Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[CH3:19][N:20](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:21].F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CNC>C1COCC1>[CH3:19][N:20]([CH3:21])[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:8][C:9]=2[CH:15]=1)=[O:18]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)Cc1nc2ccc(C(=O)O)cc2[nH]1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1nc2ccc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[(Ethoxycarbonyl)methyl]benzimidazole-5-carboxylic acid (1.0 eq) was dissolved in THF. HBTU (1.1 eq) and diisopropylethylamine (2.0 eq) were added, followed by dimethylamine (2.0 M in THF, 1.1 eq). The reaction was stirred at room temperature overnight then concentrated and the resulting residue was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to afford the desired compound. LC/MS m/z 276.2 (MH+), Rt 1.18 minutes.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:21][C:22]1[N:31]=[C:30]([C:32]([N:34]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35]2)=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[N:23]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:21][C:22]1[N:31]=[C:30]([C:32]([N:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:42]2)=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:2]3[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=3[CH2:4][NH:5][CH2:6][CH:7]3[CH2:9][CH2:8]3)[CH:28]=2)[N:23]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: Brc1ccccc1CNCC1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CNCC3CC3)ccc2n1
Temperature: 120 °C

Procedure:
114 mg of (2-bromobenzyl)cyclopropylmethylamine, 100 mg of potassium carbonate, 7 μl of water and 29 mg of [1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride are added to a solution of 150 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 5 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min; the hot mixture is filtered through kieselguhr, the filtrate is evaporated and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][Cl:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1CCN(Cc2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: ClCC1CCN(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
To a refluxing solution of 15.3 g (0.08 mole) (3RS)-1-benzyl-3-hydroxymethyl pyrrolidine in 220 ml CHCl3 was slowly added a solution of 330 ml thionyl chloride in 60 ml CHCl3, and the reflux was continued for one hour. The mixture was evaporated and the residue was dissolved in water. The water layer was washed with ethyl acetate and then made alkaline with 0.2 M NaOH-solution. The water layer was extracted three times with ethyl acetate and the combined organic layer was dried (Na2SO4), filtered and evaporated to give the product in a quantitative yield (16.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.C(N(CC)CC)C.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[S:23]([O:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1)(=[O:24])=[O:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1cc(O)cnn1C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1cc(OS(=O)(=O)C(F)(F)F)cnn1C1CCCCO1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57.9 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.4 g, 13 mmol) dissolved in methylene chloride (75 mL) and cooled to 0° C. Triethylamine (3.5 mL, 25 mmol) and Tf2O (2.3 mL, 14 mmol) were added and the mixture stirred for a further 2.5 h. Saturated NaHCO3 solution was added and the organic phase removed, dried over Na2SO4 and concentrated. Purification by flash column chromaotgraphy (silica gel, EtOAc/hexanes) provided the title compound (2.47 g, 60%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J=2.8 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 6.01 (dd, J=10.2, 2.2 Hz, 1H), 4.15-4.12 (m, 1H), 3.75 (dt, J=11.6, 2.5 Hz, 1H), 2.18-2.02 (m, 2H), 1.78-1.66 (m, 3H), 1.62-1.55 (m, 1H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:7]([C:8]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:42])([F:43])[F:41])[CH:34]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC(=O)c1cc(N)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(NC(=O)Nc2ccccc2)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Phenyl isocyanate (70 μL, 0.5 M in anhydrous DCM, 0.03 mmol, 1.1 equiv.) was added to a solution of TFA salt of 6-amino-4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}quinazoline-8-carboxamide (16 mg, 0.03 mmol, 1.0 equiv.) and triethylamine (16 μL, 0.09 mmol, 3.0 equiv.) in anhydrous DCM (1 mL). The resulting mixture was stirred at 40° C. for 3 hrs. The title compound was obtained by pre-HPLC in 79% yield. Mass: M+H+: 515.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].Br[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[CH2:13]([O:12][C:10]([CH2:9][S:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(COC(=O)CBr)cc1
Reactant: N[C@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CSCC(=O)OCc1ccccc1)C(=O)O

