Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][C:25]([CH3:27])=[C:24]([CH3:28])[N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][C:25]([CH3:27])=[C:24]([CH3:28])[N:19]3[C:20](=[O:23])[C:21]=2[C:35]2[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2nc3sc(C)c(C)n3c(=O)c2I)c1OCC1CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cccc(/C=C/c2nc3sc(C)c(C)n3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 75.2 %

Procedure:
The title compound was prepared from Intermediate 18 (100 mg, 0.196 mmol) and 4-trifluoromethoxyphenylboronic acid (56 mg, 0.275 mmol) using Pd[(C6H5)3P]4 (90 mg, 0.009 mmol) and sodium carbonate (125 mg, 1.187 mmol) in toluene (10 ml) and ethanol (5 ml) and water (4 ml) according to the procedure outlined in Example 1 to afford crude residue which was purified by column chromatography using 10% ethyl acetate in petroleum ether to afford 80 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.25-0.28 (m, 2H), 0.46-0.52 (m, 2H), 0.90-1.01 (m, 1H), 2.30 (s, 3H), 2.59 (s, 3H), 3.67 (d, J=7.5 Hz, 2H), 3.76 (s, 3H), 6.82 (d, J=15.6 Hz, 2H), 6.88-6.91 (m, 1H), 6.98-7.00 (m, 4H), 7.43 (s, 4H), 8.08 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 543.19 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([C:14]#[N:15])[N:10](CC=C)[C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]>C1COCC1.CS(C)=O.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([C:14]#[N:15])[NH:10][C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C#N)nc2c1c(=O)n(C)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(C)c(=O)c2[nH]c(C#N)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
A solution of 3-butyl-1-methyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile (230 mg, 0.80 mmol) in anhydrous THF (5 ml) and anhydrous DMSO (0.5 ml) was treated with Pd(PPh3)4 (185 mg, 0.16 mmol). The mixture was degassed under gentle vacuum, morpholine (698 uL) added, and left to stir at rt under nitrogen for 2 hours. The yellow solution was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down and amino-propyl SPE (5 g), eluting with MeOH followed by 5% AcOH then 10%, 20% and 30% AcOH/MeOH mixtures. The product fractions were combined and concentrated to afford a pale yellow solid (116 mg). This was washed with MeOH and the title compound a white solid was collected by filtration and dried under vacuum (55 mg, 28%). NMR; δH (400 MHz, d6-DMSO) 0.90 (t, 3H, J=7.5 Hz), 1.25-1.35 (m, 2H), 1.59-1.68 (m, 2H), 3.24 (s, 3H), 3.96 (t, 2H, J=7 Hz), NH not observed to δH 15; m/z 248.2 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:20]=1[CH:21]=[N+:22]([CH3:24])[CH3:23].ClC1C=CC=C(F)C=1C=O.CNC>>[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:20]=1[CH:21]([N:22]([CH3:24])[CH3:23])[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Clc1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: C[N+](C)=Cc1c(F)cccc1Cl
Agent: CNC
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Product: CN(C)C(c1c(F)cccc1Cl)c1c(-c2ccc(Cl)cc2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-chlorophenyl)-indole and (2-chloro-6-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-6-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1C=O.[F:16][C:17]([F:44])([CH2:40][CH2:41][CH2:42]I)[C:18]([F:39])([F:38])[C:19]([F:37])([F:36])[C:20]([F:35])([F:34])[C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25].O>CN(C=O)C.CCOCC>[F:16][C:17]([F:44])([CH2:40][CH2:41][CH2:42][O:7][C:8]1[CH:9]=[CH:12][C:13]([CH:1]=[O:4])=[CH:14][CH:15]=1)[C:18]([F:38])([F:39])[C:19]([F:36])([F:37])[C:20]([F:34])([F:35])[C:21]([F:32])([F:33])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Reactant: O=Cc1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 65 °C
Yield: 91 %

