Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([NH:9][C:10]1[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:8])[CH3:7].COCC(NC1C=CC=CC=1)=O>C1C=CC=CC=1>[C:6]([NH:9][C:10]1[CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][C:11]=1[CH3:16])(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccccc1C
Reactant: O=S(=O)(O)Cl
Agent: COCC(=O)Nc1ccccc1
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(S(=O)(=O)Cl)ccc1C
Temperature: 10 °C
Reaction time: 24 h

Procedure:
Chlorosulfonic acid (500 g.) was taken in a three neck round bottom flask equipped with a guard tube and cooled it to 10° C. N-acetyl 2-toluidine (100 g.) was added in small portions maintaining temperature below 10° C. After complete addition of 2-methoxy acetanilide cooling is removed and reaction was brought to 25° C. Reaction mixture was stirred at 25° C. for further 24 hours. After the completion of reaction (TLC), the reaction mixture was poured on ice-water, and the resulting slurry was filtered on buchner funnel. Solid cake on funnel was washed with 500 mL of water and the resulting solid was dried on phosphorus pentoxide in a desiccator to obtain 113.5 grams off white solid. It was found to contain a mixture of two isomers as confirmed from NMR and HPLC; however the desired isomer was obtained by partial crystallization using benzene and used for further experimentation, after the thorough carectorisation.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[O:12][C:13]3[C:22]4[C:21](=[CH:23][CH2:24][NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH2:20][CH2:19][C:18]=4[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[O:12][C:13]3[C:22]4[CH:21]([CH2:23][CH2:24][NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH2:20][CH2:19][C:18]=4[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)NCC=C1CCc2ccc3nc(CCCCc4ccccc4)oc3c21
Agent: [Pd]
Solvent: CO
Product: CCC(=O)NCCC1CCc2ccc3nc(CCCCc4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.9 %

Procedure:
N-{2-[2-(4-Phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene]ethyl}propionamide (35.7 mg, 0.0919 mmol) was dissolved in methanol (0.92 mL), a 10% palladium-carbon powder (7 mg) was added, and the mixture was stirred at room temperature for 10 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=33/67) to give the title compound (31.2 mg, yield 87%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:12][C:13](=[NH:16])[NH:14][CH3:15])=[O:11].[CH3:17]C#N.COC(OC)N(C)C.[NH4+].[OH-]>C(Cl)(Cl)Cl.O.CO>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:15]=[N:14][C:13]([NH:16][CH3:17])=[N:12][C:10]1=[O:11]
Reactant: CC#N
Reactant: CNC(=N)NC(=O)Nc1ccccc1C
Agent: COC(OC)N(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNc1ncn(-c2ccccc2C)c(=O)n1
Temperature: 25 °C