Procedure:
D-cysteine is S-alkyl substituted with p-methoxybenzyl bromoacetate in presence of sodium carbonate in a THF-water medium. The S-benzyloxycarbonylmethylcysteine thus obtained is N-acylated with (R)-3-tetradecanoyloxytetradecanoic acid chloride, and the S-alkyl-N-acyl-D-cysteine derivative is then coupled with (2R)-5-amino-2-[(R)-3-hydroxytetradecanoylamino]pentan-1-ol amine {obtained by hydrogenolysis of the (2R)-5-amino-2-[(R)-3-benzyloxy-tetradecanoyl-amino]pentan-1-ol, see 4.1.1.} in presence of IIDQ. The thus obtained product is selectively O-acylated in its primary position with the ester derived from reacting HOBt with 7-(p-methoxybenzyloxy-carbonylamino)heptanoic acid. The two p-methoxybenzyl groups are then removed by treating the ester with aqueous trifluoroacetic acid. C59H112N4O10S. MM 1069.64.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[C@H:16]3[CH2:17][N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[NH:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:2]3[CH:3]=[N:4][C:5]([O:8][C@@H:9]4[C@H:16]5[CH2:17][N:12]([CH2:13][CH2:14][CH2:15]5)[CH2:11][CH2:10]4)=[N:6][CH:7]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: Brc1cnc(O[C@H]2CCN3CCC[C@@H]2C3)nc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: c1cc2cc(-c3cnc(O[C@H]4CCN5CCC[C@@H]4C5)nc3)ccc2[nH]1
Temperature: 90 °C
Reaction time: 15 h
Yield: 66.5 %

Procedure:
5.19 g (17.4 mmol) of (4S,5R)-4-(5-bromo-pyrimidin-2-yloxy)-1-aza-bicyclo[3.3.1]nonane is dissolved in 200 ml toluene/EtOH 9:1. 5-Indolyl boronic acid (3.47 g, 21.6 mmol), Pd(PPh3)4 (1.04 g, 0.873 mmol) and a soln. of Na2CO3 (7.38 g, 69.6 mmol) in 35 ml H2O is added. The reaction mixture is stirred at 90° C. for 15 h. After cooling to rt the mixture is filtered over hyflo, the filtrate is extracted with water and brine. The aq. layers are reextracted with AcOEt and the combined organic layers are dried over Na2SO4, filtered and the filtrate is evaporated. The resulting crude product is purified by FC (255 g silica gel, eluent AcOEt/MeOH/Et3N 70:27:3) and recrystallization from EtOH to give 3.87 g (67%) (4S,5R)-4-[5-(1H-indol-5-yl)pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane. MS (ES+): m/e=335 (MH+), m.p. 195-199° C.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Br:12][C:13]1[O:17][N:16]=[C:15]([C:18]([OH:20])=O)[C:14]=1[CH3:21].[NH2:22][C:23]1[C:24](=[O:36])[N:25]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:26]([CH3:29])[C:27]=1[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[Br:12][C:13]1[O:17][N:16]=[C:15]([C:18]([NH:22][C:23]2[C:24](=[O:36])[N:25]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:20])[C:14]=1[CH3:21]
Reactant: Cc1c(C(=O)O)noc1Br
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1Br
Reaction time: 0.17 h

Procedure:
A solution of DMF (5.33 mL, 68.8 mmol) in DCM (200 mL) was cooled to 0° C. and treated with oxalyl chloride (3.31 ml, 37.9 mmol). 5-bromo-4-methylisoxazole-3-carboxylic acid (7.09 g, 34.4 mmol) was added and stirred under ice cooling for 10 mins. 4-Amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (7.92 g, 37.9 mmol) and triethylamine (14.39 ml, 103 mmol) were added at 0° C. and the mixture stirred at this temperature for 30 mins. The resulting mixture was diluted with DCM and washed with a saturated NaHCO3 (aq) solution. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 100% TBME afforded the title compound;
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 69 h
Yield: 88 %

