Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.[CH2:22](O)[CH2:23][OH:24].CN(C=O)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:21][C:10]1[C:11]([S:17](=[O:19])(=[O:18])[NH2:20])=[CH:12][C:13]([C:14]([O:16][CH2:22][CH2:23][OH:24])=[O:15])=[C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)[CH:9]=1
Reactant: OCCO
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCCO)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.9 %

Procedure:
To a solution of furosemide (OnBio, Canada, 5.2 g, 15.6 mmol) in a mixture of CH2Cl2/DMF (15 mL /20 mL) was added ethylene glycol (Aldrich, Wis., U.S., 4.4 mL, 78.0 mmol) and DMAP (377.5 mg, 3.1 mmol). A solid formed upon the addition of the DMAP and additional DMF (15 mL) was added followed by EDAC (3.9 g, 20.3 mmol). The reaction mixture was allowed to stir at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue redissolved in CH2Cl2 (100 mL). The sample was washed with H2O (3×50 mL), brine, and the sample dried (MgSO4). The residue after evaporation was chromatographed on silica gel eluting with 1:1 hexanes/EtOAc to give the title compound (1.4 g, 24% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.45-8.43 (m, 2H), 7.64 (s, 1H), 7.35 (s, 2H), 7.09 (s, 1H), 6.42-6.41 (m, 1H), 6.37-6.36 (m, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 4.28 (br t, 2H), 3.71-3.65 (m, 2H). Mass Spectrum (API-TIS) m/z 375 (MH+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:35][C:36]([CH3:41])([CH3:40])[C:37]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)=[O:38]
Reactant: CC(C)(C)C(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 100.3 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 2,2-dimethylpropionic acid (34 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(2,2-dimethylpropionylamino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[N-:20]=[N+:21]=[N-].[Na+]>O>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
4-aminobenzoic acid (500 mg, 3.65 mmol) was dissolved in 2.5 mL of water and concentrated sulfuric acid (98%, 0.75 mL) and additional water (0.75 mL) were added. The suspension was cooled to 0° C. and a solution of NaNO2 (265 mg, 3.84 mmol) in 0.75 mL of water was added under constant stirring. Sodium azide (293 mg, 4.5 mmol) was added to the brown solution. After additional 15 min of stirring at 0° C. the precipitate was filtered and washed several times with water. The solid was dried to afford 4-azidobenzoic acid (594 mg, 3.64 mmol, 100%) as a white solid. 1H NMR (CD3OD, 500 MHz) δ (ppm): 7.13 (dd, J=1.9, 8.6 Hz, 2H), 8.02 (dd, J=1.9, 8.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]([CH:21]2[CH2:23][CH2:22]2)O)=[C:17]2[C:12]([C:13](=[O:35])[C:14]([CH3:34])=[C:15]([CH:24]3[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:26][CH2:25]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[C:18]([CH2:19][CH:21]2[CH2:23][CH2:22]2)=[C:17]2[C:12]([C:13](=[O:35])[C:14]([CH3:34])=[C:15]([CH:24]3[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:26][CH2:25]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)N1CCC(c2oc3c(C(O)C4CC4)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N1CCC(c2oc3c(CC4CC4)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of 7-(benzyloxy)-8-[cyclopropyl(hydroxy)methyl]-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (100 mg, 0.21 mmol) obtained in Example 34-3 in dichloromethane (2 mL), triethylsilane (336 μL, 2.10 mmol) was added dropwise under cooling with ice. Then, trifluoroacetic acid (79 μL, 1.05 mmol) was added dropwise thereto, and the mixture was stirred for 15 minutes under cooling with ice and then at room temperature for 1 hour. Trifluoroacetic acid (79 μL, 1.05 mmol) was added dropwise to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was cooled with ice, and then a saturated aqueous solution of sodium bicarbonate (30 mL) was added dropwise thereto, followed by extraction with dichloromethane. The organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-hexane/ethyl acetate=98/2→0/100). The title compound (62 mg, yield: 64%) was obtained as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:12])(=O)[C:8]([CH3:10])=[O:9].CN(C=O)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[O:21]1[CH2:22][CH2:23][N:18]([C:7](=[O:12])[C:8](=[O:9])[CH3:10])[CH2:19][CH2:20]1
Reactant: CC(=O)C(=O)O
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (8.75 mL) was added to a solution of pyruvic acid (6.96 mL) and DMF (77 μL) in THF (200 mL) at room temperature, and the mixture was stirred at room temperature for 20 min. Under a nitrogen atmosphere, morpholine (18.4 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (11.0 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[Cl-].[Cl-].[Al+3].[F:15][C:16]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:18]([C:17]3[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:16]=3[F:15])=[O:19])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: COc1cccc(C(=O)Cl)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-bromo-1H-pyrrolo[2,3-b]pyridine (67, 2.00 g, 0.0102 mol) in methylene chloride (120 mL), under an atmosphere of nitrogen, was added aluminum trichloride (8.20 g, 0.0615 mol). The reaction was stirred at room temperature for 60 minutes, then 2-fluoro-3-methoxy-benzoyl chloride (34, 2.12 g, 0.0112 mol, prepared from the corresponding carboxylic acid using the protocol of Example 1, Scheme 13, Step 4), dissolved in methylene chloride (20.0 mL), was added. After 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography, eluting with 25% ethyl acetate in hexane to provide P-0265 (approx 2.6 g, 73%). MS (ESI) [M−H+]−=347, 349.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=O)=[C:5]([CH3:7])[N:6]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:1][C:2]1[S:3][C:4]([C:8]([NH:14][NH2:15])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: NN
Reactant: CCOC(=O)c1sc(C)nc1C
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c(C(=O)NN)s1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To ethyl 2,4-dimethylthiazole-5-carboxylate (Prep25, 50 g, 0.27 mol) in ethanol (200 mL), hydrazine hydrate (64 g, 1.08 mol) was added. The mixture was stirred at 90° C. overnight. After cooling to room temperature, the solvent was removed under vacuum to afford 41 g of crude product as a solid. The crude was purified by FC to give 23 g pure title compound product (y=50%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[N:19]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:26][CH2:27]2)[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]1=[O:17]
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CC(CCN2CCN(c3ncccn3)CC2)c2nc3ccccc3n2C1=O