Procedure:
To a magnetically stirred suspension of 9.72 g. (40 mmol) of 1-(2'-methylphenyl)-3-methylamidinourea hydrochloride in 30 ml. of CH3CN is added 9.52 g. (80 ml.) of N,N-dimethylformamide dimethylacetal. After the mixture is further diluted with 25 ml. CH3CN and stirred for 5 minutes all of the solid is dissolved. TLC (3% NH4OH) shows a new spot; about equal in size to a spot in starting material; (EtoAc/MeOH; 9:1) shows mostly a new spot. The solution is refluxed for 2 hours. The reaction mixture is allowed to cool to ambient temperature. The reaction mixture is then poured into CHCl3 /H2O and separated. The aqueous layer is extracted with CHCl3 (for a total of 3×50 ml.). The organic layers are combined and washed with H2O (2×50 ml.). The aqueous layers are combined and back extracted with CHCl3 (1×50 ml.). All organic layers are combined, dried, filtered and concentrated in vacuo to yield the product which is recrystallized from absolute EtOH, filtered and washed with cold absolute EtOH and air-dried. The product is 1-(2'-methylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one, melting point 191.5°-192.5° C.
Reaction SMILES: C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:34]([CH:36]1[C:41]2[CH:42]=[CH:43][S:44][C:40]=2[CH2:39][CH2:38][NH:37]1)[CH3:35].[CH3:45][O:46][C:47]1[CH:52]=[C:51]([CH3:53])[C:50]([S:54]([N:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH:58]2[CH2:63][CH2:64][CH2:65][C:66](O)=[O:67])(=[O:56])=[O:55])=[C:49]([CH3:69])[CH:48]=1>C(=O)(O)[O-].[Na+]>[CH2:34]([CH:36]1[C:41]2[CH:42]=[CH:43][S:44][C:40]=2[CH2:39][CH2:38][N:37]1[C:66](=[O:67])[CH2:65][CH2:64][CH2:63][CH:58]1[CH2:59][CH2:60][CH2:61][CH2:62][N:57]1[S:54]([C:50]1[C:51]([CH3:53])=[CH:52][C:47]([O:46][CH3:45])=[CH:48][C:49]=1[CH3:69])(=[O:56])=[O:55])[CH3:35]
Reactant: CCC1NCCc2sccc21
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCC(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC1c2ccsc2CCN1C(=O)CCCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
N-Ethyldiisopropylamine (0.21 ml, 1.218 mmol), 1-hydroxybenzotriazole hydrate (60 mg, 0.447 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg, 0.609 mmol) and 4-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (123 mg, 0.609 mmol) were added to a solution of 4-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)butanoic acid (AC7) (0.15 g, 0.406 mmol) in MC (10 ml) and the mixture was stirred at room temperature for 15 hours. Saturated sodium bicarbonate solution (20 ml) was added to the mixture and the aqueous phase was then extracted with MC (2×30 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/ethyl acetate 2/1. The yield was 200 mg (94%, white, resin).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][OH:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[O:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)N1CCc2cc(CO)ccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
molecular sieves (0.63 g) were added to a solution of 12 (0.24 g, 0.83 mmol) in CH2Cl2 (10 mL), PDC (0.63 g, 1.66 mmol). The mixture was stirred at room temperature overnight before it was filtered through celite. The organic layer was concentrated under reduced pressure then purified by silica gel chromatography (EtOAc:n-hexane=1:2) to afford 13 (0.19 g). 1H NMR (500 MHz, CDCl3): δ 3.05 (t, J=8.6 Hz, 2H), 4.01 (t, J=8.7 Hz, 2H), 7.46-7.49 (m, 2H), 7.58-7.62 (m, 2H), 7.71 (d, J=8.3 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.84 (d, J=7.8 Hz, 2H), 9.85 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][NH2:23]>CO>[CH3:22][NH:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Reactant: CN
Solvent: CO
Product: CNCc1ccc(-c2nc3cccc(C(=O)OC)c3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To the solution of methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (500 mg, 1.4 mmol in methanol (10 mL), was added methylamine solution (4 mL), and the resulting mixture was stirred at room temperature for 1 hr, then heated to 30° C. for 30 min. Then the solvent was evaporated and purified by pre-HPLC to obtain methyl 2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (as TFA salt, 90 mg, yield 42%). LC-MS (ESI) m/z 297 [M+1]+.
Reaction SMILES: Br[C:2]1[O:11][CH2:10][C:9]2[CH:8]([N:12]([CH3:14])[CH3:13])[CH2:7][C:6]3=[CH:15][N:16]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:17]=[C:4]([C:5]=23)[CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1>O1CCCC1.[Cl-].[NH4+]>[F:43][C:2]1[O:11][CH2:10][C:9]2[CH:8]([N:12]([CH3:14])[CH3:13])[CH2:7][C:6]3=[CH:15][N:16]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:17]=[C:4]([C:5]=23)[CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(Br)OCC3=C2C(=C1)CC3N(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(F)OCC3=C2C(=C1)CC3N(C)C
Reaction time: 1 h

Procedure:
A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml was cooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml was added dropwise to the mixture, which was stirred for 1 h. Then, N-fluorobenzenesulfonimide 694 mg was added and the mixture was stirred for 3.5 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to give a yellow oil. This was chromatographed on thin aluminum oxide plates (Merck precoated TLC plate alumina 60F254 in ethyl acetate:hexane (1:5)) to give the titled compound as a pale yellow oil, 100 mg.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>O1CCCC1.[Pd]>[NH2:13][C:12]1[C:3]([NH:2][CH3:1])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CNc1c(N)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of methyl 2-(methylamino)-3-nitrobenzoate (2.10 g, 10.0 mmol) in tetrahydrofuran (40 mL) was added palladium on carbon (210 mg), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen for 2 hr at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (1.80 g, 10.0 mmol, 100%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[CH3:19][NH:20][CH3:21].[OH-].[Na+].Cl>C1COCC1.C(OCC)(=O)C.CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([S:14](=[O:16])(=[O:15])[N:20]([CH3:21])[CH3:19])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)O)cc(S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve commercially available 5-chlorosulfonyl-isophthalic acid dimethyl ester (422 mg, 1.43 mmol) in THF (10 mL) and add dimethylamine (2.0 M in THF, 2.5 mL, 5 mmol). Stir at room temperature 3 h, dilute with ethyl acetate, wash with 10% aqueous potassium carbonate, 0.1 N citric acid and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate. Dissolve the residue in acetone (10 mL) and methanol (5 mL). Add a solution of NaOH (60 mg, 1.43 mmol) in methanol (0.7 mL). Stir at room temperature 16 h and acidify with 1 N HCl to about pH=1. Partition between ethyl acetate and water, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:23])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[CH2:20][O:21][CH3:22])[N:12]=2)=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:23])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][C@@H:16]4[CH2:20][O:21][CH3:22])[N:12]=3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC[C@H]1CCCN1CCc1nc(-c2ccc(Br)cc2)oc1C
Product: COC[C@H]1CCCN1CCc1nc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)oc1C

