Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)C>[N:16]1[CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1ccccn1
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2cnc3ccccn23)cc(O)c1O
Temperature: 25 °C

Procedure:
A mixture of 987.5 mg of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 1.01 g of 2-aminopyridine is melted at 110°. After 30 minutes the melt is treated with 15 ml of ethanol and heated to boiling under reflux for 3 hours. The reaction mixture is then cooled to room temperature and the crystals are removed by filtration under suction. There is obtained 5-(imidazo[1,2-a]-pyridin-3-yl)-3-nitropyrocatechol of m.p. 250°-252° (from N,N-dimethylformamide/methanol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[N:21]=[CH:20][N:19]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32]CCl>>[ClH:32].[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:17][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:16])[CH:23]=1
Reactant: ClCCl
Reactant: COc1ccccc1-c1cc(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Product: COc1ccccc1-c1cc(NC(=O)NC2CCNCC2)ncn1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (XLIV) (0.250 g, 0.585 mmol) in dry dichloromethane (2 ml) ethereal HCl (2 ml) was added and the mixture was stirred for 2 hours at room temperature. The reaction was monitored by TLC. After completion, the solvent was removed from the reaction mixture to provide 0.20 g of 1-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-3-piperidin-4-yl-urea hydrochloride (Compound #24A).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:17](=[O:18])[NH:16][CH3:15])[CH:24]=3)=[CH:32][CH:31]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc(Br)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Br)c(C(F)(F)F)c3)cc2)ccn1
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH2Cl2 (80 mL) was added dropwise to a solution of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2Cl2 (40 mL) at 0° C. The resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were removed by filtration, then washed with CH2Cl2 (2×50 mL) and dried under reduced pressure (approximately 1 mmHg) at 40° C. to afford N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g, 90%): mp 203-205° C.; 1H-NMR (DMSO-d6) δ2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 509 ((M+H)+).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=O.COCCO[AlH2-]OCCOC.[Na+].O.Cl>C1(C)C=CC=CC=1>[CH2:25]([CH:22]1[CH2:21][CH2:20][CH:19]([CH:18]=[CH:17][C:14]2[CH:13]=[CH:12][C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH:3]=[O:2])[CH2:10][CH2:9]3)=[CH:16][CH:15]=2)[CH2:24][CH2:23]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC1CCC(C=Cc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(C=Cc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Temperature: -40 °C

