Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)[CH3:3]>CCO.C(Cl)Cl.[Pd]>[CH:2]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([CH3:3])[CH3:1]
Reactant: C=C(C)c1ccc2c(c1)nc(N)c1ncccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)c1ccc2c(c1)nc(N)c1ncccc12
Reaction time: 8 h

Procedure:
A mixture of 8-(prop-1-en-2-yl)benzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Pd/C (wet, 10% wt) in EtOH was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The Pd/C was filtered off through celite, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-60% EtOAc/Hexanes to give 8-isopropylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid: 1H NMR (acetone-d6): δ 8.98 (dd, 1H), 8.88 (dd, 1H), 8.37 (d, 1H), 7.83 (dd, 1H), 7.49 (d, 1H), 7.27 (dd, 1H), 6.66 (br s, 2H), 3.10-3.00 (m, 1H), 1.33 (d, 6H). LRMS [M+H]=238.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:32](=[O:34])[CH3:33])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(=O)Cl
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of product from step 3 (105 mg, 0.23 mmol) in methylene chloride (1 ml) was added triethylamine (93 mg, 0.92 mmol), acetyl chloride (18 mg, 0.23 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 8 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 75 mg (80%) of the product as a solid.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[N:25]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: Cc1ccccc1
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 24 h

Procedure:
A mixture of (2RS)-2-(2-cyano-l0-phenothiazinyl)-1-propyl methanesulphonate (10 g) and pyrrolidine (11.6 cc) in toluene (50 cc) is brought to 90° C. with stirring for 24 hours. After being cooled, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and the residue is taken up with ethyl ether (200 cc) and 4N aqueous sodium hydroxide solution (15 cc). After the mixture has been stirred for 10 minutes, settling is allowed to take place and the organic phase is washed with saturated aqueous sodium chloride solution (3×25 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 20° C. The residual oil (11.3 g) is dissolved in 0.5N aqueous hydrochloric acid solution (60 cc). This solution is washed with ethyl ether (100 cc) and then alkalinized with an excess of N aqueous sodium hydroxide solution and extracted with ethyl ether (100 cc). The organic phase is washed with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 20° C. The residual yellow oil (9.5 g) is purified on a column (height: 30 cm; diameter: 5.8 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (95:5 by volume) (1 liter) of methylene chloride and methanol and collecting 100-cc fractions. Fractions 3 to 10 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-l-(l-Pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile (5.45 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[NH:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(CC)CC>O1CCOCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[NH:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=[C:2]([N:32]3[CH2:33][CH2:34][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:30][CH2:31]3)[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)N1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(N4CCN(c5ccccn5)CC4)nc23)N1
Temperature: 120 °C
Yield: 27.4 %

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (30 mg, 0.09 mmol) in 1,4-dioxane was added 1-(pyridin-2-yl)piperazine (58 μL, 4.10 mmol) and Et3N (13 μL, 0.09 mmol). Reaction was then heated 120° C. for 35 minutes in microwave. Solvent was removed under reduced pressure, and mixture was dissolved in methanol. Solid was isolated by filtration, then air dried to yield 11 mg (26% yield) 5-((7-(cyclopropylamino)-5-(4-(pyridin-2-yl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=446)
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]2[CH:6]([C:7]2([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])[CH3:10])[CH2:5]1)[CH:2]=[CH2:3].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH2:1]([N:4]1[CH2:5][CH:6]2[CH:8]([C:7]2([C:11]2[CH:12]=[C:13]([NH:14][S:19]([CH3:18])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC2C(C1)C2(C)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C=CCN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Reaction time: 16 h
Yield: 67.6 %

Procedure:
To 3-(3-allyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)aniline (Preparation 52, 8.5 g, 37.2 mmol) dissolved in pyridine (70 ml) at 0° C. was added methanesulphonyl chloride (4.32 ml, 55.8 mmol) dropwise over 20 min. The reaction mixture was allowed to stir for 16 h and was then quenched with ice (5 g). The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution, followed by water. The organic extracts were concentrated in vacuo and then purified by flash chromatography on silica gel, eluting with ethyl acetate:dichloromethane:2N ammonia in methanol (30:69:1). The product was obtained as a viscous brown oil (7.7 g, 68%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:21]=[C:22]=[O:23])(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:22]([NH2:21])=[O:23])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)NCCC1CCCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 3.35 h
Yield: 70.3 %

