Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH3:21][C:22]1[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]#[N:31])[CH:25]=[CH:24][N:23]=1>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]2[CH:10]=[C:28]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=3)[CH:29]=[C:30]([NH2:31])[N:12]2[N:13]=1
Reactant: Cc1cc(/C=C/C#N)ccn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: Cc1cc(-c2cc(N)n3nc(-c4ccco4)nc3c2)ccn1

Procedure:
The title compound, mp. 100-101° C. and MS (EI) m/e (%): 291 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and (E)-3-(2-methyl-pyridin-4-yl)-acrylonitrile.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO.CCOCC>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: Nc1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: CSc1nc(Cl)c(C#N)c(Nc2ccccc2)n1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-453] (0.222 grams (hereinafter “g”), 1.0 millimoles (hereinafter “mmol”)) in EtOH (2 milliliters (hereinafter “mL”)) and Et2O (1 mL) was treated with aniline (184 microliter (hereinafter “uL”), 2.0 mmol) in EtOH (1 mL). A clear solution formed initially but rapidly formed a heavy precipitate. The mixture was stirred 30 minutes (hereinafter “min”) and was filtered, and the solid was washed with 1:1 Et2O, EtOH and then Et2O, dried to afford 162 miligrams (hereinafter “mg”) (59%) of the title compound as a white solid. LC MS m/e=277 (MH+), Rt=2.32 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([CH2:20][O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(OCC2CC2)c1
Temperature: 70 °C

Procedure:
To a solution of ethyl 3-hydroxybenzoate (15.0 g) in DMF (150 mL) were added potassium carbonate (25.0 g) and (bromomethyl)cyclopropane (13.1 mL), and the mixture was stirred with heating at 70° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in a mixed solvent of THF (100 mL) and methanol (50 mL) was added 2 M aqueous sodium hydroxide solution (47 mL), and the mixture was stirred with heating at 60° C. for 40 min. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with diethyl ether/hexane to give the title compound (13.4 g).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[C:18]([C:31]([F:34])([F:33])[F:32])[N:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH3:15][C:16]1[CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:18]([C:31]([F:33])([F:32])[F:34])[N:17]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2nnc(N)nc2-c2ccccc2)cc(C(F)(F)F)n1
Yield: 90 %

Procedure:
6-bromo-5-phenyl-1,2,4-triazin-3-amine (1 molar eq.), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (1 molar eq.) and K2CO3 (1.5 molar eq.) are suspended in a mixture of 1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine). The resulting mixture is degassed, treated with dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol %) and refluxed until full consumption of bromotriazine is observed by LCMS. The cooled reaction mixture is then diluted with water, extracted with DCM and passed through a phase separator. The organic phase is concentrated under reduced pressure and purified by gradient flash chromatography, eluting with mixtures of ethyl acetate and hexanes to afford 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (90%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[N+:2]=[N-:3].[OH-].[Na+]>CO>[N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:2]=[N-:3]
Reactant: CCOC(=O)COCCN=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=NCCOCC(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.3 %