Procedure:
A 500 mL 2-neck flask equipped with thermometer and gas inlet charged with potassium carbonate (27.6 g), hydroxy benzaldehyde (13.4 g), and 3-(perfluorooctyl)propyl iodide (58.8 g) in DMF (200 mL) was heated to 65° C. (internal temperature). The mixture was stirred at 65° C. until the reaction was complete. The reaction mixture was cooled to room temperature. Water (300 mL) and ether (300 mL) were added and the mixture stirred vigorously for 5 min. The layers were separated and the organic layer retained. The aqueous layer was extracted with ether (3×200 mL). The combined organic layers were washed with water (2×100 mL), Na2S2O3 (1×100 mL), 2.5 N NaOH (3×100 mL), and aqueous NaCl (1×100 mL). The organic layer was dried over MgSO4, filtered and concentrated. The product was further dried under high vacuum for 5 h to give desired product (53 g, 91% yield). The structure of the product was characterized 1H NMR.
Reaction SMILES: C[Si](C)(C)OCCN(CC)[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][CH:8]=1.[F-].[CH2:24]([N+:28](CCCC)(CCCC)[CH2:29][CH2:30]CC)[CH2:25]CC.C([O:43]CC)C>CO.C1COCC1.C1COCC1>[OH:43][CH2:25][CH2:24][N:28]([C:14]#[C:13][C:10]1[CH:9]=[CH:8][CH:7]=[CH:12][CH:11]=1)[CH2:29][CH3:30]
Reactant: CCOCC
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCN(CCO[Si](C)(C)C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(C#Cc1ccccc1)CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 5.0 g, that is 15 mmole of 4-[(2-trimethylsiloxyethyl)ethylamino]trimethylsilylethynyl-benzene, prepared in the previous step, dissolved in 60 mL of methanol-THF (1:1) mixture, 33 ml, that is 33 mmole, of 1M tetrabutylammonium fluoride in THF, from Aldrich Chemical Co. was added dropwise. The solution was stirred at room temperature for 1 hour. Ethyl ether was added and the mixture was extracted with water. The organic layer was separated, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was flash column chromatographed on silica gel with 35% ethyl acetate-hexane to produce 2.5 g of a viscous yellow oil at an 88% yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1>CN(C=O)C>[NH:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cn[nH]c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cn[nH]c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 25.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.006 g of product in 24% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH:18]=[CH:17][CH:16]=[C:14]([OH:15])[C:12]=1[OH:13])[OH:11].C(Cl)Cl>C(N(CC)CC)C.O1CCCC1>[C:1]([O:11][C:10]1[CH:18]=[CH:17][CH:16]=[C:14]([O:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]=1[O:13][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(O)c1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1cccc(OC(=O)c2ccccc2)c1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
A 500 ml three-necked round-bottom flask equipped with a magnetic stirrer was charged with 20.0 g (0.142 mol) of benzoyl chloride, 6.2 g (0.05 mol) of pyrogallol, 400 ml of methylene chloride, and 50 ml of tetrahydrofuran (THF). Triethylamine (TEA; 15.3 g, 0.15 mol) was added drop-wise via an addition funnel over a period of 10 min. After the addition of TEA, the solution was stirred for an additional 15 min and subsequently transferred to a 1000 ml separatory funnel. The solution was washed with 150 ml of a 1.0 M solution of HCl (1×), 100 ml of 0.1 M solution of NaOH (2×), 100 ml of 1.0 M solution of HCl (1×), and 100 ml of deionized water (3×). The methylene chloride layer was extracted, dried over MgSO4 for 1 hour, and filtered. The methylene chloride was removed in vacuo, and a viscous oil was recovered. The viscous oil was placed into a minimal amount of methylene chloride and crystallized from hexanes after 2-3 weeks time (slow evaporation of solvent occurred during crystallization) to afford a white, crystalline solid. The solid was filtered and dried in vacuo (30 mm Hg) overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.4 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (61 mg, 51%).
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:13]3=[N:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)S2)=CC=1)C1C=CC=CC=1>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CCC(=O)C4CCCCC4)cnc32)cc1
Agent: O=C([O-])O
Agent: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ccc(C4CCCCC4)n23)cc1
Reaction time: 6 h
Yield: 42.4 %

