Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[C:4](=[N:15]\[O:16][CH3:17])/[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:18]([CH:20]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)[CH2:21][C:22]([O:24]C)=[O:23])#[N:19]>>[C:18]([CH:20]([C:26]1[CH:31]=[CH:30][C:29]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](/[CH:1]3[CH2:3][CH2:2]3)=[N:15]/[O:16][CH3:17])=[CH:8][CH:9]=2)=[CH:28][CH:27]=1)[CH2:21][C:22]([OH:24])=[O:23])#[N:19]
Reactant: CO/N=C(/COc1ccc(CO)cc1)C1CC1
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Product: CO/N=C(/COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)C1CC1
Yield: 44.24 %

Procedure:
Compound 104 was synthesized from (4-{[(2E)-2-cyclopropyl-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.5 g, 2.12 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.44 g, 2.12 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 44.24%); Purity: 85.80%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19]C)=[O:17].C[O-].[Na+]>CO>[O:21]=[C:15]([CH2:11][C:10](=[O:12])[C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of 1-(4-(trifluoromethoxy)phenyl)ethanone (5.0 g, 24.5 mmol) and diethyl oxalate (4.3 g, 29.4 mmol) in MeOH (60 mL) was added NaOMe (30% in MeOH, 5.3 g, 29.4 mmol). The mixture was stirred at RT for 4 h and then concentrated under reduced pressure. The residue was treated with 2N aq. HCl (15 mL) and extracted with EtOAc (2×100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford methyl 2,4-dioxo-4-(4-(trifluoromethoxy)phenyl)butanoate as a brown oil (6.85 g, 96%), which was used in the next step without further purification. MS (ES+) C12H9F3O5 requires: 290. found: 291 [M+H]+.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)=[O:16])C1C=CC=CC=1>CO.[Pd]>[CH3:27][N:25]([CH3:26])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:28])=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of the N-benzyloxy-4-[3-(4-dimethylamino-benzyl)-ureido]-butyramide (287 mg, 0.747 mmol) in methanol (15 mL) was added 10% palladium on carbon (30 mg) and the resulting reaction was allowed to stir under a hydrogen atmosphere for 18 hr, after which time the reaction mixture was filtered and concentrated in vacuo to provide compound 2, which was used without further purification. (203 mg, 92% yield). 1H NMR (300 MHz, DMSO-d6) δ (ppm) 10.38 (s, 1H), 8.69 (s, 1H), 7.06 (d, J=9.0 Hz, 2H), 6.67 (d, J=9.0 Hz, 2H), 6.10 (t, J=5.4 Hz, 1H), 5.87 (t, J=5.4 Hz, 1H), 4.06 (d, J=5.7 Hz, 2H), 2.97 (dt, J=6.6, 6.3 Hz, 2H), 2.85 (s, 6H), 1.94 (t, J=7.2 Hz, 2H), 1.57 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ (ppm) 168.8, 157.9, 149.4, 128.2, 127.9, 112.3, 42.4, 40.2, 38.8, 29.8, 26.3.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[NH2:11][C:12]1[C:21]2[N:22]=[C:23]3[CH2:28][O:27][CH2:26][CH2:25][N:24]3[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=2)[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:5]1([C:3](=[O:4])[CH2:2][O:29][C:16]2[CH:15]=[C:14]3[C:19]([C:20]4[N:24]5[CH2:25][CH2:26][O:27][CH2:28][C:23]5=[N:22][C:21]=4[C:12]([NH2:11])=[N:13]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: Nc1nc2cc(O)ccc2c2c1nc1n2CCOC1
Reactant: O=C(CBr)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nc2cc(OCC(=O)N3CCOCC3)ccc2c2c1nc1n2CCOC1
Temperature: 90 °C
Yield: 12.5 %

Procedure:
A glass vial was charged with 4-(bromoacetyl)morpholine (0.05 g, 0.26 mmol, 1.1 eq), 6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (0.06 g, 0.23 mmol), DMF (3 mL), and cesium carbonate (0.42 g, 1.3 mmol, 5 eq). The reaction mixture was heated at 90° C. overnight. The reaction was quenched with 30 mL water to provide an off-white precipitate. The solid was collected by vacuum filtration and recrystallized from acetonitrile to provide 0.011 g of 3-(2-morpholin-4-yl-2-oxoethoxy) 10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine, mp 204-206° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:24][CH3:25])=[N:12][N:13]3[C:18](O)=[CH:17][C:16]([CH2:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:28]>>[C:1]1([S:7]([C:10]2[C:11]([S:24][CH3:25])=[N:12][N:13]3[C:18]([Cl:28])=[CH:17][C:16]([CH2:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nn2c(O)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Product: CSc1nn2c(Cl)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A suspension of 1.3 g (3.43 mmol) of 3-benzenesulphonyl-5-dimethylaminomethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 50 ml of POCl3 was heated at reflux for 3 hrs. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 100 ml of CH2Cl2 and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/AcOEt 1:1) of the residue yielded 1.2 g (88%) of (3-benzenesulphonyl-7-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-5-ylmethyl)-dimethyl-amine as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)(=[O:10])=[O:9].[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:19]2[CH:20]=[CH:21][C:22]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([N:11]3[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]3)(=[O:10])=[O:9])=[CH:23][C:18]=2[F:17])=[CH:34][N:35]=1
Reactant: N#CC1CN(S(=O)(=O)c2ccccc2Br)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: N#CC1CN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)C1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 1-((2-bromophenyl)sulfonyl)azetidine-3-carbonitrile and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H16FN5O2S, 409.10; m/z found, 409.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 2H), 8.08-8.00 (d, J=8.0, 1H), 7.83-7.75 (m, 1H), 7.71-7.65 (m, 1H), 7.65-7.58 (m, 1H), 7.51-7.43 (d, J=7.5, 1H), 7.38-7.31 (d, J=11.7, 1H), 7.31-7.26 (m, 1H), 6.89 (s, 2H), 3.96-3.87 (m, 2H), 3.68-3.59 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=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.[Br:71][C:72]1[CH:77]=[C:76]([C:78]([F:81])([F:80])[F:79])[CH:75]=[CH:74][C:73]=1I.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:71][C:72]1[CH:77]=[C:76]([C:78]([F:79])([F:80])[F:81])[CH:75]=[CH:74][C:73]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2Br)cc1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A microwave vial was charged with INTERMEDIATE M (0.573 g, 1.372 mmol), Xantphos (0.159 g, 0.274 mmol), 2-bromo-1-iodo-4-trifluoromethyl-benzene (0.722 g, 2.059 mmol), Pd2(dba)3 (0.126 g, 0.137 mmol) and sodium tert-butoxide (0.264 g, 2.74 mmol). The mixture was diluted with toluene (13.72 mL), and purged with nitrogen, and stirred at 130° C. in the microwave for 30 minutes. The reaction was diluted with water, and washed with DCM. The organics were dried using a phase separator, and concentrated under a vacuum. The material was then purified via silica gel MPLC, eluting with 0 to 50% ethyl acetate in heptanes to yield 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light yellow solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[C:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH3:22])=[CH:14][CH:13]=1.[C:25]([O:32][CH2:33][CH3:34])(=[O:31])[C:26]([O:28]CC)=O>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]=[C:19]([CH3:24])[C:20](=[O:23])[CH:21]([CH3:22])[C:26](=[O:28])[C:25]([O:32][CH2:33][CH3:34])=[O:31])=[CH:16][CH:17]=1
Reactant: CCC(=O)C(C)=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=O)C(C)=Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of LiHMDS (1N solution in THF, 5.48 mmol, 5.17 mL) in THF (16 mL) at −78° C. was added a solution of 46b (4.98 mmol, 1.04 g) in THF (2.5 mL) drop wise. After stirring at −78° C. for 1 h, the mixture was treated with a solution of diethyl oxalate (4.98 mmol, 0.73 g) in THF (2.5 mL). After stirring at −78° C. for 1 h, then the mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated and the crude product was taken up in EtOAc, and washed with 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give 1.5 g of 46c.
