Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:11])[N:9]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2=[O:8])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3-nitrophthalimide (1 g, 5.20 mmol) in dry DMF (35 ml), cooled in an ice bath, NaH (60% w/w dispersion in mineral oil, 0.250 g, 6.25 mmol) was added, followed after 15 minutes by t-butyl bromoacetate (0.845 ml, 5.73 mmol). After stirring for 1 hour at room temperature, the mixture was poured into water and the resulting precipitate was washed with water and with a little amount of Et2O; after drying, tert-butyl 2-(4-nitro-1,3-dioxoisoindolin-2-yl)acetate was obtained (1.44 g, 4.70 mmol, 90% yield, MS/ESI+ 328.9 [MNa]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].Cl[CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1)[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:6]2
Reactant: N#Cc1cccc(CCl)n1
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 5-methoxy-2-phenyl-1H-indole (200 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (dispersed in liquid paraffin, 50% or more, 45 mg) under ice-cooling. This mixture was stirred for 30 minutes at room temperature. Subsequently, 6-chloromethylpyridine-2-carbonitrile (216 mg) was added thereto, followed by stirring at 80° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (228 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.55 (2H, s), 6.55-6.65 (1H, m), 6.77 (1H, dd, J=2.4, 8.8 Hz), 6.91 (1H, dd, J=1.5, 7.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.26 (1H, d, J=8.8 Hz), 7.35-7.55 (5H, m), 7.85-7.95 (2H, m).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)[C:19](O)=O)=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:4]=2)[N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)=[CH:14][CH:13]=1
Reactant: NC(=NO)c1ccccc1
Reactant: CS(=O)(=O)Nc1cccc2c1ccn2C(C(=O)O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cccc2c1ccn2C(c1ccc(Cl)cc1)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N′-Hydroxybenzenecarboximidamide (49 mg, 0.36 mmol) was added to a stirred solution of compound 6a (90 mg, 0.24 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), 1-hydroxybenzotriazole (44 mg, 0.29 mmol) and N,N,-diisopropylethylamine (50 μL, 0.29 mmol) in DMF (2.4 mL). The reaction was allowed to stir at rt for 2 h, at which time, the reaction was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to a crude oil that was dissolved in toluene (2.0 mL). The resulting mixture was heated to 100° C. for 1 h, at which time, the reaction was concentrated in vacuo, and the resulting crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 63. m/z (ES) 479 (MH)+; IP=C rating.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.O.O.O.[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: [O-]c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Chloro-5-nitropyridine (4.48 g) was added in portions to a mixture of sodium phenoxide trihydrate (4.80 g) in DMF (140 ml) with stirring at ambient temperature under nitrogen. The mixture was then heated at 60° C. for 2 hours and then at 90° C. for 3 hours. The mixture was allowed to cool over 18 hours. The mixture was poured into ice water and extracted with dichloromethane to give a residue which was stirred in petroleum ether, b.p. 60°-80° C. at ambient temperature for 30 minutes and then filtered to give 5-nitro-2-phenoxypyridine, m.p. 84°-86° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].II>C1COCC1.C(OCC)(=O)C.[Zn]>[CH3:26][O:25][C:23](=[O:24])[CH2:22][C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][O:20]1
Reactant: O=C(CCCCl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC1(c2ccc(OCc3ccccc3)cc2)CCCO1
Yield: 88.4 %

Procedure:
1-(4-Benzyloxy-phenyl)-4-chloro-butan-1-one (0.3 g, 1.04 mmol) was combined with methyl bromoacetate (0.24 g, 1.56 mmol) and zinc metal (0.05 g, 2.08 mmol) in THF (15 mL), a catalytic amount of iodine was added, and the reaction was heated to reflux for 18 h. The reaction was taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate, and concentrated to give [2-(4-benzyloxy-phenyl)-tetrahydro-furan-2-yl]-acetic acid methyl ester (0.3 g, 92%) as an oil. MS found: (M+H)+=327.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:16])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg]Br.OS([O-])(=O)=O.[K+]>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:16])[CH3:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)CCCNC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)CCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of 11-3 (10.0 g, 40.5 mmol) and THF (200 ml) at 0° C. was added methylmagnesium bromide (27.0 ml, 91.0 mmol; 3M in ether) dropwise over 20 minutes. After 2.0 hours, 10% KHSO4 was added slowly. The mixture was extracted with EtOAc. The organic portion was washed with sat. NaHCO3, brine, and dried over MgSO4. Evaporative removal of the solvent gave 11-4 as a colorless oil.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][CH:23]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2C(=O)C3CC[C@](C)(C2=O)C3(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-methylphenyl isocyanate (0.27 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a brown solid (0.19 g, 30% yield), mp=80–82° C.; MS (−) ESI m/z=341 (M−H)−; [α]D25=−24.0° (c=1, EtOH).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([OH:39])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:39][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28]
Reactant: COc1ccc(O)cc1OC
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(OC)c(OC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 3,4-dimethoxyphenol (0.42 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.57 g, 61%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[Br:11][C:12]1[C:13]([F:20])=[CH:14][C:15]([Cl:19])=[C:16]([OH:18])[CH:17]=1.O>CN(C)C=O>[CH2:9]([O:18][C:16]1[CH:17]=[C:12]([Br:11])[C:13]([F:20])=[CH:14][C:15]=1[Cl:19])[CH:8]=[CH2:7]
Reactant: C=CCBr
Reactant: Oc1cc(Br)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(Br)c(F)cc1Cl
Reaction time: 1 h