Procedure:
To a solution of 1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-one (0.050 g, 0.12 mmol) in THF (2 mL) was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.071 g, 0.13 mmol, TCI). After about 6 h at ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and NaHCO3 (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of 40-90% EtOAc in heptanes to provide 8-cyclohexyl-3-tosyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine as a tan solid (0.020 g, 42%). LC/MS (Table 2, Method a) Rt=3.39 min; MS m/z: 394 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5](Cl)[CH:4]=1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=1>CS(C)=O.O>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)=[CH:5][C:4]=1[Cl:1]
Reactant: Cl
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a mixture of 4-amino-2-chlorophenol hydrochloride (446 mg, 2.4 mmol) in DMSO (4 mL) was added NaH (280 mg, 7.0 mmol, 60% dispersed in mineral oil). The reaction was stirred at rt for 30 minutes, followed by the addition of 4-chloropicolinamide (345 mg, 2.2 mmol). The reaction was microwaved at 160° C. for 2 hours, then cooled to rt, and diluted with water (20 mL). The resulted mixture was extracted with ethyl acetate (20 mL×3) and the combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=1/1) to give the title compound as an orange solid (170 mg, 29%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:15])[CH3:14]>C1COCC1>[CH2:13]([NH:15][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1ccc(C#N)cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzonitrile (5.0 g, 30 mmol) in THF (15 mL, anhyd) was added a solution of ethylamine (2.0 M, 23 mL, 46 mmol) in THF. After stirring 16 h, precipitated solids were collected by filtration, triturated with a mixture of THF-hexanes (1:1, 50 mL), filtered again and dried under vacuum to give 4-ethylamino-3-nitrobenzonitrile (4.7 g, 82%) as a yellow solid. 1H-NMR (CDCl3): δ 8.51 (1H, d), 8.34 (1H, br s), 7.62 (1H, dd), 6.93 (1H, d), 3.44 (2H, m), 1.42 (3H, t).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].C(NC(C)C)(C)C.[Li].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:29])(=O)=O)=CC=1>O1CCCC1>[F:29][CH:2]([CH3:3])[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CCC(=O)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(F)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 85 %

Procedure:
1 millimole propiophenone in tetrahydrofuran was dropped into a stirred solution of lithium diisopropylamine in 2 milliliters tetrahydrofuran at -78° C. After 1 hour of stirring, a solution of 1.2 millimoles N-fluorobenzenesulfonimide prepared according to Example 1 above in 3 milliliters tetrahydrofuran was dropped into the reaction mixture and stirring was continued at -78° C. The temperature of the reaction mixture was allowed to rise to 25° C., stirring was continued for 1 hour, and the reaction was quenched by pouring the mixture into saturated ammonium chloride solution. The mixture was neutralized with 1N hydrogen chloride solution and extracted with dichloromethane and the organic phase was washed with water. 2-fluoropropiophenone was obtained in 85% yield.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH:19]1([CH2:25][NH:26][C:13]2[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:3]([NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[C:2]([F:1])[CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1F
Reactant: NCC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1NCC1CCCCC1
Yield: 34.9 %

Procedure:
A solution of 2,4-difluoro-5-nitro-N-phenylaniline (1.00 g, 4.00 mmol), cyclohexanemethylamine (0.57 mL, 4.40 mmol) and N,N′-diisopropylethylamine (0.77, 4.40 mmol) in DMF (40 mL) was stirred at room temperature under an inert atmosphere for 18.5 h. The reaction mixture was transferred to a separatory funnel containing 2 N HCl. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine and dried over MgSO4. The solution was filtered through diatomaceous earth and the solvent was evaporated. The resulting dark red residue was flash chromatographed (10% EtOAc/hexanes) to give N4-cyclohexylmethyl-2-fluoro-5-nitro-N1-phenyl-benzene-1,4-diamine as a dark red solid (0.48 g, 34.9% yield). M+, 344
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>CC(C)=O>[N:1]1[N:2]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:3]=[N:4][CH:5]=1
Reactant: c1nnn[nH]1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cn2ncnn2)cc1
Reaction time: 19 h