Reaction SMILES: [N:1]([C:4]([C:7](=[O:13])[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)([CH3:6])[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=1[C:36](Cl)=[O:37]>O.O1CCCC1.C(N(CC)CC)C>[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=1[C:36]([NH:1][C:4]([CH3:6])([C:7](=[O:13])[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH3:5])=[O:37]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(C)(N=[N+]=[N-])C(=O)c1ccsc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1c(F)cccc1F)C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
4 ml of tetrahydrofuran and 0.08 ml of water were added to 0.68 g of 2-azido-2-(3-thenoyl)propane, then 1.10 g of triphenylphosphine was gradually added thereto with stirring at room temperature, and after completion of addition, a reaction was carried out for 18 hours. 15 ml of tetrahydrofuran was added to the reaction mixture, then 0.30 g of triethylamine was added, followed by cooling with ice, and a mixed solution of 0.46 g of 2,6-difluorobenzoyl chloride and 5 ml of tetrahydrofuran was dropwise added thereto. After completion of the dropwise addition, a reaction was carried out for 30 minutes under cooling with ice, and then a further reaction was carried out for 2.5 hours at room temperature. After completion of the reaction, the reaction mixture was put into 100 ml of water and extracted by ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=4/6) to obtain 0.60 g of the desired product having a melting point of from 139 to 142° C. The NMR spectrum data of this product were as follows.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:24][NH:25][OH:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.Cl.O1CCOCC1>>[ClH:23].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[CH2:24][NH:25][OH:26]
Reactant: CC(C)(C)OC(=O)N[C@H](CNO)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](CNO)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132.1 %

Procedure:
To {(S)-2-[4-(4-chloro-phenoxy)-phenyl]-1-hydroxyaminomethyl-ethyl}-carbamic acid tert-butyl ester (18 mg, 0.046 mmol, 1 eq) in a 2 ml-vial was added 4 N HCl in dioxane (1 ml, 4 mmol, 86 eq.). The mixture was shaken at rt overnight. Then the volatile material was removed to give the desired product (10 mg, 74% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.94-3.01 (dd, J=6.8, 11.2 Hz, 1H), 3.01-3.05 (dd, J=5.2, 11.2 Hz, 1H), 3.17-3.20 (dd, J=2.4, 11.2 Hz, 1H), 3.37-3.42 (m, 1H), 3.80 (m, 1H), 7.02-7.05 (m, 4H), 7.34-7.35 (d, J=6.8 Hz, 2H), 7.43-7.45 (m, 2H); LCMS (UV, ESI), 294 (M+1), 87% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.O1CCO[CH2:13][CH2:12]1>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]>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1)[CH3:13]
Reactant: C1COCCO1
Reactant: CC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCc1ccc(C(C)=O)nc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)ethanone (6.30 g, 31.5 mmol; Supplier=Kalexsyn; Lot=90) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (560 mg, 0.76 mmol) in dioxane (120 ml) was degassed by sparging with N2 for 10 minutes. Added a solution (15% w/w) of diethyl zinc in hexane (50 ml) slowly, dropwise and heated to 50° C. The orange mixture turned dark, ultimately generating a dark orange with yellow solids as it stirred at 50° C. for 30 minutes. Allowed to cool to room temperature. The reaction mixture was partitioned between EtOAc (200 ml) and water (200 ml), and the aqueous phase was extracted 2× with EtOAc. The combined organic phases were washed with brine (500 ml), dried (Na2SO4), filtered and evaporated in