Procedure:
96.5 g (0.7 mol) of potassium carbonate and 54.9 g (0.45 mol) of allylbromide were added to a solution of 78.7 g (0.35 mol) of 5-bromo-2-chloro-4-fluorophenol in 350 ml of dimethylformamide. The reaction mixture was subsequently stirred for 1 hour and stirred into 2.5 l of water. The mixture was then extracted with dichloromethane (three times). The combined organic phases were washed with water (three times) and saturated aqueous sodium chloride solution (once), dried over magnesium sulfate and finally concentrated. The crude product was purified by distillation. Bp.: 106° C. (0.8 mbar); Yield: 85 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9](N)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:14].[K+].[K+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(Cl)Cl>O.S(=O)(=O)(O)O>[CH:7]1[C:8]2[C:9](=[O:14])[CH:10]=[CH:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][N:6]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: Nc1ccc(O)c2ccncc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C1C=CC(=O)c2cnccc21

Procedure:
Nineteen grams of 5-hydroxy-8-amino-isoquinoline were dissolved in 450 ml of water and 10 ml of concentrated sulfuric acid. The solution was cooled in an ice bath and then 50 ml of a potassium dichromate solution were added. (The dichromate solution was made by dissolving 50 g of potassium dichromate in 500 ml of water.) Forty ml of concentrated sulfuric acid were added, followed by 190 ml of the potassium dichromate solution, then 20 ml of concentrated sulfuric acid, and finally 400 ml of methylene chloride.
Reaction SMILES: C[O:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)=O.O.[NH2:15][NH2:16].C(O)C(C)C>O>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:2])[NH:15][NH2:16])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: COC(=O)Nc1cc(F)cc(Cl)c1
Reactant: NN
Solvent: CC(C)CO
Solvent: O
Product: NNC(=O)Nc1cc(F)cc(Cl)c1
Temperature: 25 °C

Procedure:
N-methoxycarbonyl-3-chloro-5-fluoroaniline (51.8 gms, 254M) is added to a mixture of hydrazine hydrate (125 ml) and isobutyl alcohol (160 ml). The mixture is heated to 100° for 10 hours under nitrogen. The solution is cooled to room temperature, diluted with water and filtered. The solid is rinsed with water (2×) and dried under vacuum to give 4-(3-chloro-5-fluorophenyl)semicarbazide as a white solid.
Reaction SMILES: [ClH:1].[NH2:2]N.C[N:5](/[CH:7]=[C:8]1/[CH:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]/1=O)C>C(O)C.C(O)(=O)C>[ClH:1].[CH3:15][C:12]1([CH3:16])[C:13]2[C:8](=[CH:7][NH:5][N:2]=2)[CH:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:11]1
Reactant: NN
Reactant: Cc1cc(C#N)ccc1C1CCC(C)(C)C(=O)/C1=C\N(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C#N)ccc1C1CCC(C)(C)c2n[nH]cc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Hydrazine hydrochloride (0.14 g, 2 mmol) is added to 4-[(2Z)-2-(dimethylaminomethylene)-4,4-dimethyl-3-oxo-cyclohexyl]-3-methyl-benzonitrile (0.2 g, 0.67 mmol) in ethanol (30 mL), then acetic acid (two drops) is added to the mixture. After the addition is complete, the reaction mixture is stirred at 80° C. for 3 h. The mixture is cooled to room temperature and concentrated in vacuo. The residue is diluted with ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic phase is separated and the aqueous phase extracted with ethyl acetate (3×50 mL). The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (eluted with pet ether:EtOAc=2:1 to 1:1) to give the title compound. The product is added to HCl/ethyl acetate and concentrated in vacuo to give the HCl salt of the title compound (0.12 g, 67%). ES/MS 266 (M+H).
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1C(Cl)=O.CO.S(=O)(=O)(O)O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:4]([CH2:6][C:7]([O:9][CH3:2])=[O:8])=[O:5]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC(=O)c1c(F)cccc1F

Procedure:
To 3.6 g (25 mmole, 1 eq) of Meldrum's acid and 6.1 g of 4-dimethylamino-pyridine in 60 ml of methylenechloride was added with stirring, 4.4 g (25 mmole) of 2,6-difluorobenzoylchloride. The temperature was maintained at 0° throughout the addition period and for three additional hours of stirring under argon atmosphere. Most of the methylene chloride was then removed by distillation at 25° or less using a water aspirator to maintain reduced pressure. There was then added 60 ml of anhydrous methanol containing 25 mmole of conc. sulfuric acid.
Reaction SMILES: CCOCC.[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:10]=[CH:11][CH:12]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH2:27]([O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:10]=[CH:11][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCc2ccccc2)c1
Temperature: 70 °C