Procedure:
6.3 g of tetrazole, 8.28 g of potassium carbonate and 0.675 g of potassium iodide are added in succession to a solution of 12 g of 4-bromomethylbenzonitrile in 400 ml of acetone and the mixture is then stirred for 19 hours at 40°-45°. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between CH2Cl2 and water. The organic phase is washed with brine, dried over sodium sulfate and then concentrated by evaporation. Subsequent chromatography (silica gel) yields first, with toluene/ethyl acetate (2:1), 4-(2-tetrazolyl)methyl-benzonitrile [TLC (hexane/ethyl acetate, 1:2) Rf =0.76); 1H-NMR (CDCl3): δ=5.8 (2H, s), 7.4 and 7.7 (4H, m), 8.5 (1H, s) ppm], and then, with ethyl acetate, 4-(1-tetrazolyl)methyl-benzonitrile [TLC (hexane/ethyl acetate, 1:2), Rf =0.36); 1H-NMR (CDCl3): δ=5.63 (2H, s), 7.4 and 7.7 (4H, m), 8.6 (1H, s) ppm].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6](=[O:22])[CH2:7][C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6](=[O:22])[CH2:7][C:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([O:21][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][O:35]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CC(O)(c1ccccc1)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CC(=O)CC(OC1CCCCO1)(c1ccccc1)c1ccccc1

Procedure:
The title compound (J. W. Wolfe, et al, J. Org. Chem. 29, 3249 (1964) ) was prepared from δ-hydroxy-β-oxo-δ-phenylbenzenepentanoic acid ethyl ester (2.0 g, 0.006 mol), p-toluenesulfonic acid (0.014 g, 0.60 mmol), and 3,4-dihydro-2H-pyran (0.77 g, 0.009 mol) using the procedure described in Example 6, Step A.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]=2[CH:20]=1)#[N:2].[C:21](=[O:38])([O:36][CH3:37])[O:22][C:23]1[CH:28]=[C:27]([NH2:29])[C:26]([Br:30])=[CH:25][C:24]=1[CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1.C(OCC)(=O)C>[Br:30][C:26]1[CH:25]=[C:24]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:23]([O:22][C:21]([O:36][CH3:37])=[O:38])=[CH:28][C:27]=1[NH:29][C:12]([CH:10]1[O:11][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=2[N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:14]
Reactant: COC(=O)Oc1cc(N)c(Br)cc1C1CCCC1
Reactant: CCOC(=O)N1CC(C(=O)O)Oc2ccc(C#N)cc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2Br)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 6-cyano-4-ethoxycarbonyl-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid (552 mg, 2.0 mmol) and (5-amino-4-bromo-2-cyclopentyl-phenyl) methyl carbonate (691 mg, 2.20 mmol) in 2-methyltetrahydrofuran (7 mL) at room temperature was added pyridine (404 μL, 5.0 mmol) followed by the addition of T3P (3181 mg, 2.98 mL of 50% w/w solution, 5.0 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate then quenched with a saturated aqueous solution of NaHCO3 (4 mL) and stirred for 15 min. The layers were separated, and the aqueous layer was extracted once more with ethyl acetate. The combined organic extracts were filtered to give a white solid. The remaining filtrate was dried over Na2SO4, filtered and concentrated in vacuo to obtain a creamy solid. The combined solids were triturated with hexane (5×5 mL) and washed with ethyl acetate (1 mL) and dichloromethane (1 mL) to provide ethyl 2-(2-bromo-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate as a white solid (403 mg, 99% yield). LC/MS m/z 573.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:25]=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CCO>[N:27]1([CH2:25][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=[CH:14][NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:8][CH:9]=3)[C:16]2=[O:24])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C=O
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(N2CCOCC2)cc1
Reactant: C1COCCN1
Solvent: CCO
Product: O=C1C(=CNc2ccc(N3CCOCC3)cc2)c2ccccc2N1CN1CCOCC1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of 3-[(4-morpholinophenylamino)-methylene]-1,3-dihydro-indol-2-one (0.71 g, 2.21 mmol) and paraformaldehyde (0.10 g, 3.33 mmol.) in 8 mL of EtOH was treated with morpholine (213 μL, 2.44 mmol). The reaction mixture was then heated at a reflux temperature overnight during which time a yellow precipitate formed. The reaction mixture was allowed to cool to room temperature and the solid was collected by filtration and washed with EtOH and dried under vacuum to give the title compound (0.769 g, 83%) as a yellow solid.