Procedure:
Starting with 2-(4-Bromo-phenyl)-4-[2-(R)-(+)-(2-methoxymethyl-pyrrolidin-1-yl)-ethyl]-5-methyl-oxazole (See Example 31) and 4-methylsulfonylphenylboronic acid, follow a procedure significantly analogous to that found in Example 22 to give the titled compound. MS (m/e): 455.2 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N=C=N.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(OCc2ccccc2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 4-benzyloxybenzoic acid (116 mg, 0.51 mmol) and PS-carbodiimide (500 mg, 0.66 mmol, 1.32 mmol/g) in 5% DMF in CH2Cl2 (5 mL) is added (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (80 mg, 0.51 mmol). The mixture is stirred at room temperature for 3 days. The reaction mixture is filtered, and the resin is washed with CH2Cl2. The filtrate is concentrated and applied to silica-gel column chromatography (in CH2Cl2 followed by 5% 2M NH3 in MeOH/CH2Cl2) to give the product. 62.7 mg (34%): Observed mass: 365 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To stirred solution of the (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (2.5 g, 10 mmol), benzyl bromide ( 1.8 gm, 10 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and the mixture was refluxed for 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethyl acetate: hexane. The product, 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester was isolated as a low melting solid. Yield: 3.0 gm 86%; Low melting solid; MS: 349 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([F:25])([F:24])[F:13]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Yield: 92.3 %

Procedure:
A mixture of methyl 4-bromo-3-methylbenzoate (20 g, 87 mmol), 2-(trifluoromethyl)benzeneboronic acid (24.9 g, 131 mmol), potassium carbonate (24 g, 175 mmol) and bis(tricyclohexylphosphine)palladium (II) dichloride (65 mg, 0.1 mmol) was prepared in dioxane (200 mL) and water (50 mL) under N2 atmosphere. The mixture was heated at 100° C. for 3 hours. A 5N aqueous solution of NaOH (100 mL) was added and the reaction mixture was stirred at 100° C. for one additional hour. The reaction mixture was cooled at RT and the aqueous layer was removed. The organic layer was filtered through a celite pad, concentrated until 75 mL under reduced pressure, diluted with water (125 mL) and washed with MTBE (2×200 mL). The aqueous layer was acidified to pH 1 with a 5N aqueous solution of HCl (25 mL) and extracted with MTBE (2×100 mL). The organic layers were combined, dried (Na2SO4) and filtered through a celite pad. The solution was concentrated until 100 mL, then heptane was added (200 mL). The mixture was concentrated until 100 mL. The precipitate was filtered off and rinsed twice with heptane, then dried under reduced pressure to give the title compound as a white powder (22.5 g, 92%). HPLC (Method A), Rt 4.4 min (purity: 100%). LC/MS (Method B): 279.0 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.0 (s, 1H), 7.87 (m, 2H), 7.80 (dd, J=7.9, 1.6 Hz, 1H), 7.75 (m, 1H), 7.64 (m, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 2.02 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][C:9]([O:11]C)=[O:10])#[N:2]>Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])#[N:2]
Reactant: COC(=O)CCOc1cccc(C#N)c1
Agent: Cl
Product: N#Cc1cccc(OCCC(=O)O)c1

Procedure:
500 mg (2.4 mmol) of methyl 3-(3-cyanophenoxy)propionate was heated in 40 ml of 6 N hydrochloric acid at 70° C. for 30 minutes. After the extraction with ethyl acetate, the extract was washed with saturated aqueous NaCl solution and then dried on anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(OCCCCl)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 91.1 %