Procedure:
3-(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19 mmoles) was dissolved in anhydrous dichloromethane (10 mL) and trimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The mixture was stirred under argon at 25° C. for 3.35 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, evaporated to dryness and chromatographed on a silica gel column (15×5 cm) using 5% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide (417.7 mg, 70%): FABMS: m/z 272.0 (MH+); HRFABMS: m/z 272.1979 (MH+). Calcd. for C13H26O3: m/z (9H, s, —COOC(CH3)3), 1.68 (1H, m, CH2), 1 84 (1H, m, CH2), 2.54 (1H, dd, CH2), 2.73 (1H, m, CH2), 3.08 (1H, m, CH2), 3.42 (1H, m, CH2), 4.02 (1H, m, CH2), 410 (1H, m, CH2), 4.84 (1H, m, NH) and 4.96 ppm (2H, bm, CONH2); δc (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 25.2, 31.7, 34.9, 37.3, 44.6, 50.3; CH: 32.9; C: 79.5, 156.4, 158.2.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:27])=[O:26])[N:21]=[C:20]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:27])=[O:26])[N:21]=[C:20]([C:32]2[CH:38]=[CH:37][C:35]([NH:36][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:34][CH:33]=2)[N:19]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C(C)(C)C)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C(C)(C)C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (0.227 mL, 1.81 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(tert-butylsulfonylmethyl)pyrimidin-2-yl]aniline (665 mg, 1.64 mmol) and sodium hydrogen carbonate (207 mg, 2.47 mmol) in dioxane (12 mL). The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25%-80% ethyl acetate in isohexane, to give the desired material as a yellow dry film (860 mg).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[C:10]([SH:12])[C:9]([Cl:13])=[CH:8][C:6]=1[NH2:7])(=[O:4])(=[O:3])[NH2:2].[C:14](Cl)(=O)[CH3:15]>O1CCOCC1>[CH3:14][C:15]1[NH:2][S:1](=[O:3])(=[O:4])[C:5]2[CH:11]=[C:10]([SH:12])[C:9]([Cl:13])=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cc(Cl)c(S)cc1S(N)(=O)=O
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Product: CC1=Nc2cc(Cl)c(S)cc2S(=O)(=O)N1

Procedure:
A mixture of 2-sulfamoyl-4-mercapto-5-chloroaniline, prepared as described in Example 13, Step A-3 (0.02 mole) and acetyl chloride (0.022 mole) in 75 ml. of dioxane is heated under reflux for 24 hours. The solution is concentrated to dryness in vacuo and the residue dissolved in 75 ml. of ethanol and treated with 75 ml. of concentrated ammonium hydroxide in the cold. Thereafter the solution is heated under reflux for 3 hours and concentrated to dryness in vacuo. The residue is suspended in 100 ml. of water acidified with hydrochloric acid and the product, following recrystallization from dimethylformamide-water, melts at 304°-305° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:3]=1.[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.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:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:3][C:2]([C:38]2[C:33]([F:32])=[N:34][CH:35]=[CH:36][CH:37]=2)=[N:7][CH:6]=1)#[N:25]
Reactant: OB(O)c1cccnc1F
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
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: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2cccnc2F)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
10 mg of 4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in DMF/H2O=1:1 (0.46 mL), and 3.2 mg of (2-fluoropyridin-3-yl)boronic acid, 0.8 mg of Pd(PPh3)4 and 7.4 mg of Na2CO3 were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, DMF was removed by concentrating under reduced pressure. After extracting with EA, the extract was treated with MgSO4 and concentrated under reduced pressure. The residue was separated by PLC (developing solvent, EA) to obtain 3.2 mg (28% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1)[NH2:12]
Reactant: NN
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Solvent: CCO
Product: Cn1c(=O)cc(NN)[nH]c1=O
Temperature: 75 °C
Yield: 99.7 %