Procedure:
To 60 mL of toluene was added 4.0 g (0.0152 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one, 6.0 g (0.033 mol) of 1-(2-pyrimidyl)piperazine, and 4.0 g (0.04 mol) of triethylamine. The reaction mixture was heated at reflux for 2 days and subsequently washed with 2×50 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. Crystallization from ethyl acetate afforded 4.0 g, 67% of analytically pure crystals, mp 161°-62° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][C:4]1=[O:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:26]([N:3]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][C:4]1=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCOC(=O)C1CCC(=O)N1
Reactant: CCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN1C(=O)CCC1C(=O)OCC
Temperature: 25 °C

Procedure:
To a stirred solution of 1.92 g NaH (60%, washed with pet ether) in dry THF at room temperature under N2 was added dropwise a solution of 7.06 g of ethyl 2-pyrrolidone-5-carboxylate in 20 mL of THF. The mixture was refluxed for 1 h, cooled to room temperature, followed by dropwise addition of 1.3 equivalents of 1-bromododecane. After additional reflux overnight and workup, the crude oil was subjected to flash chromatography (silica, 8:2 pet ether/EtOAc) to give 3.14 g of ethyl 1--N-dodecyl-2-pyrrolidone-5-carboxylate as a clear oil: NMR (CDCl3) δ 4.2(m), 3.68(m), 2.9(m), 2.6-2.2(m), 2.1(m), 1.6-1.0(m), 0.9(t).
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.N1C=CC=CC=1.[NH2:16][CH2:17][CH2:18][CH2:19][Si:20]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>C1CCCCC1>[CH3:9][C:3]1[C:4](=[O:6])[N:16]([CH2:17][CH2:18][CH2:19][Si:20]([O:27][CH2:28][CH3:29])([O:21][CH2:22][CH3:23])[O:24][CH2:25][CH3:26])[C:7](=[O:8])[C:2]=1[CH3:1]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: CCO[Si](CCCN1C(=O)C(C)=C(C)C1=O)(OCC)OCC
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To an appropriately sized reaction vessel equipped with a thermowell, Dean Stark trap connected to condenser with a nitrogen inlet, addition funnel, and mechanical stirrer. was charged 2.2 L of cyclohexane followed by dimethylmaleic anhydride (DMMA, 107.8 g, 0.85 mol) and pyridine (3.5 mL, 0.042 mol) with stirring. A slight endotherm was observed (20 to 14° C.) as the dimethylmaleic anhydride dissolved in the cyclohexane. The mixture was warmed to 25° C. and a turbid solution was observed. The addition funnel was charged with 3-aminopropyltriethoxysilane (189.2 g, 200 mL, 0.85 mol) which was added slowly over 15 minutes. An additional 300 mL cyclohexane was added to rinse in the 3-aminopropyltriethoxysilane and the addition funnel was replaced by a stopper. The mixture immediately exothermed to 24° C. and a white turbid solution was observed. The mixture was heated carefully (to avoid excessive foaming) over 30 minutes to reflux. A clear solution was observed at 40° C. and again turned to a white turbid solution at 70° C. The reaction mixture was refluxed for 1 h at 70° C. and aliquot was analyzed and indicated that the reaction was completed (88% product with 11% DMMA and no 3-aminopropyltriethoxysilane). The