Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][N:6]=1.[CH:17](OC)=[O:18]>COCCOC>[CH3:16][O:15][C:13](=[O:14])[C:12]([CH2:11][C:8]1[CH:9]=[N:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1)=[CH:17][OH:18]
Reactant: COC=O
Reactant: COC(=O)CCc1cnc(OC)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C(=CO)Cc1cnc(OC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a suspension of NaH (14.7 g, 367 mmol) in DME (216 mL) was added dropwise a mixture of methyl 3-[2-(methyloxy)-5-pyrimidinyl]propanoate (18 g, 92 mmol) and methyl formate (33.1 g, 550 mmol) in DME (216 mL) under N2 at 0° C. The reaction mixture was stirred at 25° C. overnight, then filtered through a pad of Celite. The filtrate was diluted with ether (500 mL), kept standing for about 2 h and re-filtered. The filtrated cake was washed with diethyl ether and dried to give the title compound (14 g, 51.7%), which was used into next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:15])[C:44](=[O:45])[CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)Cc2ccccc2)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R,4R)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 3.35 mmol) in CH2Cl2 (25 mL), phenylacetyl chloride (0.53 mL, 4.02 mmol) and triethylamine (0.56 mL, 4.02 mmol) are added under N2 atmosphere at 0° C. The mixture is stirred 30 min at 0° C., then allowed to reach RT and further stirred for 1 h. The reaction mixture is diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 20:80 to 0:100) to give the title compound. TLC, Rf (CH2Cl2/MeOH 95:5)=0.4. MS (LC-MS): 526 [M-Boc+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.71 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.Cl.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:8](=[O:10])[CH2:7][C@H:5]3[O:6][C:2]([CH3:1])([CH3:12])[O:3][C:4]3=[O:11])[CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H](CC(=O)N2CCN(c3ccc(F)cc3)CC2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
To a solution of [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (3.48 g; 20.0 mmol; 1.0 eq.), TEA (6.07 g; 60.0 mmol; 3.0 eq.) in DCM (60 mL) was added HOBt (2.97 g; 22.0 mmol; 1.1 eq.) and the mixture was chilled to 0° C. EDC (4.6 g; 24.0 mmol; 1.2 eq.) was then added and the resulting reaction mixture was stirred for 15 min at 0° C. 1-(4-fluorophenyl)piperazine dihydrochloride (5.57 g; 22.0 mmol; 1.1 eq.) was added and the resulting reaction mixture was stirred at RT over night. Purification by flash chromatography (AcOEt/c-Hex: 50/50) gave the title compound as a colorless oil (5.12 g, 76%). M+(ESI): 337.2. HPLC (Condition A): Rt: 2.5 min (HPLC purity: 97.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=1[CH:13]=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=1[CH:13]=[N:9][NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COc1ccc(F)c(C=O)c1
Reactant: NNc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(C=NNc2ccc(F)cc2)c1

Procedure:
(4-fluorophenyl)hydrazine (6.5 g, 40 mmol), 2-fluoro-5-methoxybenzaldehyde (6.2 g, 40 mmol) and cesium carbonate (13 g, 40 mmol) were stirred in DMF (40 mL) at r.t. under argon atmosphere for 1.5 h and was then poured with stirring into water and extracted with ethyl acetate. The organic phase was washed trice with water, then brine and evaporated. The residue crystallized slowly to afford the subtitle compound as a beige-light brown crystal mass (10.21 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:17]=1)[CH3:12]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-2-pyridinecarboxylic acid (113 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:11].CO>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:8]=[C:9]([CH3:10])[C:2]([NH2:1])=[C:3]([I:11])[CH:4]=1
Reactant: Cc1cc(C#N)cc(I)c1N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CN)cc(I)c1N
Reaction time: 12 h
Yield: 96.1 %