Procedure:
To a solution of ethyl 2-azidoethoxyacetate (6.56 g, 37.9 mmol) in MeOH (80 ml) was added 1 N aq. NaOH (80 ml) and the mixture was stirred at room temperature overnight (17 h). After removing the insoluble material, the methanol was evaporated in vacuo and this was saturated with sodium chloride and washed with ether (30 ml×3). The aqueous layer acidified with 3 N HCl (30 ml) was extracted with ether (40 ml×4). The ether extracts were washed with brine, dried (MgSO4) and evaporated to yield 4.25 g (29.3 mmol, 77.3%) of 2-azidoethoxyacetic acid as a colourless oil: 1Hmr (CDCl3) δ: 3.3-4.0 (4H, m, --OCH2CH2N3), 4.22 (2H, s, --COCH2O--), 9.52 ppm (1H, s, --CO2H, exchanged with D2O); ir (neat) νmax : 2600-3300 (br, --CO2H) 2100 (azide) and 1740 cm-1C=O--CO2H). This material was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]#[N:13])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>COCCOC>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:12]#[N:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CN=C(c2ccccc2)C1
Solvent: c1ccncc1
Solvent: COCCOC
Product: N#Cc1c[nH]c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
Under a nitrogen purge 2,3-dichloro-5,6-dicyano-1,4-bonzoquinone (0.23 g; 0.001 mol) and 2-phenyl-1-pyrroline-4-carbonitrile (0.17 g; 0.001 mol) is dissolved in 1,2-dimethoxyethane (13 mL) to form a clear orange solution. Pyridine (0.08 mL; 0,001 mol) is added in a single portion, causing a slight exotherm (to ca. 28° C.) and an immediate formation of a green/grey precipitate. The suspension is stirred at room temperature for 18 hours during which time much of the solvent evaporates. The brownish semi-solid residue is partitioned between ether and a half-saturated solution of sodium carbonate. The red-brown aqueous layer is extracted twice with ether and the combined ether layer is washed with fresh water, then saturated sodium chloride. After drying with MgSO4, solvent is removed under reduced pressure to obtain a white semi-solid. This material was recrystallized from ethylene dichloride (DARCO treatment) to yield lavender crystals (0.1 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]=[CH:5][C:4]2[CH:8]=[CH:9][S:10][C:3]1=2.CN(C=O)C.[H-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1>[Cu](I)I.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:1][C:2]2[C:3]3[S:10][CH:9]=[CH:8][C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: Clc1ccc(I)cc1
Reactant: O=C1CN=Cc2ccsc21
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Oc2cncc3ccsc23)cc1
Temperature: 25 °C

Procedure:
Example 145D can be processed as in Lindley (Tetrahedron, 1983, 1433). A solution of Example 145C (1.0 mmol) and DMF (2.0 mL) is treated at 0° C. with sodium hydride (1.0 mmol), slowly warmed to room temperature, treated with 1-chloro-4-iodobenzene (1.0 mmol) and copper iodide (0.1 mmol), heated at 80° C. overnight, and cooled. The solution is poured into water and extracted with diethyl ether. The extracts are combined, dried (MgSO4), filtered, and concentrated. Recrystallization from ethyl acetate/hexanes provides the title compound.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][CH2:16][C:17]#[N:18]>CN(C=O)C>[Si:6]([O:14][CH2:15][CH2:16][C:17]#[N:18])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: N#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
Imidazole (33.6 g, 495 mmol) and tert-butyldimethylsilyl chloride (27.2 g, 180 mmol) were added to a 0° C. solution of 3-hydroxypropanenitrile (10.6 g, 150 mmol) in DMF 50 mL). The mixture was allowed to warm to rt, then was stirred at rt for 12 hrs. The mixture was quenched with water (500 mL), and then extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0˜5% EtOAc/petroleum ether) to give 3-(tert-butyldimethylsilyloxy) propanenitrile (18 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.74 (t, J=6.0 Hz, 2H), 2.43 (t, J=6.0 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH:14]([CH3:18])[NH:13]1>C(#N)C>[CH3:11][CH:12]1[NH:13][CH:14]([CH3:18])[CH2:15][N:16]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:17]1
Reactant: CC1CNCC(C)N1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CC#N
Product: CC1CN(c2ccc([N+](=O)[O-])cc2)CC(C)N1
Yield: 89.7 %