Procedure:
The mixture of ethyl 4-hydroxybenzoate(50.0 g), 1-bromo-3-chloropropane (56.8 g), and potassium carbonate (125 g) in acetonitrile (500 ml) was stirred 40° C. for 48 hr. The reaction mixture was concentrated and the residue was diluted with water, then extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=20:1) to yield the entitled compound (66.5 g) as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([CH2:19]O)=[CH:16][C:15]=2[CH:21]=1.CCN(C(C)C)C(C)C.S(Cl)([Cl:33])=O>C(Cl)Cl>[Cl:33][CH2:19][C:17]1[O:18][C:14]2[CH:13]=[CH:12][C:11]([O:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:21][C:15]=2[CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2cc(Oc3nc4ccccc4s3)ccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: ClCc1cc2cc(Oc3nc4ccccc4s3)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of [5-(benzothiazol-2-yloxy)-benzofuran-2-yl]-methanol (55 mg, 0.19 mmol) and DIEA (0.042 mL, 34 mg, 0.24 mmol) in DCM (0.8 mL) was added thionyl chloride (0.017 mL, 26 mg, 0.22 mmol) and the resulting mixture was stirred (rt, 2 h). The reaction mixture was concentrated under a stream of nitrogen to afford the title compound (50 mg, 100%). MS (ESI): mass calcd for C16H10NO2SCl, 315.0; m/z found 316.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:12][C:13]1[CH:29]=[CH:28][C:27]2[C:18]3[NH:19][C:20](=[O:26])[C:21]4[N:22]([CH:23]=[CH:24][N:25]=4)[C:17]=3[CH2:16][C:15]=2[CH:14]=1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:12][C:13]2[CH:29]=[CH:28][C:27]3[C:18]4[NH:19][C:20](=[O:26])[C:21]5[N:22]([CH:23]=[CH:24][N:25]=5)[C:17]=4[CH2:16][C:15]=3[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 12 h
Yield: 54.9 %

Procedure:
A solution of 1.76 g of 4-fluorophenyl isocyanate in 20 ml of dimethylformamide is added over 30 minutes to a solution of 2 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 20 ml of dimethylformamide and 1.3 g of triethylamine and stirring is carried out for 12 hours at a temperature in the region of 20° C. The reaction mixture is filtered and the insoluble material is washed with dimethylformamide (2×10 ml) and then with water (3×15 ml) and dried in the air. The crude product is then triturated in 30 ml of dimethylformamide, filtered, washed with water and then with isopropyl ether and dried at 60° C. under vacuum (1 mm Hg, 0.13 kPa). There are obtained 1.5 g of 8-[3-(4-fluoro-phenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-4-one in the form of a beige solid melting above 260° C. (Analysis, % calculated C: 64.00, H: 3.76, F: 5.06, N: 18.66, O: 8.52, % found C: 64.0, H: 3.8, N: 19.0).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[O:29][CH3:30].C(O)(=O)C.C(Cl)Cl.CO.[NH4+].[OH-]>CN(C=O)C.[Cu]I.CCOC(C)=O>[CH3:30][O:29][C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:19]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc(C(F)(F)F)ccc1Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(F)(F)F)ccc1Nc1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
Dissolved 2-amino-5-nitrophenol (4.0 g, 26.0 mmol), cesium carbonate (23.25 g, 71.4 mmol), and copper(i) iodide (4.94 g, 26.0 mmol) in DMF (43.3 ml) in a 250 mL sealed tube and stirred at 25° C. for 30 min. Then added 1-bromo-2-methoxy-4-(trifluoromethyl)benzene (5.52 g, 21.63 mmol) and stirred for 18 h at 100° C. Added acetic acid (8.67 ml, 151 mmol) to neutralize base and product. Diluted the reaction with a solution of DCM/MeOH/NH4OH (90:10:1) and filtered through a frit of silica to remove some of the copper and base, rinsing with more of the solution. The collected eluent was concentrated, then purified using silica gel chromatography using a gradient of (0-100%) Hex:EtOAc to yield 2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-nitrophenol (1.75 g, 5.33 mmol, 24.65% yield) as a yellow solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25](OC)=[O:26])=[CH:20][CH:19]=3)[CH:12]=[CH:13][CH:14]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([CH2:25][OH:26])=[CH:20][CH:19]=3)[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3cccc(OC)c3)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(-c2nc3cc(CO)ccc3nc2-c2ccccc2)c1
Reaction time: 2 h
Yield: 62.6 %

Procedure:
LiAlH4 (10 mg, 0.26 mmol, 2.00 equiv) was added to a solution of methyl 3-(3-methoxyphenyl)-2-phenylquinoxaline-6-carboxylate (50 mg, 0.14 mmol, 1.00 equiv) in THF (30 mL) at 0° C. The resulting solution was allowed to react, with stifling, for 2 hrs at room temperature. The reaction was quenched by the addition of 10 mL of ethyl acetate. The solids were filtered out, and the filtrate was concentrated under vacuum, affording 30 mg (65%) of (3-(3-methoxyphenyl)-2-phenylquinoxalin-6-yl)methanol as a white solid.