Procedure:
To a mixture containing 10.0 g (62.28 mmol) of 6-chloro-3-methyluracil in 200 ml of ethanol was added 13.70 ml (436.50 mmol) of hydrazine. The mixture was heated to 75° C. under a nitrogen atmosphere overnight. The solids were filtered, washed with ethanol and dried to afford 9.70 g (99.74%) of product as a pale yellow solid.
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)C.[BrH:20].O>C(OCC)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][Br:20])=[CH:13][CH:14]=1
Reactant: Br
Reactant: CCOC(=O)c1ccccc1Oc1ccc(Br)cc1
Solvent: O
Solvent: CCOCC
Product: BrCc1ccccc1Oc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 413.0 g of the 2-(4-bromophenoxy)benzyl alcohol and 1290 ml of 48% hydrobromic acid is boiled under reflux for 4 hours, then cooled and poured onto 2000 ml of ice and water. The greenish oil that separates out is dissolved in 2000 ml of diethyl ether. The organic phase is washed twice with 400 ml of water and with 400 ml of a 1N aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation at 40° under 11 mm Hg. The 2-(4-bromophenoxy)benzyl bromide, obtained in the form of an oily residue, is used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([OH:15])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1cc(Br)cc2c1CCC2
Solvent: ClCCl
Product: OC1CCc2cc(Br)cnc21
Reaction time: 6 h
Yield: 77.1 %

Procedure:
3-Bromo-6,7-dihydro-5H-[1]pyrindine 1-oxide (6.97 g, 32.6 mmol) was dissolved in CH2Cl2 (150 ml); then, trifluoroacetic anhydride (20.5 g, 13.6 ml, 97.7 mmol) was added drop by drop below 25° C. with intense stirring and stirring was continued for 6 hours at RT. The mixture was then quenched with aqueous 1M NaOH solution. The aqueous mixture was stirred for two hours and extracted three times with CH2Cl2/2-propanol 4:1. The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (6.279 g) which was purified by flash chromatography (silica gel, 50 g, 20% to 100% EtOAc in heptane) to yield the title compound (5.38 g, 77%) as light brown solid. MS: 214.0 (MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH2:5][C:6](=[CH:10]Br)[CH:7]=[CH:8][CH:9]=1.[C-]#N.[K+].[C:16](#[N:18])C.CO>ClCCl.C1OCCOCCOCCOCCOCCOC1.CO.ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:16]#[N:18])[CH:5]=1
Reactant: COC(=O)C1=CC=CC(=CBr)C1
Reactant: CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
Methyl-3-bromomethylenebenzoate (5.0 g, 0.022 mol, Ryan Chemicals (Maybridge)), dry potassium cyanide (2.9 g, 0.044 mol), and 18-crown-6 (0.5 g, 0.0018 mol) was added to ~50 mL acetonitrile in a 100-mL round-bottom flask. The mixture was vigorously stirred for 24 h at room temperature. The reaction was monitored by TLC (Bakerflex) in dichloromethane, 2% methanol, and 5% methanol/dichloromethane. A heavy white precipitate (KBr) was removed by filtration. The filtrate was concentrated to 1/3 of the original volume and water was added until the final volume was ~100 mL. The yellow solution was added to a 250-mL separatory funnel and was extracted with dichloromethane until the organic phase was colorless and then twice more. The organic layers were combined and dried with magnesium sulfate. The drying agent was removed by filtration and the solvent was concentrated to a light yellow oil. The oil was dissolved into an equal volume of ether and was added to a 15×2.5 cm column of TLC grade silica gel and eluted with ether. The progress of the column was followed with a hand-held UV lamp. When the faster-running impurities had eluted, the product was collected and the solvent was concentrated leaving a light yellow oil. Though this oil was pure by TLC, the product was distilled (101.5° C. at 0.05 mm Hg) leaving 3.5 g (92%) of methyl-3-cyanomethylbenzoate.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[CH:30]2)([O-:26])=[O:25]>CN(C=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:32]3[C:33]4[C:29](=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:35][CH:34]=4)[CH:30]=[N:31]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1ncc2cc([N+](=O)[O-])ccc21)N1CCN(c2ccc(F)cc2)CC1
Temperature: 70 °C

