Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18](O)([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18]([F:28])([CH3:20])[CH3:19])=[N:9][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:12][CH:13]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 25 °C

Procedure:
To a solution of 2-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]propan-2-ol (200 mg, 0.57 mmol) in dry DCM (2 mL) at 0° C. under an atmosphere of nitrogen was introduced (diethylamino)sulphur trifluoride (0.14 mL, 1.15 mmol). The reaction was left to warm to RT for 1 hr. Following addition of sodium bicarbonate (5 mL of a saturated aqueous solution), the reaction mixture was washed with DCM (2×5 mL), and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, eluent heptane:EtOAc [0-100%] gradient) to furnish the title compound as a yellow solid: 1H NMR (500 MHz, CDCl3) delta 1.81-1.97 (6H, m), 5.18 (2H, br. s.), 7.28 (1H, s), 7.40-7.50 (1H, m), 7.78-7.92 (1H, m), 8.32 (1H, d, J=5.67 Hz), 9.01 (1H, d, J=1.10 Hz); LC-MS: m/z=+349.95/351.80 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:23]([C:22]3[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]([OH:28])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)[NH:32][C:33](=[O:34])[NH:35][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(Cl)c1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccc(Cl)c2)cc([N+](=O)[O-])c1O
Yield: 22 %

Procedure:
To a mixture of 2-(3-chlorophenyl)-1-phenylethanone (200 mg, 0.88 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (220 mg, 1.04 mmol), and urea (159 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, the reaction mixture was concentrated and purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 21 as a yellow solid (90 mg, yield 22.3%). 1H NMR (DMSO-d6 400 MHz): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.25 (d, J=4.0 Hz, 3H), 7.15-7.25 (m, 3H), 7.03 (d, J=4.8 Hz, 2H), 6.71-6.81 (m, 2H), 5.25 (s, 1H), 4.00-4.10 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]+.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH:18]([C@@H:21]1[CH2:26][CH2:25][O:24][C:23](=[O:27])[N:22]1[C:28](=[O:39])[CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.[CH2:49]([N:55]1[C:59]([CH:60]=[O:61])=[CH:58][N:57]=[CH:56]1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>ClCCl>[CH2:49]([N:55]1[C:59]([C@@H:60]([OH:61])[C@@H:29]([C:28]([N:22]2[C@H:21]([CH:18]([CH3:20])[CH3:19])[CH2:26][CH2:25][O:24][C:23]2=[O:27])=[O:39])[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:58][N:57]=[CH:56]1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: COC(=O)CC/C=C\CCC(=O)N1C(=O)OCC[C@H]1C(C)C
Reactant: CCCCCCn1cncc1C=O
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCn1cncc1[C@@H](O)[C@H](C/C=C\CCC(=O)OC)C(=O)N1C(=O)OCC[C@H]1C(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A 1M solution of dibutylboron triflate in dichloromethane (1.56 ml) was added to a solution of the product of step (iv) (422 mg, 1.42 mmol) in dry dichloromethane (9 ml) at 5° C. under argon, followed by diisopropylethylamine (0.295 ml, 1.7 mmol). The reaction mixture was stirred at 5° C. for 30 minutes and then cooled to -78° C. A solution of the product of step (iii) (280 mg, 1.56 mmol) in dichloromethane (2 ml) was added dropwise. The mixture was stirred at -78° C. for 30 minutes before being allowed to warm to room temperature. The reaction was quenched by the addition of pH7.2 phosphate buffer solution (1.36 ml) followed by hydrogen peroxide (0.4 ml, 30% w/v aqueous solution). The mixture was stirred for 30 minutes and then poured into water and extracted three times with dichloromethane. The combined extracts were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate, to give methyl (7S,4Z)-7-[(S)-(1-hexylimidazol-5-yl)hydroxymethyl]-8-[(S)-4-isopropyl-2-oxo-1,3-oxazinan-3-yl]-8-oxo-oct-4-enoate (450 mg, 66% yield) as an oil; NMR 0.8-0.95(9H,m), 1.25-1.4(6H,m), 1.7-1.9(2H,m), 2.1-2.9(8H,m), 3.68(3H,s), 3.85-4.22(4H,m), 4.6-4.72(1H,m), 4.88(1H,m), 5.36-5.6(2H,m), 6.93(1H,s), 7.54(1H,s).