Procedure:
Vitride (3.3M in toluene, 10 eq, 26.6 ml, 87.7 mmol) was added with syringe to a flask filled with Argon gas at 0° C., and morpholine (10 eq, 7.67 ml, 87.7 mmol) was added slowly dropwise with syringe. Then, toluene (a half of morpholine mmol, 44 ml) was added dropwise with syringe to produce vitride solution. 88 ml of a solution including cyclohexane carboxylate compound (3.48 g, 8.77 mmol) obtained in Example 4-1 in toluene a solution was added to another 2-neck flask filled with argon gas, and vitride solution was added slowly dropwise at −70° C. for 30 minutes. Then, the solution was stirred with maintaining −30 to −50° C. for 6 hours and water was added very slowly dropwise to the flask. 1M HCl was slowly added to the flask to neutralize the reaction solution. White precipitate was filtered under reduced pressure and the filtrate was extracted by toluene (20 ml×three times). The organic layer was collected, washed by distilled water (10 ml×two times), dried with anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane:ether=5:1, Rf=0.32) to produce 1.77 g (55%) of trans-4-{4-[2-(4-pentylcyclohexyl)ethenyl]phenyl}cyclohexane carbaldehyde.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([C:18]#[CH:19])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>O1CCCC1>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:13]=[C:14]([C:18]2[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl chlorooximidoacetate (6.68 g, 44.09 mmol) in tetrahydrofuran (90 mL) in an ice bath was added 3-(trifluoromethyl)phenylacetylene (5.0 g, 29.39 mmol) slowly, followed by triethylamine (8.19 mL, 58.78 mmol) dropwise. The resulting mixture was stirred at room temperature overnight, which was then filtered through a layer of silica gel (top) and anhydrous Na2SO4 (bottom), and washed with ethyl acetate. The filtrate was washed with water, the organic layer dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:Hexanes=1:9) to afford ethyl 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylate.
Reaction SMILES: CC[Mg+].[Br-].CCOCC.[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])([CH3:12])[CH3:11].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[C:20]#[N:21]>C1(C)C=CC=CC=1>[CH:10]([N:13]([CH:14]([CH3:16])[CH3:15])[C:20](=[NH:21])[C:19]1[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=1[F:26])([CH3:12])[CH3:11]
Reactant: N#Cc1c(F)cccc1F
Reactant: CC(C)NC(C)C
Agent: CC[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)N(C(=N)c1c(F)cccc1F)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A solution of EtMgBr in ether (8.0 ml, 3.0 M, 23 mmol) was added to a solution of diisopropylamine (2.5 g, 23.8 mmol) in toluene (60 ml) at 50° C. The mixture was stirred for 1 h and a white precipitate formed. The mixture was cooled to 0° C. and 2,6-difluorobenzonitrile (3.33 g, 23 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16 hours subsequently. The conversion, determined by GC, appeared to be 98%. The mixture was quenched with an aqueous solution of ammonium chloride (10%, 100 ml). The organic phase was separated from the aqueous phase and the latter was extracted twice with diethylether (200 ml). The combined organic phases were dried over sodium sulphate, filtered and the solvent was removed under reduced pressure giving 5.30 g (91%) of pure product. The ligand was characterized by 1H NMR 300 MHz (CDCl3) δ (ppm): 7.2 (m, 1H), 6.8 (m. 2H), 5.5 (bs, 1H), 3.7 (bs, 1H), 1.5 (bs, 6H), 1.0 (bs 6H), by 13C NMR 75 MHz (CDCl3) δ (ppm): 158.9 dd, J=238 Hz, J=8 Hz), 155.7, 130.1, v130.0, 129.8, 112.1, 112.0, 111.9, 111.8, 52.0 (bs), 36.2 (bs), 21.3, 20.5 and by 19F NMR 282 MHz (CDCl3) δ (ppm): −113.5
Reaction SMILES: [F:1][CH2:2][CH:3]([CH:8]([F:12])[CH:9]([F:11])[F:10])[C:4]([F:7])([F:6])[F:5].S(=O)(=O)(O)[OH:14]>O>[F:1][CH2:2][C:3]([OH:14])([CH:8]([F:12])[CH:9]([F:11])[F:10])[C:4]([F:7])([F:5])[F:6]
Reactant: FCC(C(F)C(F)F)C(F)(F)F
Reactant: O=S(=O)(O)O
Solvent: O
Product: OC(CF)(C(F)C(F)F)C(F)(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,4,4-hexafluoro-2-butanol may be prepared by fluorinating commercially available 3-chloropropionic acid to form 1,1,1,3-tetrafluoropropane which may then be reacted with CHF2CF carbene to form 2-fluoromethyl-1,1,1,3,4,4-hexafluorobutane. The 2-fluoromethyl-1,1,1,3,4,4-hexafluorobutane may then be dehydrogenated and reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,4,4-hexafluoro-2-butanol.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22]([S:25]([N:28]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]1=2)CO.I([O-])(=O)(=O)=O.[Na+].CO.[BH4-].[Na+]>C1COCC1.O>[CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:14])[F:13])[CH:8]=[CH:7][C:6]=1[N:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22]([S:25]([N:28]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]1=2)=[O:1]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2C(O)CO)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-(2-(1,2-dihydroxyethyl)-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (from EXAMPLE 204, intermediate in Step 2; 0.100 g, 0.161 mmol) in THF (0.619 ml)/water (0.619 ml) was added sodium periodate (0.052 g, 0.241 mmol). The reaction mixture was stirred at RT for 2 h. Upon completion, the reaction was filtered and washed well with THF. The filtrate was concentrated in vacuo and 4-(2-formyl-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was carried on without purification. To a solution of 4-(2-formyl-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.095 g, 0.161 mmol, 100% yield) in methanol (1.609 ml, 0.161 mmol) was added sodium borohydride (0.012 g, 0.322 mmol) at 0° C. (turned from yellow to clear solution upon addition), and the reaction was stirred in the ice-bath for 30 minutes until completion. The reaction was quenched with sat ammonium chloride solution (aq) and washed with DCM (×2). After drying via phase separator (Radley's Discovery Technology), the organics were concentrated in vacuo to yield an orange oil. The oil was taken up in DCM, and TFA was added (color change from orange solution to light pink). The reaction was stirred for 1 h until complete deprotection. The material was concentrated in vacuo and purified via silica gel chromatography, eluting with 0-100% ethyl acetate in heptane to yield 4-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.017 g, 0.036 mmol, 22.41% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.58 (br. s., 1 H) 3.66-3.79 (m, 1 H) 4.30-4.37 (m, 2 H) 4.38-4.58 (m, 2 H) 5.42 (t, J=5.48 Hz, 1H) 6.12 (d, J=8.51 Hz, 1 H) 6.78 (d, J=4.50 Hz, 1 H) 7.10 (dd, J=8.46, 2.10 Hz, 1H) 7.15 (d, J=2.05 Hz, 1 H) 7.21 (d, J=4.60 Hz, 1 H) 7.53 (d, J=8.31 Hz, 1 H) 7.73 (d, J=8.22 Hz, 1 H) 7.92 (s, 1 H) 12.55 (br. s., 1 H). m/z (ESI) 472.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
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: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96.1 %