Procedure:
2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (0.834 g, 3.3 mmol) was taken in dry DMF (15 mL) and dry potassium carbonate (1.6 g, 11.6 mmol) was added to it and the reaction mixture stirred at room temperature for 1h under nitrogen. 5-Nitro-1H-indazole (0.5 g, 2.9 mmol) in DMF (2 mL) was then added to the mixture through a syringe. The reaction was heated at 70° C. for 14 h, cooled and then quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded material that on purification on neutral alumina column (pet ether/ethyl acetate) gave title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH2:32][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)[CH:22]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)nn1-c1ccccc1
Yield: 47.7 %

Procedure:
Compound 79 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [K].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>C(O)(C)(C)C>[C:2]([CH:4]([C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CC#N
Agent: [K]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C#N)c1ncccc1[N+](=O)[O-]
Yield: 64.8 %

Procedure:
Potassium (2.5 g, 63 mmol) was carefully added in small lumps to dry t-butanol (80 mL, distilled from calcium hydride). Upon complete addition, the reaction was warmed to 50° and stirred until all the potassium was consumed. Ethyl cyanoacetate (6.71 mL, 63 mmol) was added and a thick white precipitate was formed. 2-Chloro-3-nitropyridine (5 g, 31.5 mmol) was added in hot (60° C.) t-butanol (80 mL) and the reaction turned dark orange upon addition. The reaction was heated to reflux for two hours, the t-butanol was removed and the residue partitioned between hydrochloric acid (1N) and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was dried over magnesium sulfate, filtered and the solvent removed. The brown solid residue was recrystallized from ethyl acetate to give the desired product as red needles (4.8 g, 65%); m.p. 133-134° C.
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH3:20])[CH2:3][NH:4][C:5]([C@@H:7]1[C@H:14]2[C@@H:10]([O:11][C:12]([CH3:16])([CH3:15])[O:13]2)[C@H:9]([O:17][CH3:18])[O:8]1)=[O:6].C(O)(=O)C.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>ClCCl>[CH3:18][O:17][C@H:9]1[C@@H:10]2[O:11][C:12]([CH3:16])([CH3:15])[O:13][C@H:14]2[C@@H:7]([C:5]([NH:4][CH2:3][C:2](=[O:1])[CH2:19][CH3:20])=[O:6])[O:8]1
Reactant: CCC(O)CNC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(=O)CNC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 20 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of (3aR,4S,6R,6aR)-N-(2-hydroxybutyl)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole4-carboxamide (3.81 g) in anhydrous dichloromethane (115 ml), containing powdered 4 Å molecular sieves (5.7 g) at 0° C., under nitrogen, were added acetic acid (2.59 ml) and potassium dichromate (7.93 g), portionwise. The reaction mixture was stirred at 0° C. for 15 min and at 20° C. for a further 2 h. The mixture was quenched with isopropanol (40 ml) and stirred for 30 min, silica gel (Merck 9385) (40 g) and ethyl acetate (100 ml) were added, and the mixture was stirred for a further 30 min. This mixture was filtered through ‘harborlite®’ filter aid and the filtrate concentrated in vacuo to give a crude product which was purified by flash column chromatography on silica gel, eluting with 2:1 ethyl acetate:cyclohexane to give the title compound (1.91 g)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([NH2:30])=[CH:25][C:24]=2[CH3:31])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([N:30]=[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][NH:6]3)=[CH:25][C:24]=2[CH3:31])=[CH:21][CH:22]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1CCCCN1
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2)c(C)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(C)(C)C)cc2)c(C)cc1N=C1CCCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 0.2 g (1.5 mmol) of phosphoric trichloride in 5 ml toluene was added to a mixture of 0.3 g (3.0 mmol) of piperidin-2-one, the exothermic reaction was stirred for 2 hrs at ambient temperature. Then a solution of 0.38 g (1.5 mmol) of 4′-tert-butyl-2,5-dimethylbiphenyl-4-amine in 5 ml of toluene was added and the reaction mixture was refluxed for 5 hrs. At ambient temperature 5 ml of a 10% aqueous solution of sodium hydroxide was added. Separation of the layers, extraction of the watery layer with 10 ml of toluene, drying over magnesium sulfate, concentration in vacuo and column chromatographic (gradient: cyclohexane->ethyl acetate) yielded 0.3 g (1.0 mmol) 63% of 4′-tert-butyl-2,5-dimethyl-N-[piperidin-2-ylidene]biphenyl-4-amine; log P (pH 2.3)=2.6.