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:7]\[N:8]([CH3:10])C)[CH2:3][CH2:2]1.[CH3:20][NH:21]C(N)=N.C([O-])([O-])=O.[K+].[K+].C[N:32](C=O)C>>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:7][N:8]=[C:10]([NH:21][CH3:20])[N:32]=2)[CH2:2][CH2:3]1
Reactant: CN(C)C=O
Reactant: CSc1nccc(/C(=C/N(C)C)C(=O)CC2CC2)n1
Reactant: CNC(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNc1ncc(-c2ccnc(SC)n2)c(CC2CC2)n1
Reaction time: 18 h
Yield: 86 %

Procedure:
A solution of (3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(methylsulfanyl)pyrimidin-4-yl]but-3-en-2-one (3) (810 mg, 2.92 mmol), N-methylguanidine (480 mg, 4.38 mmol), and K2CO3 (1211 mg, 8.76 mmol) in DMF (28 mL) was stirred at 120° C. for 2 hours, followed by stifling at rt for 18 hours. The reaction was partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [100 g SNAP column, 30% EtOAc/heptane to 100% EtOAc] to afford the desired product as a white solid (720 g, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.12 (br. s., 2 H) 0.37 (d, J=7.07 Hz, 2 H) 1.07 (br. s., 1 H) 2.81 (d, J=6.57 Hz, 2H) 2.87 (d, J=5.05 Hz, 3 H) 7.39 (d, J=5.05 Hz, 1 H) 7.49 (br. s., 1 H) 8.49 (br. s., 1 H) 8.60 (d, J=5.05 Hz, 1 H). MS (ES+): m/z=288.2/289.2/290.2 (100/20/10) [MH+]. HPLC: tR=1.28 minutes over 3 minutes. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25].FC(F)(F)C(O)=O>C(Cl)Cl.CC(N(CC)C(C)C)C>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:25])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of N-tert-butyoxycarbonylpiperazine (2a) (1.86 g) in DCM (100 mL) and N,N-di-2-propyl-ethylamine (2 mL) was cooled in ice-water as a solution of 2-naphthalenesulfonylchloride (2.27 g) in DCM (50 mL) was added drop-wise. After addition, the cooling was removed and the reaction stirred overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was sequentially washed with 0.5 N hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine. After drying, the solvent was evaporated to provide a white solid. The white solid was dissolved in DCM (35 mL) and treated with trifluoroacetic acid (15 mL). After one hour, the solvent was evaporated, the residue suspended in water and the solution made basic with 1 N sodium hydroxide. The mixture was extracted with ethyl acetate. The extracts were washed with water, dried, and the solvent evaporated to give a white solid (2.7 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H][H].[CH3:18]O>[Pd]>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[C:3]([CH3:18])[CH:2]=1
Reactant: [H][H]
Reactant: CO
Reactant: COc1ccc(C2=CCNCC2)cc1F
Agent: [Pd]
Product: COc1ccc(C2CCNCC2)c(C)c1
Reaction time: 12 h
Yield: 87 %

Procedure:
To a solution of 4-(3-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (300 mg, 1.4 mmol) in MeOH (10 mL) was added Pd/C (154 mg). Hydrogen gas was introduced under balloon pressure and the reaction mixture was stirred vigorously for 12 h. The reaction mixture was filtered through a glass fiber filter cartridge, and the filter pad was washed with ethyl acetate. The combined organic layers were evaporated under reduced pressure to give 4-(4-methoxy-2-methylphenyl)piperidine (500 mg, 87% yield). LC/MS (Method P) RT=0.60 min. (M+H)+=210.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]2[CH3:44])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Yield: 68.9 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (333 mg, 1.1 mmol) and 3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H9) (314 mg, 1.0 mmol) according to the general procedure K. Obtained as a light yellow solid (374 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].C[N+]1([O-])CC[O:22]CC1>C(#N)C>[Cl:17][C:4]1[C:3]([CH:2]=[O:22])=[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
A solution of 41.0 g (0.12 mol) of methyl 3-bromomethyl-2-chloro-4-methylsulfonylbenzoate in 250 ml of acetonitrile was admixed with 42.1 g (0.36 mol) of N-methylmorpholine N-oxide. The reaction was stirred at room temperature for 12 hours and then concentrated and the residue was taken up in ethyl acetate. The solution was washed with water, dried and concentrated. 31.2 g (94% of theory) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: Br[C:2](=[CH:4][CH3:5])[CH3:3].[Li].[Br:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=O.O>CCCCC>[OH:13][C:11]([CH2:10][CH2:9][CH2:8][Br:7])([C:2]([CH3:3])=[CH:4][CH3:5])[C:4]([CH3:5])=[CH:2][CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CC=C(C)Br
Agent: [Li]
Solvent: CCCCC
Solvent: O
Product: CC=C(C)C(O)(CCCBr)C(C)=CC
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Analogously to example I, 2-lithium-2-butene was prepared from 2-bromo-2-butene (15.0 g; 0.11 mol) and lithium (2.8 g; 0.26 mol). To the product obtained, ethyl 4-bromobutanoate (11.0 g; 0.056 mol) was added dropwise and with reflux at -40-20° C., followed by stirring for 30 minutes at -20° C. Water (200 ml) and subsequently pentane (100 ml) were slowly added dropwise at -20° C. After separation of the layers the water layer was washed two times with 100 ml of pentane/ether (1/1, v/v), after which the combined organic layers were washed with water (50 ml). The organic layer was dried (K2CO3), filtered and evaporated. The yield was 14.0 g (96%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+]=[N-].[H][H]>[Pd].C1(C)C=CC=CC=1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCOCCN
Yield: 95 %

Procedure:
Under a nitrogen purge, 10% palladium on carbon (9.2 g) was added to a solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (92.0 g, 399 mmol) in toluene (900 mL) in a pressure vessel. The vessel was placed under hydrogen pressure (30 psi, 2.0×105 Pa), and for the first 20 minutes, the hydrogen was replaced every five minutes and brought to a pressure of (20 psi, 1.4×105 Pa). The reaction was maintained under hydrogen pressure (20 psi, 1.4×105 Pa) overnight. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure to yield 77.4 g of tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a light green oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=O)C.[NH2:21][NH2:22]>C(O)C>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[C:7]1=[O:20])[CH3:19]
Reactant: NN
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(CC)c1=O
Solvent: CCO
Product: CCn1c(=O)c(C(=O)NN)c(O)c2ccc(C)nc21

Procedure:
A stirred mixture of 1.38 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared as in Example 1) and 0.32 g. (0.01 mole) of hydrazine in 30 ml. of ethanol was heated under reflux for 1 hour. The mixture was filtered and the filter cake was triturated with 100 ml. of 20% aqueous acetic acid. The insoluble material was collected, air dried and was recrystallized from ethanol to give 0.7 g. of the title compound, m.p. 211°-13° C.