Procedure:
An amount 4-nitrophenylfluoride (2.0 mL, 18.85 mmol) in 20 mL of acetonitrile is added 2,6-dimethylpiperazine (2.58 g, 22.62 mmol). The reaction mixture is reflux under N2 overnight. Mass spectroscopy suggested the completion of reaction. Solvent is subsequently evaporated under vacuum. The collected yellow solid is dissolved in chloroform and washed twice with 200 mL of saturated NaHCO3 solution, and once with 100 mL of brine. The organic portion is dried over Mg2SO4, filtered, evaporated to give yellow solid which is re-crystallized from EtOAc/Hexane to give 3.98 g (89.8% yield) of bright yellow crystals: mp 124-125° C.; MS (ESI) m/z 236.1 (M+H)+1
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([NH:27][C:28]([NH:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)=[O:29])[CH:4]=[N:3]1.[ClH:41]>CO.O1CCOCC1>[ClH:41].[ClH:41].[ClH:41].[NH2:33][CH2:32][CH2:31][NH:30][C:28]([NH:27][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH2:7])=[O:29]
Reactant: Cn1ncc(NC(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)NCCN)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl {2-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]ethyl}carbamate (10.8 g) in methanol (50 ml) was added 4M hydrogen chloride solution in dioxane (50 ml). The mixture was stirred at room temperature for 3 hours. The solvent was concentrated in vacuo, and the residue was triturated with ethyl acetate and dried in vacuo to give N-(2-aminoethyl)-N′-(5-amino-1-methyl-1H-pyrazol-4-yl)urea trihydrochloride (5.6 g) as a solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.[Na].C(OCC)(=[O:31])C.[Cl-].[Na+]>CO.O>[CH3:1][S:2]([C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:31]
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: CCCCCC(O)C=CC1C=C(S(C)=O)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 18 h
Yield: 42 %

Procedure:
To a solution of 21.9 mg of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 544 in methanol (3 ml) was added a solution of sodium metaperiodide (118.7 mg) in water (0.5 ml), and the mixture was stirred for 18 hours. To the reaction mixture were added ethyl acetate and saturated aqueous sodium chloride, and the product was extracted into the organic layer. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to give 9.6 mg (yield 42%) of 2-methylsulfinyl-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: [C:1]([O:10]C(OC(C)(C)C)=O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(O)([C:20]([F:23])([F:22])[F:21])=O>>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:20]([F:23])([F:22])[F:21])=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: CC(C)(C)OC(=O)OC(=O)c1ccccc1N
Reactant: O=C(O)C(F)(F)F
Product: Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(trifluoromethyl)aniline (25 g, 0.15 mol) was dissolved in THF (275 mL), then treated with Boc anhydride (41 g, 0.19 mol), ET3N (19 g, 0.19 mol), and 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was refluxed for 3 hours, the solvents removed in vacuo, and the organic residue dissolved in EtOAc, washed with 1 M NaOH, then 1 M HCl, then dried and concentrated. The resulting product was recrystallized from heptane yielding 39 g final product as a white solid. The solid (0.15 mol) was dissolved in THF (350 mL) and cooled to −78° C. under nitrogen, then treated dropwise with BuLi (1.6 M in hexane, 282 mL, 0.45 mol). After 1 h, the solution was warmed to 0° C. and held for 1.5 h. The mixture was poured onto excess solid CO2 and stirred overnight at RT. After partitioning against 1 M HCl, the THF layer was evaporated and the residue dissolved in EtOAc, washed with 1 M HCl, then dried and concentrated. The solid product was triturated with hexan to yield the final product as a white solid (15.8 g). LC/MS retention time 2.70 min, m/z (obs, M−H)=304.1. Finally the Boc anthranilate (11.3 g) was dissolved in CH2CL2 (26 mL) and treated with TFA (21 mL). After stirring at RT for 2 h, the solution was dried in vacuo, the resulting residue dissolved in toluene (100 mL), concentrated to dryness, and the dissolution/drying process repeated twice more, yielding the desired product as a white solid (10.8 g), LC/MS retention time 1.2 min, m/z (obs, M−H)=204.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)(C)[CH3:12].ICC>C1COCC1>[CH2:11]([C:5]1[O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH3:12]
Reactant: c1ccc2occc2c1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc2ccccc2o1