Procedure:
4-Amino-3-iodo-5-methylbenzonitrile (200 mg, 0.77 mmol) was dissolved in THF at 0° C. After Borane-THF complex (4 eq, 3.10 mmol, 3.10 ml) was slowly added into the reaction mixture, a reaction temperature was heated to reflux. The reaction mixture was stirred for 12 hr with reflux. After confirming the completion of the reaction, MeOH was added. The mixture was stirred for 4 hrs. The reaction solvent was removed in vacuo. A residue was extracted with Ethyl acetate, washed with H2O and brine, dried with Na2SO4 and concentrated in vacuo to yield 4-Aminomethyl-2-iodo-6-methyl-phenylamine (194 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[C:26]([F:38])=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=2)[CH:28]=[CH:29][CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:24][C:25]1[C:26]([F:38])=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:2]3[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]4[CH:15]=[CH:14][C:13]([CH2:16][N:17]5[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]5)=[CH:12][CH:11]=4)[CH:5]=[CH:6][CH:7]=3)[N:32]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(CN2CCCCC2)cc1
Reactant: Nc1nccc(-c2cccc(Cl)c2F)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(Nc2nccc(-c3cccc(Cl)c3F)n2)c1)c1ccc(CN2CCCCC2)cc1
Temperature: 150 °C

Procedure:
A mixture of N-(3-bromophenyl)-4-(piperidin-1-ylmethyl)benzamide (20 mg, 0.054 mmol) and 4-(3-chloro-2-fluorophenyl)pyrimidin-2-amine (18 mg, 0.080 mmol), KOBut (12 mg, 0.11 mmol), Pd2(dba)3 (2.5 mg, 0.027 mmol) and Xantphos (2.5 mg, 0.043 mmol) in a microwave reaction vessel was suspended in 0.6 mL of toluene. The reaction mixture was heated in a microwave at 150° C. for 1 h. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder. MS (ESI+) m/z 516.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([O:24][N:25]=[C:26]1[C:30]2([CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]2)[CH2:29][NH:28][CH2:27]1)[CH3:23].C(#N)C>C(N(CC)CC)C>[C:37]([O:36][C:34]([N:32]1[CH2:33][C:30]2([C:26](=[N:25][O:24][CH2:22][CH3:23])[CH2:27][N:28]([C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[C:9]([NH2:17])[C:10]=3[F:16])[CH2:29]2)[CH2:31]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CCON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
400 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid, 690 mg of t-butyl 8-(ethoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 2 g of Amberlite® IRA-420 were added to 15 ml of acetonitrile and thereto 1.5 ml of triethylamine was dropped and the resulting mixture was refluxed for 5 days and filtered. The filtrate was concentrated under the reduced pressure and to the resulting residue 10 ml of isopropanol was added and the resulting solution was stirred for 1 hour at room temperature. The precipitated solid was filtered and dried to give 380 mg of the titled compound(yield: 51.1%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:16]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][O:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][C:4](=[O:12])[CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cc(=O)oc2ccccc12)c1ccccc1
Temperature: 0 °C
Yield: 62.8 %

Procedure:
To a solution of 4-hydroxycoumarin (1.62 g, 10 mmol) in acetone (60 ml) were added 2-bromoacetophenone (1.99 g, 10 mmol) and potassium carbonate (5.53 g, 40 mmol). The mixture was refluxed for 3 h. (monitored by TLC). Evaporation of the solvent gave a residue which was poured into ice water (50 ml). The resulting solid was collected and crystallized from ethyl acetate to afford 4-(2-Oxo-2-phenylethoxy)-2H-1-benzopyran-2-one (2a) (1.76 g, 62.9%) as a needle crystal. mp: 183°-184° C.; IR(KBr) νmax : 1721, 1703, 1626; UV(CHCl3) λmax (log ε): 306 (3.79), 253 (4.28); 1H-NMR (CDCl3): δ5.50 (s, 2H, OCH2), 5.61 (s, 1H, 3-H), 7.26-7.35 (m, 2H, 6- and 8-H), 7.50-7.71 (m, 4H, 5-, 7-H and aromatic H), 7.94-8.02 (m, 3H, aromatic H). Anal. Calcd for C17H12O4 : C, 72.85; H, 4.32. Found: C, 72.85; H, 4.72.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[N:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCCl>[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([C:37]4[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=4)[N:24]=3)=[CH:21][CH:22]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc(-c2ccc(-c3ccc(F)cc3)nc2-c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: Oc1ccc(-c2ccc(-c3ccc(F)cc3)nc2-c2ccc(OCCN3CCCCC3)cc2)cc1
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
The AlCl3 (1.9 g, 14 mmol) was stirred in 50 mL of DCE at 0° C., ethanethiol (1.5 mL, 20 mmol) was added, and the mixture stirred for 15 min. The 2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-methoxyphenyl)-6-(4-fluorophenyl)pyridine (1 g, 2 mmol) in 25 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 25 mL THF at 0° C., followed by 25 mL 1N HCl and worked up. The crude product was triturated with Et2O, filtered, and dried in vacuo to give 0.86 g (91% yield) of white solid: mp 194°-195° C.; 1H NMR (CDCl3) d 1.63-167 (comp, 6H, piperidine), 2.59 (bs, 4H, piperidine), 2.81-2.84 (t, 2H, J=5 Hz, CH2N), 4.12-4.15 (t, 2H, J=5 Hz, OCH2), 6.64-6.70 (m, 4H, ArH), 7.00-7.03 (d, 2H, J=8 Hz, ArH), 7.12-7.18 (m, 2H, ArH), 7.37-7.40 (d, 2H, J=8 Hz, ArH), 7.61-7.67 (m, 2H, ArH), 8.08-8.12 (m, 2H, ArH); MS (FD) 468 (M+). Anal. Calcd for C30H29N2O2F: C, 76.90; H, 6.24; N, 5.98. Found: C, 77.13; H, 6.36; N, 5.86.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:3][CH2:2]1.[N-:12]=[N+:13]=[N-:14].[Na+]>C(O)C.O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][N:9]2[C:10](=[S:11])[NH:14][N:13]=[N:12]2)[CH2:5][CH2:6]1
Reactant: S=C=NCCN1CCOCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: S=c1[nH]nnn1CCN1CCOCC1
Temperature: 20 °C
Yield: 53 %