Reaction SMILES: B(Br)(Br)Br.Cl.[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:26]C)=[C:11]2[C:16]=1[O:15][CH2:14][C@H:13]([N:17]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:12]2>C(Cl)Cl>[F:6][C:7]1[CH:8]=[CH:9][C:10]([OH:26])=[C:11]2[C:16]=1[O:15][CH2:14][C@H:13]([N:17]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20])[CH2:12]2
Reactant: CCCN(C(CC)CC)[C@H]1COc2c(F)ccc(OC)c2C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CCCN(C(CC)CC)[C@H]1COc2c(F)ccc(O)c2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Demethylation was done by addition of BBr3 (2.6 ml, 27.5 mmol) in 10 ml dry CH2Cl2 during 20 min., to a stirred, cooled solution (-70° C.) of (R)-8-fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chroman hydrochloride (4.44 g, 12.8 mmol) in 100 ml dry CH2Cl2 under N2 atmosphere and dry conditions. The solution was stirred for 1 hour at -70° C., 1 hour at 0° C. and 1 hour at room temp. and was thereafter poured into 80 ml saturated NaHCO3 aq. under vigirous stirring. After 0.5 hour the layers where separated and the aqueous phase was extracted with 2×150 ml CH2Cl2. The combined organic layers where dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on silica with a gradient of petroleumether-petroleumether: EtOAc, 4:1 to give 3.72 g of (R)- 8-fluoro-5-hydroxy-3-(N-3-pentyl-N-n-propylamino)chroman (NAG 134) as an yellow-brown oil. [α]D22 -85° (c 1.02 in MeOH).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=O)[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([Cl:27])[CH:3]=1.[CH3:28][O:29][NH3+:30].[Cl-].C(O)C.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[N:30][O:29][CH3:28])[C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([Cl:27])[CH:3]=1
Reactant: CO[NH3+]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(Cl)cc(Cl)c3c2OC(C)(C)C3=O)c1=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1c2c(Cl)cc(Cl)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2OC1(C)C
Yield: 21.2 %

Procedure:
In a flask were placed 3.20 g (0.0076 mole) of 3-(4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl)-1-methyl-6-trifluoromethyluracil, 1,20 g (0.0144 mole) of 0-methylhydroxylamine hydrochloride, 4 mL of ethanol, and 4 mL of pyridine. This mixture was heated at reflux for five hours and then was evaporated under reduced pressure, leaving a residue. The residue was dissolved in ethyl acetate, and this solution was washed with water. The aqueous washings were then extracted twice with ethyl acetate, and these extracts were combined with the ethyl acetate solution of the product. The combined extracts and solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure, leaving a light reddish, viscous oil as a residue. This oil was passed through a column of silica gel, eluting with methylene chloride. Product-containing fractions were combined, and the solvent evaporated under reduced pressure, leaving 0.73 g of 3-(4,6-dichloro-2,3-dihydro-2,2-dimethyl-3-methoxyiminobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil (Compound 26) as an off-white, fluffy solid, m.p. 145°-149° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[NH:16][C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[C:31]#[CH:32]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[N:16]([CH2:32][C:31]#[CH:30])[C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: Cn1nc(-c2cc3c(cc2F)NC(=O)CO3)c(Cl)c1C(F)(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C#CCN1C(=O)COc2cc(-c3nn(C)c(C(F)(F)F)c3Cl)c(F)cc21
Temperature: 45 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
At 25° C., 2.7g (7.7 mmole) the product of step A, 1.1g (8.0 mmole) K2CO3 and 0.9 mL (8.0 mmole) 80% propargyl bromide were slurried in 25 mL DMSO. The mixture was stirred at 45° C. for 16 hours. The mixture was cooled, diluted with 100 mL cold water and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4 and stripped in vacuo. The residue was purified chromatographically using methylene chloride as the eluent to give 2.7 g (90%) of 7-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one as a white solid, mp 184° C.