Procedure:
2-Ethylbenzo[b]furan was prepared by the method of example 40A with benzo[b]furan (7.3 mmols), 0.86 g) t-BuLi (1.7 m, 9.4 mmols) iodoethane (4 mmols, 0.9 mls) and THF (15 ml). 1.0 g (95%) of a yellow liquid was isolated.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@H:4]2[CH2:3]1.CC(C)([O-])C.[K+].Br[C:27]1[CH:32]=[N:31][C:30]([CH:33]2[CH2:35][CH2:34]2)=[CH:29][N:28]=1.CO>O1CCCC1>[CH:33]1([C:30]2[N:31]=[CH:32][C:27]([O:1][C@H:2]3[CH2:19][N:5]4[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@H:4]4[CH2:3]3)=[N:28][CH:29]=2)[CH2:35][CH2:34]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@H](O)C[C@@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
tert-Butyl (8R,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (60 mg, 0.222 mmol, 1.0 equivalent, Example 46, Part D) was dissolved in tetrahydrofuran (1.0 mL). Potassium tert-butoxide (0.311 mL, 0.311 mmol, 1 M in tetrahydrofuran, 1.4 equivalents) was added at room temperature, and the resulting yellow solution was stirred for five minutes. Then 2-bromo-5-cyclopropylpyrazine (57.4 mg, 0.289 mmol, 1.3 equivalents) was added as a solution in tetrahydrofuran (0.5 mL), and the reaction mixture was stirred for 16 hours at the same temperature. The reaction mixture was quenched with 1 drop of saturated sodium bicarbonate, the solvent was removed in vacuo, and the crude material was loaded onto a 12 g silica column with 5% methanol/dichloromethane and eluted with 100:0 to 95:5 dichloromethane:methanol over 20 minutes to give the titled compound (50 mg, 0.129 mmol, 58.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (s, 1H), 7.94 (d, J=1.1 Hz, 1H), 5.38 (br s, 1H), 4.23 (br s, 2H), 3.95 (t, J=7.2 Hz, 1H), 3.90-3.73 (m, 2H), 3.00 (br s, 2H), 2.71-2.45 (m, 3H), 2.18-1.86 (m, 2H), 1.47 (s, 9H), 1.05-0.85 (m, 4H); MS (ESI+) m/z 333.0 (M-tBu+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([NH:14][C:15](=[O:38])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:18]=2[CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([NH:14][C:15](=[O:38])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:18]=2[CH3:37])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)c(CC(=O)NN1CCN(C(=O)OC(C)(C)C)CC1)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)NN1CCNCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 0.300 g (0.57 mmol) of N-(4-t-butoxycarbonylpiperazin-1-yl)-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide in 8 mL of anhydrous dichloromethane was added 1.7 mL of trifluoroacetic acid (TFA). The reaction was stirred at room temperature for 1.75 hr then evaporated to dryness, diluted with more dichloromethane (20 mL) and re-evaporated. Residual TFA was removed with a sodium carbonate wash to give the title compound. 1H NMR (CDCl3) δ 7.58 (2H, d), 7.41 (2H, d), 6.93 (1H, d), 6.73 (1H, d), 6.60 (1H, dd), 3.75 (3H, s), 3.64 (2H, s), 3.57 (2H, m), 3.42 (2H, m), 2.75 (2H, m), 2.67 (2H, m), 2.32 (3H, s). Mass Spectrum m/e 426/428 (M+1).
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].S(Cl)(Cl)=O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:15]1[CH:16]=[C:11]([Cl:10])[CH:12]=[C:13]([S:2]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)(=[O:5])=[O:3])[CH:14]=1
Reactant: Clc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: O=S(=O)(c1cccc(Cl)c1)c1cccc(Cl)c1
Temperature: 195 °C
Yield: 197.3 %