Procedure:
Instead of a Mitsunobu reaction, the ether was formed by alkylation as described. A suspension of phenol 58 (1 g, 3.5 mmol), benzyl bromide (0.3 mL, 3.5 mmol), cesium carbonate (1.158 g, 3.5 mmol) in NMP (3.5 mL) was heated at 70° C. for 24 h. The reaction mixture was quenched by the addition of water, extracted with DCM, washed with water, and dried over anhy. Na2SO4. Filtration and concentration under reduced pressure gave the crude product, which was purified by flash chromatography (hexane-ethyl acetate (0-30%) gradients) to give 2-(3-(3-(benzyloxy)phenyl)propyl) isoindoline-1,3-dione as a white solid. Yield (0.708 g, 55%): 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.84 (m, 2H), 7.69-7.72 (m, 2H), 7.30-7.44 (m, 5H), 7.13-7.18 (m, 1H), 6.83-6.85 (m, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.74 (dd, J=7.8, 2.0, 1H), 5.03 (s, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.0-2.08 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]([NH2:27])[CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([CH:25]([NH:27][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:26])[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Reactant: COc1cc(OC)cc(C(C)N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2C(=O)C(F)(F)F)c1
Yield: 33.7 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (1.0 g, 4.8 mmol), 1-(3,5-dimethoxyphenyl)ethanamine (0.95 g, 5.2 mmol) and N,N-diisopropylethylamine (1.2 g, 9.6 mmol) were stirred at 60° C. in dry acetonitrile (50 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (600 mg, 34% yield). 1H NMR (400 MHz, CDCl3): δ 9.27 (s, 1H), 7.79 (t, 1H), 6.44 (s, 2H), 6.35 (m, 2H), 6.23 (d, 1H), 4.48 (m, 1H), 3.77 (s, 6H), 1.61 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1I.[C:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)#[N:11].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[C:15]1[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Clc1nccc(I)c1Br
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: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(-c2ccnc(Cl)c2Br)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.7 %

Procedure:
A suspension of impure 3-bromo-2-chloro-4-iodopyridine (2.23 g), 4-cyanophenylboronic acid (1.62 g, 11.0 mmol), 2 M aqueous Na2CO3 solution (6 mL, 12 mmol), and toluene (40 mL) was purged with argon, then (Ph3P)4Pd (1.1 g, 0.95 mmol) was added in one portion. The resulting yellow mixture was vigorously stirred under argon at 100° C. for 4 h. Analysis by HPLC/MS indicated the reaction was not complete, and additional 4-cyanophenylboronic acid (0.82 g, 5.57 mmol), 2 M aqueous Na2CO3 solution (3.5 mL) and (Ph3P)4Pd (850 mg) were added. The reaction mixture was stirred at 100° C. for 12 h more. Additional (Ph3P)4Pd (1.0 g) was added, and the reaction mixture was stirred for another 20 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (40 mL×3). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (80 g) eluted with a gradient of EtOAc (0-60%) in hexanes to obtain 590 mg (29%) of the title compound as an off-white solid. HPLC/MS: retention time=3.11 min, [M+H]+=292.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1.C(O)C.[BH4-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([OH:17])[C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)CC(O)c1cc(F)ccc1S2

Procedure:
103 G. of 8-fluoro-2-methyl-dibenzo[b,f]thiepin-10(11H)-one are suspended in 550 ml. of ethanol and treated with 24.3 g. of sodium borohydride. The mixture is heated under reflux for about 10 minutes. After the addition of water, the mixture is extracted with chloroform. The organic phase is washed with water, dried over sodium sulfate, evaporated, and there is obtained 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH2:18][Cl:19])=[CH:9][C:10]=2[O:12][CH:13]([CH3:15])[CH3:14])[N:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[C:23]2[O:28][CH2:29][O:30][C:22]=12>>[Cl:19][CH2:18][CH2:17][O:16][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][N:24]=[C:23]4[O:28][CH2:29][O:30][C:22]=34)=[N:3][CH:4]=[N:5]2)=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=1
Reactant: CC(C)Oc1cc(OCCCl)cc2ncnc(Cl)c12
Reactant: Nc1c(Cl)cnc2c1OCO2
Product: CC(C)Oc1cc(OCCCl)cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c12
Yield: 86 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(2-chloroethoxy)-5-isopropoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 86% yield; NMR Spectrum: (CDCl3) 1.55 (d, 6H), 3.9 (t, 2H), 4.4 (t, 2H), 4.9 (m, 1H), 6.2 (s, 2H), 6.6 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.65 (s, 1H); Mass Spectrum: M+H+ 437 and 439.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[N+](=[CH2:11])=[N-]>>[C:1]([O:8][CH3:11])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCC(=O)O
Reactant: C=[N+]=[N-]
Product: C#CCCCC(=O)OC

Procedure:
The starting material methyl 5-hexynoate was prepared by the reaction of 5-hexynoic acid with diazomethane according to Method E above.