Reaction SMILES: CN1CCOCC1.Cl[S:9]([C:12]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](=[O:24])[C:13]=1[N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(=[O:11])=[O:10].Cl.[CH:41]1([CH2:45][NH2:46])[CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[NH2:25][C:13]1[C:14](=[O:24])[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:17][C:12]=1[S:9](=[O:10])(=[O:11])[NH:46][CH2:45][CH:41]1[CH2:44][CH2:43][CH2:42]1
Reactant: CCOC(=O)Cn1ccc(S(=O)(=O)Cl)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1=O
Reactant: NCC1CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)Cn1ccc(S(=O)(=O)NCC2CCC2)c(N)c1=O
Temperature: 25 °C

Procedure:
NMM (1.43 mL, 13.0 mmol) was added to a stirred mixture of 4-chlorosulfonyl-3-(N,N-di-t-butoxycarbonylamino)-1-ethyloxycarbonylmethyl-2-pyridinone (as a mixture from Step H, 0.84 g) and cyclobutylmethylamine hydrochloride (348 mg, 2.86 mmol) in methylene chloride (15 mL). After 16 h the reaction was diluted with methylene chloride and washed with 10% citric acid solution. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica (40% ethyl acetate/hexanes). HCl gas was bubbled through a stirred solution of the resulting compound in ethyl acetate (10 mL) at 0° C. for 15 min. The reaction was warmed to rt and after a further 3 h it was evaporated to give the title compound as a solid;
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].Cl[CH2:8][C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=2[Cl:22])[N:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:10]=1>C(OCC)(=O)C>[C:23]([C:11]1[N:10]=[C:9]([CH2:8][O:4][CH2:1][CH:2]=[CH2:3])[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=2[Cl:22])[N:12]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: C=CCO
Reactant: CC(C)(C)c1nc(CCl)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=CCOCc1nc(C(C)(C)C)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To 20 ml of allyl alcohol, 0.4 g (0.008 mol) of 50% sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then, 2.8 g (0.008 mol) of 5-chloromethyl-3-(tert-butyl)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole was gradually added thereto under stirring at room temperature. After completion of the dropwise addition, the solution was heated and stirred under reflux for 2 hours. Then, 50 ml of ethyl acetate was added thereto, and the mixture was washed with water. The organic layer was dried, and the solvent was distilled off. The oily substance thereby obtained was purified by silica gel column chromatography to obtain 1.8 g (yield: 60.0%) of the desired compound as pale yellow prismatic crystals. Melting point: 34°-37° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:29])[CH:3]=1.FC1C=C([N+]([O-])=O)C=CC=1N1C[CH2:44][C:43](=[C:46]([C:49]2C=CC=C(F)C=2)C#N)[CH2:42][CH2:41]1.C(Cl)(C(Cl)=O)=[O:57].N(CC)CC>Br.O>[CH2:18]([N:17]([CH2:20][CH3:21])[C:15]([C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)=[C:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:44](=[O:57])[CH:43]([CH2:46][CH3:49])[CH2:42][CH3:41])=[CH:3][C:4]=2[F:29])[CH2:9][CH2:10]1)=[O:16])[CH3:19]
Reactant: CCN(CC)C(=O)C(=C1CCN(c2ccc(N)cc2F)CC1)c1cccc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CC(=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1)c1cccc(F)c1
Agent: Br
Solvent: CCNCC
Solvent: O
Product: CCC(CC)C(=O)Nc1ccc(N2CCC(=C(C(=O)N(CC)CC)c3cccc(F)c3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-[1-(4-Amino-2-fluoro-phenyl)-piperidin-4-ylidene]-N,N-diethyl-2-(3-fluoro-phenyl)-acetamide. A solution of [1-(2-fluoro-4-nitro-phenyl)-piperidin-4-ylidene]-(3-fluoro-phenyl)-acetonitrile in 48% HBr (75 mL) was stirred at 100° C. for 8 h. The mixture was cooled to rt and diluted with H2O (500 mL). The resulting yellow solid was collected by filtration and dried under vacuum. A mixture of this yellow solid and DMF (0.50 mL) in DCE (100 mL) was treated with (COCl)2 (100 mmol) dropwise and was stirred at rt for 30 min. The mixture was concentrated and dried under vacuum. The residue was diluted with DCE (100 mL) and treated with TEA (2.8 mL, 20 mmol) and Et2NH (1.1 mL, 10 mmol). The reaction mixture was stirred at rt for 4 h, then was washed with H2O (100 mL). The organic layer was separated and concentrated. The residue was dissolved in 1:1 EtOH/EtOAc (100 mL), treated with SnCl2.2H2O (10 g), and heated at 100° C. for 16 h. The mixture was cooled to rt, diluted with ice water (100 mL), basified to pH=9 with NaHCO3, and extracted with EtOAc (3×200 mL). The organic layers were combined, dried (Na2SO4), and concentrated to give the crude title compound.