reaction mixture was cooled to room temperature and the cyclohexane layer decanted to a 5 L flask leaving the white polymeric residue (120 g). The cyclohexane layer was concentrated on the rotary evaporator at 60° C. bath temperature. The residue was transferred to a 500 mL RBF and dried under high vacuum for 2 h at 7° C. bath temperature to give 132 g of crude product as a viscous oil (crude purity 96.5% with 3.2% DMMA). The crude product was further purified via Kugelrohr distillation at 150-170° C. oven temperature under vacuum 0.15-0.2 torr to give 64.4 g (23% yield) of product with 99.7% purity by gas chromatography (GC) as a clear liquid. 1H NMR and mass were consistent with the desired structure. Pot residue was 60.6 g and total polymeric residue was 180.1 g (64%). Data: GC analysis performed on a DB-5MS Column, 25 meters, 0.32 mm ID, 0.52 μm film, heat from 75° C. to 200° C. @15° C./min, then 200° C. to 300° C. hold for 2 min @300° C., Injector temperature: 200° C., Detector temperature: 350° C., Retention time: 9.250 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=S)=[C:4]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:3]=1[S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28].CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:4]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[C:3]=1[S:27]([N:30]([CH3:32])[CH3:31])(=[O:28])=[O:29]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2ccccc2Br)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 116.3 %

Procedure:
To a solution of N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-bromophenyl)thiourea (240 mg, 0.42 mmol) in dichloromethane (10 mL) at 0° C., methanesulfonyl chloride (0.065 mL, 0.84 mmol) and triethylamine (0.12 mL, 0.84 mmol) were added. 4-Dimethylaminopyridine was added as a catalyst. The reaction mixture was stirred at 0° C. for 1 hour, then it was partitioned between dichloromethane and water. The combined organic phase was dried and concentrated to give the desired product (266.2 mg, crude). 1H NMR (CDCl3) δ 0.4 (s, 6H), 1.09 (s, 9H), 2.86 (s, 6H), 7.06 (d, 2H), 7.1-7.37 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])/[CH:10]=[CH:12]/[N:13]([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(F)c(F)c1
Product: CN(C)/C=C/C(=O)c1ccc(F)c(F)c1
Yield: 84 %

Procedure:
The title compound was prepared in 84% yield from 1-(3,4-difluorophenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.93 (3H, s), 3.16 (3H, s), 5.62 (1H, d, J=12.0 Hz), 7.13-7.20 (1H, m), 7.63-7.76 (2H, m), 7.83 (1H, d, J=12.0 Hz).
Reaction SMILES: C(OC(=O)[N:7]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:8][CH:9]([C:31](=[O:34])[NH:32][OH:33])[CH:10]([OH:30])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([NH:7][CH2:8][CH:9]([CH:10]([OH:30])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)[C:31]([NH:32][OH:33])=[O:34])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cc(COc2ccc(C(O)C(CN(Cc3ccccc3)C(=O)OC(C)(C)C)C(=O)NO)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(COc2ccc(C(O)C(CNCc3ccccc3)C(=O)NO)cc2)c2ccccc2n1
Reaction time: 2 h
Yield: 154.8 %

