: O
Product: CC(O)C(=O)NCCOCCO

Procedure:
Equimolar quantities of lactic acid and 2-(2-aminoethoxy)ethanol were mixed together. This mixture was then heated to 120° for 2 hours and the resulting water of reaction was continuously removed. The final product was a viscous, amber colored liquid.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]1([C:11]2[CH:36]=[CH:35][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>C(OCC)C>[Br:2][CH:25]([CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:14]1[CH:35]=[CH:36][C:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:12][CH:13]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CCCCC(O)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCCCC(Br)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At 0° C., 140 mg (0.51 mmol) of phosphorus tribromide were added to a solution of 500 mg (1.14 mmol) of methyl 8-{2-[(4-cyclohexylbenzyl)oxy]phenyl}-6-hydroxyoctanoate XVI in 5 ml of diethyl ether. The mixture was stirred at 0° C. for 1 h and at room temperature for another 16 h. Water was added, the mixture was extracted with cyclohexane and the combined organic phases were dried over Na2SO4. The product was purified chromatographically (silica gel, cyclohexane(ethyl acetate 10:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)([C:11]#[N:12])[CH3:10])[CH:7]=1.[C:30]([O-:33])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[C:26]([C:4]1[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])=[CH:17][CH:18]=2)([C:11]#[N:12])[CH3:10])[CH:7]=[C:2]([C:6]2[C:30](=[O:33])[NH:12][CH:11]=[CH:9][CH:8]=2)[CH:3]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: COc1c(CC(C)(C#N)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1c(CC(C)(C#N)c2ccc(NS(C)(=O)=O)cc2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Yield: 49 %

Procedure:
step 5—A sealed tube containing 288 (69 mg, 0.144 mmol), 112 (30 mg, 0.216 mmol), Pd(PPh3)4 (16 mg, 0.014 mmol), Na2CO3 (41 mg, 0.387 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was irradiated in a microwave reactor at 115° C. for 30 minutes. The reaction mixture was concentrated, diluted with EtOAc, washed with brine, and dried na2so4, filtered and concentrated. The crude product was purified on a SiO2 preparative TLC plate developed with 20% EtOAc/hexane to afford 33 mg (49%) of I-196 a white solid (49% yield).
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:3]1[CH:4]=[C:5]([C:16]([O:18]CC)=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.[OH-].[Li+].OS(O)(=O)=O>O1CCOCC1.O>[OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:3]1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2ccccn2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3ccccn3)c2)cc1
Temperature: 25 °C

Procedure:
Ethyl 5-(hydroxy(pyridin-2-yl)methyl)-4′-methylbiphenyl-3-carboxylate (319 mg, 0.92 mmol) was dissolved in 1,4-dioxane (6 mL) and water (0.3 mL). To the stirred solution was added lithium hydroxide (120 mg, 5.0 mmol) and the reaction mixture was stirred at room temperature until the reaction was complete. The mixture was cooled and acidified with 2N aq. H2SO4 to pH 5-6 and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to yield a light yellow solid. 1H NMR (400 MHz, CD3OD): 8.47 (m, 1H), 8.13 (t, 1H, J=1.6 Hz), 8.02 (t, 1H, J=1.6 Hz), 7.91 (t, 1H, J=1.6 Hz), 7.87 (td, 1H, J=7.6, 1.6 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.51 (d, 2H, J=8.0 Hz), 7.31 (ddd, 1H, J=7.6, 5.2, 1.2 Hz), 7.27 (d, 2H, J=8.0 Hz), 5.93 (s, 1H), 2.37 (s, 3H).
Reaction SMILES: CN(C)C=O.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-]#N.[Na+].[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18]>O>[C:7]1([C:6](=[O:13])[CH2:18][CH2:17][C:19](=[O:20])[CH3:21])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC(C)=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CCC(=O)c1ccccc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To 1200 ml of dimethylformamide (DMF) containing 3 moles of benzaldehyde and heated at 35° C., a mixed solution of 0.3 mole of sodium cyanide and 2400 ml of DMF was added dropwise in 30 minutes, and the reaction was carried out for further 30 minutes with stirring. To the reaction solution, a mixed solution of 2.25 moles of methyl vinyl ketone and 2400 ml of DMF was added dropwise in 30 minutes, and the reaction was carried out for further 1 hour. After the reaction, water was poured into the reaction solution, followed by extraction with chloroform. The obtained chloroform solution was washed with dilute sulfuric acid, saturated aqueous solution of sodium bicarbonate, and water in this order, and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The resulting residue was distilled under reduced pressure to give a fraction of pale yellow liquid of 1-phenyl-1,4-pentanedione having a boiling point of 124°-127° C./0.15 mmHg (yield 40% ).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:10]=12>C(#N)C>[CH:1]1([NH:7][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]3[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:10]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: NC1CCCCC1
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCCCC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Cyclohexyl amine (9.07 ml, 0.7905 mole) was added to a mixture of ethyl 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (10 gm, 0.0395 mole) (example 3) in acetonitrile. After stirring for about 2 h at 110° C., acetonitrile was removed under reduced pressure. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo to give brownish solid.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=[O:14])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH:23]([N+:34]#[C-:35])S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CO>O1CCOCC1.O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[N:34]=[CH:35][O:14][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=2)[N:9]=1
Reactant: [C-]#[N+]C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)c1nnc2ccc(C=O)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nnc2ccc(-c3ocnc3-c3cc(F)ccc3F)nn12
Temperature: 80 °C
Yield: 71.8 %

Procedure:
To a solution of 3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carbaldehyde (0.150 g, 0.789 mmol, Preparation #2) in 1,4-dioxane (3 mL) was added 1,4-difluoro-2-(isocyano(tosyl)methyl)benzene (0.202 g, 0.657 mmol, Preparation #4), K2CO3 (0.218 g, 1.58 mmol) and MeOH (3.00 mL). The reaction mixture was heated to about 80° C. for about 3 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient; 1:1 to 0:1) to give the title compound (0.161 g, 71% yield). LC/MS (Table 1, Method a) Rt=2.20 min; MS m/z: 342.1 (M+H)+.