Procedure:
To a solution of the alcohol from above (200 mg, 0.796 mmol) in CH2Cl2 (8 mL) was added activated MnO2 (814 mg, 7.96 mmol) and the mixture stirred at room temperature for 69 h. The reaction mixture was filtered through Celite and the cake was washed with CH2Cl2. The solvent was removed from the filtrate under reduced pressure to give the desired aldehyde as colourless crystals (175 mg, 88%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.89 (m, 2H), 3.41 (m, 2H), 4.55 (br s, 1H), 7.37 (d, 2H, J=8.1 Hz), 7.83 (d, 2H, J=7.8 Hz), 9.99 (s, 1H).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:40])[CH2:19][C:20]1[C:29]([CH3:30])=[C:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:39])[CH:26]=2)[CH:21]=1.N1C=CC=CC=1.O>ClCCl>[CH3:16][O:17][C:18](=[O:40])[CH2:19][C:20]1[C:29]([CH3:30])=[C:28]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:36][CH:37]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:39])[CH:26]=2)[CH:21]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(O)cc2)c1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Trifluoromethanesulfonic anhydride (2.6 mL, 15.0 mmol) was added drop-wise to a -6° C. solution of [6-fluoro-4-(4-hydroxy-benzyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (3.9 g, 11.5 mmol) and pyridine (1.4 mL, 17.4 mmol) in dichloromethane (100 mL). The reaction mixture was warmed to room temperature, and stirred for 1 hour. The reaction mixture was then cooled to 4° C. Water (20 mL) was added, and the organic layer was dried over MgSO4, filtered, and concentrated. A solution of this crude product in dichloromethane was concentrated over silica gel, and the resulting silica gel-supported product was subjected to flash chromatography (Analogix SuperFlash™ column, 5%-20% ethyl acetate in hexane) to give 3.8 g (70%) of [6-fluoro-3-methyl-4-(4-trifluoromethanesulfonyloxy-benzyl)-naphthalen-2-yl]-acetic acid methyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.94 (dd, J=8.9, 6.2 Hz, 1 H), 7.79 (s, 1 H), 7.70 (dd, J=12.1, 1.8 Hz, 1 H), 7.37 (d, J=8.8 Hz, 2 H), 7.29-7.38 (m, 1 H), 7.20 (d, J=8.8 Hz, 2 H), 4.53 (s, 2 H), 3.94 (s, 2 H), 3.64 (s, 3 H), 2.29 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([NH:13][CH3:14])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C([O-])(O)=O.[Na+].[C:24](Cl)([Cl:26])=[O:25]>CCOCC.O.C1C=CC=CC=1>[CH3:14][N:13]([C:12]1[CH:15]=[CH:16][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:17])([F:18])[F:1])=[CH:10][CH:11]=1)[C:24]([Cl:26])=[O:25]
Reactant: O=C(Cl)Cl
Reactant: CNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CN(C(=O)Cl)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 99.5 %

Procedure:
To a cold (10°) stirred mixture of 137 g (0.50 mole) 4-(hexafluoro-2-hydroxy-2-propyl)-N-methyl aniline in 500 ml Et2O and 168 g (2.0 mole) NaHCO3 in 500 ml H2O add dropwise 500 g (0.6 mole) 12% phosgene in benzene over 1 hour. Add 500 ml Et2O, separate the organic phase, dry, concentrate and wash the residue with hexane to give 167 g white solid; m.p. 152°-154°.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: [OH-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C(N)=O)cc1
Temperature: 78 °C
Yield: 40 %