Procedure:
The filtrate from Example 1 is freed from methoanol by distillation, the residue is returned to the reaction vessel, and 562.5 g (5 mol) of chlorobenzene is added. chlorobenzenesulfonic acid chloride is formed by adding 476 g (4 mol) of chlorosulfonic acid and 466 g (4 mol) of thionyl chloride, the mixture is heated to 195° C., and 337.5 g (3 mol) of chlorobenzene is added at such a rate that the temperature does not fall. the charge is subsequently treated as described in Example 1, giving 850 g (74% yield) of dichlorodiphenyl sulfone of melting point 149°-150° C. Gas-chromatographic analysis of the product gives 99.6% 4,4'-isomer, 0.3% 2,4'-isomer, and 0.1% 3,4'-isomer.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC>>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[O:9][C:10]3[C:2]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][C:4]([OH:19])=[CH:5][C:6]=3[N:7]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: Oc1ccc(-c2nc3cc(O)cc(-c4cccs4)c3o2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 53, Step a, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole and 2-(tributylstannyl)thiophene. The product was obtained as a white solid (95% yield), m.p. 95-100° C.); MS m/e338 (M+H).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[O:7])=[CH:4][N:3]=1.[CH3:20][NH2:21]>CO>[OH:17][C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([NH:21][CH3:20])=[N:3][CH:4]=1
Reactant: CN
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(O)c1
Solvent: CO
Product: CNc1ccc(C(=O)Nc2ccc(OC)cc2O)cn1
Temperature: 250 °C

Procedure:
6-Chloro-N-(2-hydroxy-4-methoxyphenyl)nicotinamide (0.40 g, 1.44 mol) was mixed with a solution of 8M methylamine in methanol (4 mL) and heated in a microwave reactor at 250° C. for 10 minutes. The solvent was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted five timed with ethyl acetate The pooled organics were dried (MgSO4), filtered and evaporated. The solid was titurated with CH2Cl2, filtered and dried, giving the title compound (0.25 g) as a solid. 1H NMR δ ppm 9.73 (s, 1H) 9.38 (s, 1H) 8.65 (d, 1H) 7.92 (dd, 1H) 7.33 (d, 1H) 7.16 (d, 1H) 6.24-6.58 (m, 3H) 3.70 (s, 3H) 2.83 (d, 3H); MS m/z (M+H) 274; (M−H) 272.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:15]([CH:18]([CH2:20][CH3:21])[CH3:19])([O-:17])=[O:16]>>[CH3:19][C:18]([N+:15]([O-:17])=[O:16])([CH2:20][CH3:21])[CH2:4][C:5]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([F:14])[CH:10]=2)[NH:7][CH:6]=1
Reactant: CCC(C)[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2ccc(F)cc12
Product: CCC(C)(Cc1c[nH]c2ccc(F)cc12)[N+](=O)[O-]

Procedure:
The procedure described in Example 3 applied to 5-fluorogramine and 2-nitrobutane yielded the intermediate product 3-(2'-methyl-2'-nitrobutyl)-5-fluoro-indole. Melting point 71°-72°C. (from benzine). Catalytic reduction thereof yielded 3-(2'-methyl-2'-aminobutyl)-5-fluoro-indole; melting point of the hydrochloride salt 248°-250°C. (from isopropanol).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[F:34].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:16])([F:18])[F:17])=[O:12])[CH2:2][CH2:3]2)=[O:30])=[CH:27][C:26]=1[F:34]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC(C)(NC(=O)c1cccc(CN2CCNCC2)c1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1)C(F)(F)F
Reaction time: 0.08 h
Yield: 70.6 %

Procedure:
3-(Piperazin-1-ylmethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (1.518 mmol, 0.5 g), 4-amino-3-fluorobenzoic acid (1.518 mmol, 0.235 g) and triethylamine (3.80 mmol, 0.529 mL, 0.384 g) were dissolved in dichloromethane (15.18 mL) and stirred for 5 minutes. 1-Propanephosphonic acid cyclic anhydride (3.04 mmol, 1,799 mL, 1.932 g, 50% solution in ethyl acetate) was added dropwise and the reaction mixture was allowed to stir for 1 hour. Dichloromethane was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated to yield the title compound (500 mg). MS (ESI) m/z 467.4 [M+H]+