Procedure:
To a mechanically stirred slurry of 25.8 g (0.15 mole) of 2-morpholinoethylisothiocyanate (S-7) in 250 ml ethanol under a nitrogen atmosphere was added in a slow stream 19.5 g (0.3 mole) of sodium azide dissolved in 600 ml water. The resultant solution was refluxed for 16 hrs, cooled to room temperature (20° C.) and filtered. The filtrate was extracted twice with ether, and then acidified to pH=1 with concentrated hydrochloric acid. The resultant solution was extracted three times with ether. The pH of the aqueous solution was adjusted to 4.5 using a 50% NaOH solution and a fine white precipitate formed. The precipitate was collected by filtration to yield 17.1 grams of intermediate S-8 with a melting point of 226°-8° C.
Reaction SMILES: [CH3:1][C@H:2]1[N:7](C(OCC2C=CC=CC=2)=O)[CH2:6][C@@H:5]([C:18]([O:20]C)=[O:19])[CH2:4][CH2:3]1.Cl>O1CCOCC1>[CH3:1][C@H:2]1[NH:7][CH2:6][C@@H:5]([C:18]([OH:20])=[O:19])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@H](C(=O)O)CN1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Into a 75 mL sealable tube, were added 3-methyl 1-(phenylmethyl) (3S,6R)-6-methyl-1,3-piperidinedicarboxylate (10 g, 34.3 mmol), 1,4-dioxane (20 mL) and concentrated HCl (20 mL), and the mixture was stirred at 100° C. for 3 hours. The mixture was then cooled to room temperature. HPLC showed no starting material and NMR showed major was the desired product. The solution was transfered to a 500 mL round bottom flask, and concentrated to dryness. Trituration with Et2O and CH3CN afforded the HCl salt of the title compound (6.17 g) as a colorless oil that turned into a white solid after standing overnight. 1H NMR (400 MHz, CD3OD): δ 6.51 (s, 1H), 7.04 (m, 1H), 7.32 (m, 2H), 7.46 (dd, J=8.6, 1.3 Hz, 1H), 7.66 (m, 2H), 7.75 (dd, J=8.3, 0.8 Hz, 1H), 7.81 (s, 1H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[C:11]([CH:22]=1)=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[O:13][N:14]=2.[I:23][C:24]1[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=1.O>C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([C:12]2[O:13][N:14]=[C:10]3[CH:9]=[CH:8][C:7]([C:28]([C:27]4[CH:34]=[CH:35][C:24]([I:23])=[CH:25][CH:26]=4)=[O:29])=[CH:22][C:11]=23)[CH:20]=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(I)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
BuLi 1.6M (0.106 mol) was added dropwise at −70° C. to a solution of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.0816 mol), obtained in Example A1a, in THF (250 ml) under N2 flow. The mixture was stirred at −70° C. for 15 min. A solution of 4-iodo-N-methoxy-N-methyl-benzamide (0.098 mol) in THF (150 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour then brought to room temperature. The mixture was hydrolysed with water, extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (48 g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 16.5 g (44%) of [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-iodophenyl)-methanone, mp.196° C. (intermediate 35).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: CN1CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCN(C)CC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 73 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and N-methylpiperazine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 73%; MS: m/z=414 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:39]([NH:38][C:34]6[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=6)=[O:40])=[CH:25][CH:24]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(N)cc5)cnc4c3)cn2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(NC(=O)Nc6cccc(C(F)(F)F)c6)cc5)cnc4c3)cn2)CC1
Temperature: 25 °C