vacuo to give 4.14 g brown oil. Distilled under high vac using short-path distillation apparatus. BP=55° C. @ 0.32 torr to give 2.249 g of slightly tinted oil. 1H-NMR (CDCl3): δ 8.50 (d, J=1.9 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.63 (dd, J=8.0, 2.2 Hz, 1H), 2.71 (m, 2H), 2.69 (s, 3H), 1.27 (t, J=7.6 Hz, 3H). HPLC: 2.011 min., 57 area % @ 210 nm; 2.012 min., 75 area % @ 254 nm. LCMS: MS (ESI—) for C10H12O m/z 150.1 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[C:7]([O:27][CH3:28])[CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:31][C:32]([CH3:36])=[CH:33][CH2:34]Br>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)=[C:7]([O:27][CH3:28])[CH:6]=1)[CH2:34][CH:33]=[C:32]([CH3:36])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(C)=CCBr
Reactant: COc1cc(NC(C)=O)ccc1OCCCN1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N(CC=C(C)C)C(C)=O)ccc1OCCCN1CCN(c2ccccc2)CC1
Yield: 75.6 %

Procedure:
2 g of 1-[3-(4- acetamido-2- methoxyphenoxy)-n-propyl]-4-phenyl-piperazine, 232 mg of 65% sodium hydride, 940 mg of 3-methyl-2- butenyl bromide and 60 ml of anhydrous dimethylformamide are treated in the same manner as described in Example 13. 1.78 g of 1-{3-[4-(N-acetyl-N-(3-methyl-2-butenyl)-amino)-2-methoxyphenoxy]-n-propyl}-4-phenyl-piperazine are thereby obtained as a pale yellow oil. Yield: 86.3%
Reaction SMILES: NC1C=CC(OC2C3C(=CC(OC)=C(C(OC(C)(C)C)=O)C=3)N=CC=2)=C(F)C=1.[Cl:29][C:30]1[CH:52]=[C:51]([N+:53]([O-])=O)[CH:50]=[CH:49][C:31]=1[O:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:47][CH3:48])=[C:40]([C:43]([O:45][CH3:46])=[O:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>[Fe].O.CO.O1CCCC1>[NH2:53][C:51]1[CH:50]=[CH:49][C:31]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:47][CH3:48])=[C:40]([C:43]([O:45][CH3:46])=[O:44])[CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[C:30]([Cl:29])[CH:52]=1
Reactant: COC(=O)c1cc2c(Oc3ccc([N+](=O)[O-])cc3Cl)ccnc2cc1OC
Agent: [Fe]
Agent: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2c(Oc3ccc(N)cc3Cl)ccnc2cc1OC

Procedure:
Similar to the synthesis of compound 1c, from compound 48a (111 mg), a mixture of water-methanol-tetrahydrofuran (1:1:1) (5 mL), iron powder (49.7 mg), and ammonium chloride (111 mg), compound 48b was yielded as a crude product (31.2 mg, yield: 31%). ESI-MS m/z 359, 361 (MH+)
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[N:7]([CH3:13])[C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O>[CH2:1]([N:5]1[C:10]([CH3:11])=[C:9]([N+:15]([O-:17])=[O:16])[C:8](=[O:12])[N:7]([CH3:13])[C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])O
Reactant: CCCCn1c(C)cc(=O)n(C)c1=O
Agent: O=S(=O)(O)O
Product: CCCCn1c(C)c([N+](=O)[O-])c(=O)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 1.69 g (8.61 mmol) of 1-butyl-3,6-dimethyl-1H-pyrimidine-2,4-dione in 30 mL concentrated H2SO4 at 0° C. was added 1.7 mL fuming HNO3 in drops over 10 min. After stirring at 0° C. for an additional 30 min, the reaction mixture was poured into 300 mL of ice, extracted with 2×150 mL CH2Cl2, and the combined organics were dried over MgSO4, filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with CH2Cl2 /EtOAc (40/1), gave 1.72 g (7.13 mmol, an 83% yield) of the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ 0.99 (t, J=7.3 Hz, 3H), 1.46 (hex, J=7.3 Hz, 2H), 1.62-1.73 (m, 2H), 2.42 (s, 3H), 3.39 (s, 3H), 3.92 (t, J=7.4 Hz, 2H); IR (KBr, cm-1): 2961s, 2874s, 1722s, 1670s, 1620s, 1363s, 1224m; MS (ES) m/z (relative intensity): 242 (M+ +H, 100). Anal. Calcd for C10H15N3O4 : C, 49.79; H, 6.27, N, 17.42. Found: C, 49.47; H, 6.03; N, 17.37.