Procedure:
A mixture of 4-bromobenzaldehyde (10.0 g), 4-fluorophenylboronic acid (11.3 g), tetrakis(triphenylphosphine)palladium(0) (3.12 g), sodium carbonate (28.6 g), toluene (150 mL), ethanol (70.0 mL) and water (70.0 mL) was stirred at 100° C. for 12 hours. After cooling the reaction mixture to room temperature, water was added and extraction with toluene was conducted twice. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10) and after adding n-hexane to the residue, the mixture was stirred. The precipitate was recovered by filtration and dried under reduced pressure to give the titled compound as a colorless solid (10.4 g).
Reaction SMILES: [I:1]I.[C:3]1([C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)([OH:12])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[I:1][C:11]#[C:10][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[OH:12]
Reactant: C#CC(O)(c1ccccc1)c1ccncc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(C#CI)(c1ccccc1)c1ccncc1
Reaction time: 3 h
Yield: 79.1 %

Procedure:
50.8 g (0.2 mol) of iodine were gradually introduced into a suspension of 42 g (0.2 mol) of 3-phenyl-3-pyridin-4-yl-1-propyn-3-ol in 500 ml of methanol at room temperature, while simultaneously adding 80 ml of concentrated sodium hydroxide solution dropwise. An almost clear solution was thereby obtained. After stirring the solution at room temperture for three hours, it was diluted with a large amount of water and the crystals which had separated out were filtered off, washed with water and dried in vacuo. After recrystallization from methanol, 53 g (79.2% of theory) of 1-iodo-3-phenyl-3-pyridin-4-yl-1-propyn-3-ol were obtained as colorless crystals of melting point 175° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](SC)=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[NH2:27]O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15]2[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][N:27]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1
Reactant: COc1cc(NC(=CC(=O)c2ccccc2)SC)ccc1-c1cnco1
Reactant: NO
Solvent: CCO
Product: COc1cc(Nc2cc(-c3ccccc3)on2)ccc1-c1cnco1
Reaction time: 8 h
Yield: 0 %

Procedure:
To an oven dry flask was added acetophenone (0.4 mL, 3.33 mmol) followed by 10 mL of anhydrous DMF. The flask was cooled to 0° C. and to it was added sodium hydride (0.084 g, 3.33 mmol) over a 10 min. The flask was stirred at RT for 10 min. 1E (0.772 g, 3.33 mmol) was added over a 10 min. period and the reaction mixture was stirred at RT for 1 hour. Iodomethane (0.2 mL, 3.33 mmol) was added and the reaction mixture was stirred at RT for an additional hour, concentrated under reduced pressure and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield 3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-(methylthio)-1-phenyl-2-propen-1-one (1.3 g), which was used for the subsequent step without further purification. To a solution of 3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-(methylthio)-1-phenyl-2-propen-1-one (1.2 g, 3.32 mmol) in 10 mL of ethanol was added hydroxylamine (50% solution in water, 0.3 mL, 4.98 mmol) and the contents refluxed for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was left at RT overnight and the solid that separates out (700 mgs) was filtered. 100 mgs of this solid was purified using preparative HPLC (YMC S5 ODS 30×250 mm Ballistic. Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA). The fraction having a retention time of 4.61 min. was collected, concentrated under reduced pressure, neutralized with 10% aqueous sodium carbonate and extracted into ethyl acetate. The ethyl acetate layer was concentrated to yield 0.015 mgs of the title compound. m.p. 173-175° C. (LC/MS retention time=4.61 min.; M+=334.22 Column: YMC S5 ODS 4.6×5.0 mm Ballistic. Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:27]([O:29][NH2:30])[CH3:28]>C(Cl)Cl>[CH2:27]([O:29]/[N:30]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:13][CH2:12]3)=[N:15][N:16]=2)[N:19]=1)\[CH3:24])[CH3:28]
Reactant: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Reactant: CCON
Agent: Cl
Solvent: ClCCl
Product: CCO/N=C(\C)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1