Procedure:
Combine the amine (0.164 g, 0.425 mmol), 3-trifluoromethylphenyl isocyanate (0.060 mL, 0.425 mmol) and triethylamine (0.119 mL, 0.851 mmol) in DMSO (5 mL). Stir the mixture at room temperature for ninety minutes. Extract the mixture with ethyl acetate versus water. Wash the organic layer with saturated aqueous saturated sodium chloride. Dry the resulting organics over magnesium sulfate, filter, and concentrate. Purify by column chromatography (ethyl acetate→5% methanol in dichloromethane→10% methanol in dichloromethane) to afford product (0.056 g, 13%, two steps). MS(ES), m/z 573 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH:11]([OH:18])[C:12]([N+:15]([O-])=O)([CH3:14])[CH3:13])=[CH:7][CH:6]=1>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH:11]([OH:18])[C:12]([NH2:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: COCCc1ccc(OCC(O)C(C)(C)[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COCCc1ccc(OCC(O)C(C)(C)N)cc1

Procedure:
19 g of 1-[4-(2-methoxyethyl)-phenoxy]-3-nitro-3-methyl-butan-2-ol are hydrogenated at 60° C. and under a pressure of 6 bar in a mixture of 250 ml of ethanol and 50 ml of glacial acetic acid in the presence of 4 g of palladium-on-charcoal (10% Pd). After the mixture has been filtered and the solvent has been evaporated off, the residue is rendered alkaline with 2N NaOH and the mixture is extracted with CH2Cl2. The organic phase is washed with water and dried with Na2SO4 to give, after evaporation, 15 g of the amine, which is converted into the hydrochloride with ethanolic hydrochloric acid. Melting point: 120°-122° C. (ethyl acetate).
Reaction SMILES: Cl.O1CCOCC1.[CH:8]1([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:20][CH:19]([NH:34]C(OC(C)(C)C)=O)[C:18]2=[O:42])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:20][CH:19]([NH2:34])[C:18]2=[O:42])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: NC1CN(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCCC2)C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
4N HCl-dioxane (10 ml) was added to a solution of 1-cyclohexylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (500 mg) in ethanol (10 ml), and the mixture was stirred at 50° C. for one hour. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate, extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 400 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:23])(=O)=O)=CC=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:23])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Solvent: CN(C)C=O
Product: Oc1ccc2cc(Br)ccc2c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6-bromo-naphthalen-2-ol (5 g, 22.4 mmol, Aldrich) in dry DMF (50 mL, Aldrich) was added N-fluorobenzene sulfonimide (21.9 g, 67.2 mmol, Aldrich). The reaction was stirred at RT for 48 h. The volatile portion was removed in vacuo and the residue was purified by silica gel chromatography (CHCl3) to give title compound as a yellow solid. MS (ESI, neg. ion) m/z: 240.0 (M−1). Mass Calc'd for C10H6BrFO: 239.96.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]1>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1
Reactant: Nc1ccccc1F
Reactant: O=C1CCCC(=O)C1
Product: O=C1C=C(Nc2ccccc2F)CCC1
Yield: 80.9 %

Procedure:
2-Fluoroaniline (10 g) and cyclohexane-1,3-dione (10 g) were heated together under nitrogen at 120° for 1 h. The cooled mixture was triturated with ether and filtered to give the title compound (14.8 g), m.p. 116°-118°.