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C:5]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)([OH:21])[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:80]1[CH2:85][CH2:84][O:83][CH2:82][CH2:81]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:80]1([C:2]2[S:10][C:9]3[S:8](=[O:12])(=[O:11])[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C:5]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)([OH:21])[C:4]=3[CH:3]=2)[CH2:85][CH2:84][O:83][CH2:82][CH2:81]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCN1CC(O)(c2ccc3ccccc3c2)c2cc(Cl)sc2S1(=O)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN1CC(O)(c2ccc3ccccc3c2)c2cc(N3CCOCC3)sc2S1(=O)=O
Temperature: 140 °C
Yield: 18 %

Procedure:
A 5 mL microwave vial was charged with 6-chloro-4-(2-naphthyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazin-4-ol 1,1-dioxide (0.140 g, 0.282 mmol, tris(dibenzylideneacetone)dipalladium(0) (0.0129 g, 0.0141 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0163 g, 0.0282 mmol) and cesium carbonate (0.2758 g, 0.8466 mmol). The vial was flushed with Ar and 1,4-dioxane (4.4 mL) and morpholine (0.0738 mL, 0.847 mmol) were added. The reaction mixture was sealed and heated at microwave irradiation to 140° C. for 1 hour. Solvent was evaporated, and the residue was purified using column chromatography on silica gel (24 g Analogix column, gradient hexane to 50% EA in hexane over 20 minutes) to provide the title compound (0.030 g, 18%). LCMS (FA) ES+: 547. 1H NMR (400 MHz, DMSO) δ 7.94-7.88 (m, 4H), 7.53-7.51 (m, 2H), 7.30-7.27 (m, 1H), 6.50 (s, 1H), 5.69 (s, 1H), 4.87 (d, 1H), 4.53 (d, 1H), 4.11 (d, 1H), 3.87 (d, 1H), 3.64-3.61 (m, 4H), 3.50-3.45 (m, 2H), 3.06-3.03 (m, 4H), 0.79-0.74 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:20](=O)([O:23]C)[O:21][CH3:22].[NH4+].[Cl-]>C1COCC1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][C:20]([O:21][CH3:22])=[O:23])[N:15]=1
Reactant: Cc1cccnn1
Reactant: COC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a solution of diisopropylamine (19 ml, 130 mmol, 1.3 equiv) in dry THF (100 mL) at 0° C. under a N2, was added n-butyllithium (81 ml, 130 mmol, 1.3 equiv) slowly. The mixture was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of 3-methylpyridazine (9 ml, 100 mmol, 1.0 equiv) in THF (50 mL) was added dropwise over a period of 1:5 min. The resulting mixture was stirred at −78° C. for 1 h, and a solution of dimethyl carbonate (17 ml, 200 mmol, 2 equiv) in THF (50 mL) was added dropwise. The mixture was allowed to warm slowly to 25° C. and stirred for 2 days. Sat.NH4Cl was added and the resulting solution was extracted with 10% MeOH/DCM. The combined organics were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (2.5% MeOH/DCM) to give 1.6 g of methyl 2-(pyridazin-3-yl)acetate as a brown liquid (11 mmol, 11%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([C:10](=[O:15])N(OC)C)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH3:9])[C:10](=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 103.9 %

Procedure:
In a round-bottomed flask, [(R)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (300 mg, 1.29 mmol) was dissolved in THF (8 ml). The solution was cooled to −16° C. (NaCl/ice bath) and benzylmagnesium chloride (1.0 M in diethyl ether, 3.8 ml, 3.8 mmol) was added dropwise. After the addition, the reaction mixture was allowed to warm slowly to room temperature and stirred for 5.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 353 mg (99%) of ((R)-1-methyl-2-oxo-3-phenyl-propyl)-carbamic acid tert-butyl ester as a colorless oil.