Procedure:
A solution of 1-(3-(1-(quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (30 mg, 0.09 mmol) and O-ethyl-hydroxylamine hydrochloride (18 mg, 0.18 mmol) in 2 mL of DCM was stirred at 40° C. overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, CDCl3) 3 ppm 8.84 (d, 1H), 8.29 (d, 1H), 8.25 (d, 1H), 7.92-7.91 (m, 2H), 7.72-7.68 (m, 2H), 7.49 (dd, 1H), 4.26 (q, 2H), 2.01 (s, 3H), 1.76 (s, 2H), 1.66 (s, 2H), 1.27 (t, 3H). LCMS (method A): [MH]+=373, tR=5.56 min.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.O>CS(C)=O>[C:1]1([C:7]2([O:13][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Temperature: 25 °C
Yield: 11.7 %

Procedure:
A mixture of 4-phenyl-4-piperidinol (7.1 g, 40 mM), DMSO (50 ml) and sodium hydride (2 g of a 50% dispersion in oil) was heated at 80° until homogenous, cooled to ambient temperature and treated with 4-fluorobenzotrifluoride (6.6 g, 40 mM) in DMSO (10 ml). After 24 hours the reaction mixture was poured on to cold water (250 ml) and extracted with ether (2×250 ml). The combined organic layers were washed with brine, dried and the solvent removed under reduced pressure. The residue was triturated with cyclohexane, filtered and the mother liquors evaporated and the residue triturated with pentane. Sublimation of the resulting crystals at 0.1 mm Hg (bath temp. 100°) gave the title compound (1.5 g), m.p. 104°-5°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH:13]3[CH3:20])=[O:23])=[CH:27][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC1OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1OCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 16, 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid and 4-fluorobenzylamine. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.67 (3H, d, J=6.6 Hz, CH3), 3.91 (2H, m, CH2), 4.12–4.35 (2H, m, CH2), 4.52 (2H, d, J=5.9 Hz, NCH2), 4.70 (1H, q, J=6.6 Hz, OCH), 5.33 (2H, s, OCH2), 7.02 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.35 (3H, m, aromatics), 7.47 (2H, m, aromatics), 7.71 (1H, broad t, NH).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)C.O>[C:18]([NH:1][CH2:2][C:3]12[CH2:17][CH:10]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=31)[C:11]1[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:20])[CH3:19]
Reactant: NCC12CC(c3ccccc31)c1ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCO
Product: CC(=O)NCC12CC(c3ccccc31)c1ccccc12

Procedure:
A solution of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene (235 mg) and acetic anhydride (217 mg) in ethanol (5.0 ml) was refluxed for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-acetylaminomethyl-9,10-dihydro-9,10-methanoanthracene. M.P. 184°-185.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][C@@H:9]([CH2:21][CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=Cc1ccccc1)C[C@H]1CN(Cc2ccccc2)CCN1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Dissolve (S)-4-benzyl-2-(3-phenyl-allyl)-piperazine-1-carboxylic acid tert-butyl ester (2.37 g, 6.04 mmol) in toluene (50 mL) and treat with trifluoroacetic acid (10.3 g, 90.5 mmol) at room temperature, and stir the reaction mixture. After overnight, dilute the reaction with CH2Cl2, and basify with 2N NaOH (50 mL), extract the aqueous solution with CH2Cl2, wash the combined organic layers brine, dry over Na2SO4. Pass the crude product through a SCX column (10 g), collect the 0.2N NH3/MeOH eluent and concentrate to give 1.46 g of the title compound: mass spectrum (Electrospray): m/z=293.3 (M+1). 1H NMR (400 MHz, CDCl3): δ7.35–7.19 (m, 10H), 6.54–6.47 (m, 1H) 6.18–6.11, 5.70–5.60 (m, 1H), 3.70 (s, 2H), 2.97–2.73 (m, 5H), 2.40–2.18 (m, 2H), 2.09–2.00 (m, 1H), 1.83 (t, 1H, J=9.8 Hz).