Procedure:
Terephthalonitrile (128 g) and ethanol (1700 g) were placed in a four-neck flask, and the mixture was heated to 78° C. with stirring. To the mixture, a 20% aqueous solution (10 g) of sodium hydroxide was added over three hours by use of a tube pump. Liquid chromatographic analysis revealed that the reaction mixture contained 71.5 g of p-cyanobenzamide (yield 40%) and 38.4 g of terephthalonitrile (conversion 70%). The reaction mixture was cooled to 25° C., neutralized with concentrated sulfuric acid, and heated under reduced pressure so as to concentrate the mixture and to remove ethanol (1275 g). After normal pressure was restored, the mixture was cooled to 25° C., and water (720 g) was added thereto. Subsequently, an aqueous solution (887.5 g) of sodium hypochlorite (effective chlorine 12%) was added to the reaction mixture over six hours while a 50% aqueous solution of sulfuric acid was added so as to maintain the pH of the mixture at 5-6. Liquid chromatographic analysis revealed that the reaction mixture contained 55.9 g of crude p-cyanobenzoic acid (yield 38%) and terephthalonitrile (38 g). Subsequently, the residual solvent (1090 g) was removed from the reaction mixture through distillation under reduced pressure. To the resultant mixture, a 48% aqueous solution of sodium hydroxide was added to thereby adjust the pH to 8, and precipitated terephthalonitrile (36 g) was recovered through filtration. To the filtrate, concentrated sulfuric acid was added so as to adjust the pH to 3.0 and precipitate p-cyanobenzoic acid from its salt. The precipitate was dissolved by adding ethanol (309 g) with heat, and the solution was cooled for crystallization, to thereby obtain 52.6 g of p-cyanobenzoic acid having a purity of 95% (yield 34%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[C:10]3[N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CS(C)=O.[Cl-].[Na+].O>[CH2:25]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:11]=[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[N:8]=2)[CH2:2][CH2:3]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: c1ccc2nc(N3CCNCC3)nc-2cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCN1CCN(c2nc3cccccc-3n2)CC1
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
A mixture of 2-(1-piperazinyl)cycloheptimidazole (3.15 g, described in Example 2) and potassium carbonate (1.14 g) in dimethyl sulfoxide (10 ml) was stirred for 15 min and a solution of 2-propenyl bromide (1.18 g) in dimethyl sulfoxide was added. The reaction mixture was stirred for 2.5 hr and diluted with brine. The solution was extracted with ethyl acetate and the organic extract was dried and evaporated to give the title compound (1.8 g): mp 108°-111° C.; ir(CHCl3) 1600, 1565 and 1520 cm-1 ; uv max (MeOH) 263(ε29,965), 237(ε25,490) and 362 nm (ε21,620) and nmr(CDCl3)δ 2.6(4H,s), 3.0(2H,d), 4.05(4H,t), 5.15(2H,m), 5.75(1H,m) and 7.65(5H,m).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH:23]=[CH:22][C:21]=1[NH:34][C:35](=[O:44])[NH:36][CH2:37][C:38]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:19][C:20]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[CH2:30][CH2:29]2)=[O:27])[CH:23]=[CH:22][C:21]=1[NH:34][C:35](=[O:44])[NH:36][CH2:37][C:38]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39]1
Reactant: NC(=O)C1(CNC(=O)Nc2ccc(C(=O)N3CCNCC3)cc2F)CC1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C1(CNC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2F)CC1
Yield: 9.6 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.303 mmol, 102 mg), 1-((3-(2-fluoro-4-(piperazine-1-carbonyl)phenyl)ureido)methyl)cyclopropanecarboxamide (0.303 mmol, 110 mg) and potassium carbonate (0.303 mmol, 42 mg) were stirred in acetonitrile (2 ml) at room temperature for 4 hours. The reaction was concentrated under reduced pressure and the residue obtained was purified by silica chromatography eluting with dichloromethane increasing to dichloromethane:methanol (10%). Further purification by HPLC and SCX chromatography yielded the title compound (18 mg). MS (ESI) m/z 620.7 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][C:27]1([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:30][NH:29][CH2:28]1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([N:29]4[CH2:30][C:27]([CH3:26])([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28]4)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(NC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1

Procedure:
A mixture of 1 g (3 mmoles) of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.98 g (4.5 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 0.6 g (6 mmoles) of triethylamine is heated under reflux for 3 hours in 10 ml of pyridine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[CH:9]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Br.O>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:19][CH:18]([O:21][CH3:22])[O:17][CH3:16])=[C:10]([CH3:15])[CH:9]=1
Reactant: COC(CBr)OC
Reactant: Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccc(Br)cc1C)OC
Temperature: 25 °C
Yield: 39.9 %

Procedure:
Powdered potassium carbonate (3.36 g, 24.3 mmol) is added to a stirred solution of 4-bromo-2-methylphenol (3.03 g, 16.2 mmol) and bromoacetaldehyde dimethyl acetal (3.56 g, 21.1 mmol) in anhydrous DMF (20 mL). The resultant mixture is stirred at 85° C. under nitrogen for 24 hours. The mixture is cooled to ambient temperature; then water (100 mL) and EtOAc (100 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The oil is chromatographed on silica (gradient 5-20% EtOAc in hexane) to give 1.78 g (6.47 mmol, 40% yield) of the title compound. EIMS: m/z 274 (M+, 79Br), 276 (M+, 81Br). Analysis for C11H15BrO3: calcd: C, 48.02; H, 5.50; found: C, 48.32; H, 5.53.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:12]([CH2:34][CH:35]=C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:50]CC1>C(OCC)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:30])([CH3:32])[CH3:31])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:12]([CH2:34][CH:35]=[O:50])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H]1C[C@](COCc2ccccc2)(n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOCC
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CC=O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
A solution of 18 (1 mmol), OsO4 (0.1 mmol) and 4-methylmorpholine N-oxide (2 mmol) in diethyl ether and water are stirred overnight. A solution of NaIO4 is added and the solution further stirred. The aqueous layer is extracted with diethyl ether and the combined organic layer is evaporated under vacuum to yield the crude product, compound 55.