Procedure:
Benzyl-{3-hydroxy-2-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propyl}-carbamic acid tert-butyl ester (0.07 g, 0.10 mmol) from Example 21 was taken up in methylene chloride (3 mL) and TFA (2 mL) under nitrogen atmosphere at room temperature. The reaction was complete after 2 h, was concentrated, taken up in water (5 mL), and freeze-dried to give the title compound (0.073 g, 100%) as a white solid. MS found: (M+H)+=472.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:5])#[N:2].N12CCN(CC1)CC2.CO/[CH:24]=[CH:25]/[C:26](=O)[CH2:27][CH3:28]>COCCO.Cl.C(OCC)(=O)C>[CH2:27]([C:26]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:24][CH:25]=1)[CH3:28]
Reactant: CCC(=O)/C=C/OC
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: COCCO
Solvent: CCOC(C)=O
Product: CCc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
To a solution of 2-cyano-N-(4-fluorophenyl)acetamide (1.7 g, 10.6 mmol) in dimethyleneglycol monomethylether (20 mL) were added 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10.6 mmol) and (1E)-1-methoxypent-1-en-3-one (1.82 g, 15.9 mmol), and the mixture was stirred at 120° C. for 12 hr. The reaction mixture was diluted with 1N hydrochloric acid and ethyl acetate, and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=50/50→100/0) to give a white solid. The white solid was washed with ethyl acetate to give the title compound (410 mg, 16%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(Cl)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,6-dichloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-chloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][C:15](Cl)=[N:16][CH:17]=1)=[O:11].[Cl:23][C:24]1[N:25]=[N:26][C:27]([N:32]2[CH2:37][CH2:36][NH:35][C@H:34]([CH3:38])[CH2:33]2)=[C:28]([CH3:31])[C:29]=1[CH3:30]>ClCCl>[CH3:8][O:9][C:10]([C:12]1[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][C:15]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[N:26]=[N:25][C:24]([Cl:23])=[C:29]([CH3:30])[C:28]=3[CH3:31])[CH2:33][C@H:34]2[CH3:38])=[N:16][CH:17]=1)=[O:11]
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.0 mL, 14.4 mmol, 2.9 eq) is added to a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (1.25 g, 5.0 mmol, 1 eq), 3-chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (1.20 g, 5.0 mmol, 1 eq) in dichloromethane (40 mL) and the resulting solution is stirred at rt for 2 h. The reaction mixture is diluted with dichloromethane (50 mL) and washed with water (25 mL), then brine (25 mL). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The desired compound is isolated by silica gel chromatography (10-75% EtOAc/heptane) as a white solid (1.83 g, 82%).
Reaction SMILES: [C:1]12[C:18](=[O:19])O[C:15](=[O:16])[C:13]3=[C:14]1[C:5](=[CH:6][C:7]1[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]=[CH:3][CH:2]=2.[OH-].[NH4+:21]>>[C:15]1(=[O:16])[C:13]2[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][C:1]=3[C:18](=[O:19])[NH:21]1)[CH:6]=[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]1=2
Reactant: O=C1OC(=O)c2c3ccccc3cc3cccc1c23
Reactant: [NH4+]
Agent: [OH-]
Product: O=C1NC(=O)c2c3ccccc3cc3cccc1c23
Yield: 86 %

Procedure:
1.51 g (6 mmol) of anthracene-1,9-dicarboxylic acid anhydride was treated with 10 ml of ammonium hydroxide (28%). After refluxing for 16 hours the solid was collected, washed with water, dried in vacuo, and crystallized from dimethylformamide-water to give 1.3 g (86%) of 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione. M.p. 310° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].Cl.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:2]([O:3][C:4](=[O:5])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1=[N:23][O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:1]
Reactant: NOCc1ccccc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CCCCC1=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
Ethyl 2-cyclohexanoneacetate (4.28 g, 23.3 mmol) and O-benzyl hydroxylamine hydrochloride were combined in 100 mL of ethanol (EtOH) and 2.59 g (25.6 mmol, 3.55 mL) of triethyl amine(Et3N) was added. The reaction was stirred at room temperature for 12 hours at which point it was concentrated in vacuo. The residue was taken up in EtOAc and washed with 1N HCl (2×20 mL), saturated NaHCO3 (1×20 mL), dried over Na2SO4, filtered, and concentrated. Purification by chromatography (SiO2, 90:1 hexanes-EtOAc) afforded (2-benzyloxyimino-cyclohexyl)-acetic acid ethyl ester (4.76 g, 72%) as a mixture of oxime isomers.